No. Records Request
1 46 "ANGIOTENSIN-II"/ drug-effects
2 88739 HEART
3 20 #1 and #2
4 58 ATI
5 109088 RECEPTOR
6 6147 BLOCKER
7 1 ATI RECEPTOR BLOCKER
8 1500 AT1
9 109088 RECEPTOR
10 6147 BLOCKER
* 11 65 AT1 RECEPTOR BLOCKER

Record 1 of 65 - MEDLINE (R) 2001/01-2001/02
TI: Preserving target-organ function with candesartan cilexetil in patients
with hypertension.
AU: Zannad,-F
AD: Service de Cardiologie, Hopital Central, Nancy, France.
SO: Blood-Press-Suppl. 2000; 136-9
IS: 0803-8023
PY: 2000
LA: English
CP: NORWAY
AB: Epidemiological evidence suggests that reducing blood pressure alone in
hypertensive patients delaysthe onset of cardiovascular events without
necessarily preventing the progression of chronic target-organ disease,
such as end-stage renal failure and heart failure. Successful clinical
management of hypertensive patients will therefore not be possible unless
therapies are aimed both at the effective control of blood pressure and at
thepreservation of target-organ function. The new angiotensin II type I (AT1)
receptor blocker candesartan cilexetil has been shown to be effective in
reducing target-organ damage in animal models of hypertension, even at doses
that do not produce significant reductions in blood pressure. Protective effects
of candesartan cilexetil towards the heart and kidney have also been demonstrated
in the clinical studies that have been conducted to date.
Thus, candesartan cilexetil has been shown to induce regression of left ventricular
hypertrophy within 8-12 weeksof treatment and to improve renal haemodynamics, both
acutely and after 6 weeks of treatment in hypertensive patients. Furthermore,
in hypertensive patients with co-existent non-insulin-dependent diabetes mellitus and
microalbuminuria, 12 weeks of treatment with candesartan cilexetil, 8-16 mg,
significantly reduced urinary albumin excretion. Clinical evidence is therefore
accumulating that the antihypertensive efficacy and tolerability profile already
established for candesartan cilexetil is combined with the renal and cardioprotective
effects necessary for optimal management of hypertension.
MESH: *Antihypertensive-Agents-therapeutic-use; *Benzimidazoles-therapeutic-use;
*Biphenyl-Compounds-therapeutic-use; *Hypertension-drug-therapy; *Receptors,
-Angiotensin-antagonists-and-inhibitors
MESH: Hypertension-physiopathology; Hypertrophy,-Left-Ventricular-drug-therapy;
Kidney-drug-effects; Kidney-physiopathology
TG: Human
PT: Journal-Article; Review; Review,-Tutorial
SH: therapeutic-use; drug-therapy; physiopathology; drug-effects; antagonists-and-
inhibitors
RN: 0; 0; 0; 0; 0; 145040-37-5
NM: Antihypertensive-Agents; Benzimidazoles; Biphenyl-Compounds; Receptors,
-Angiotensin; angiotensin-II-type-1-receptor; TCV-116
SB: Index-Medicus
UD: 20010208
AN: 20511414
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 2 of 65 - MEDLINE (R) 2001/01-2001/02
TI: Achieving quality 24-h blood pressure control with candesartan cilexetil.
AU: Meredith,-P
AD: Department of Medicine and Therapeutics, University of Glasgow, UK.
SO: Blood-Press-Suppl. 2000; 123-6
IS: 0803-8023
PY: 2000
LA: English
CP: NORWAY
AB: Epidemiological evidence suggests that optimal blood pressure control requires strategies that
lower blood pressure consistently and fully throughout 24 h. In order to maximize compliance, ant
ihypertensive agents also need to be well tolerated and effective when administered at a convenient
once-daily dose. The new angiotensin II type 1 (AT1) receptor blocker candesartan binds tightly to, and
dissociates slowly from, the AT1-receptor and thereby provides long-lasting suppression of the
renin-angiotensin system. This is likely to explain its pronounced antihypertensive efficacy, which
is maintained smoothly over 24 h. The trough-to-peak ratio is a useful measure of the persistence of
antihypertensive efficacy at the end of the dosing interval. This ratio was found to be close to the
ideal of 1.0 for candesartan cilexetil, 8 and 16 mg, whereas it was 0.7 for the prototype AT1-receptor
blocker losartan, 50 mg. The antihypertensive effect of candesartan cilexetil, 16 mg, was also significantly
greater than that of losartan, 100 mg, as demonstrated by ambulatory blood pressure measurements
0-36 h after dosing and by clinic measurements 48 h after dosing. By controlling blood pressure well
beyond the normal dosing interval, candesartan cilexetil provides cardiovascular protection even
in those patients who may occasionally miss doses.
MESH: *Antihypertensive-Agents-therapeutic-use; *Benzimidazoles-therapeutic-use; *Biphenyl-Compounds-therapeutic-use; *Hypertension-drug-therapy; *Receptors,-Angiotensin-antagonists-and-inhibitors
MESH: Blood-Pressure-Monitoring,-Ambulatory; Hypertension-physiopathology; Time-Factors
TG: Human
PT: Journal-Article; Review; Review,-Tutorial
SH: therapeutic-use; drug-therapy; physiopathology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 145040-37-5
NM: Antihypertensive-Agents; Benzimidazoles; Biphenyl-Compounds; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; TCV-116
SB: Index-Medicus
UD: 20010208
AN: 20511411
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 3 of 65 - MEDLINE (R) 2001/01-2001/02
TI: Inhibition of arterial thrombogenesis by quinapril but not losartan.
AU: Bavry,-A-A; Li,-D; Zander,-D-S; Phillips,-M-I; Mehta,-J-L
AD: Departments of Medicine, Pathology, and Physiology, University of Florida, College of Medicine and the VA Medical Center, Gainesville, Florida 32610, USA.
SO: J-Cardiovasc-Pharmacol-Ther. 2000 Apr; 5(2): 121-7
IS: 1074-2484
PY: 2000
LA: English
CP: UNITED-STATES
AB: The cardioprotective effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin type I (AT1)
receptor blockers may relate to their antithrombotic effect. We determined the differential effects of
the ACE inhibitor quinapril and the AT1 receptor blocker losartan on arterial thrombus formation in the rat.
Sprague-Dawley rats were fed regular chow or chow mixed with low-dose quinapril (0. 6 mg/kg/day), high-dose
quinapril (1.2 mg/kg/day), or losartan (10 mg/kg/day) for 15 days. Abdominal aorta was exposed and wrapped
with Whatman paper impregnated with 29% FeCl(3) (ferric chloride). Time to occlusive thrombus formation and
weight of the thrombus were recorded. Aortic superoxide anion generation, platelet aggregation, plasma
angiotensin II levels, and morphology of the thrombus were also examined. Both losartan and quinapril caused
similar reductions in arterial pressure. Losartan did not affect the time to thrombus formation, whereas
quinapril (both low and high doses) delayed the time to thrombus formation (P<.01 vs control).
Weight of the thrombus was similar in all groups of rats. Platelet aggregation was inhibited by approximately
50 in both quinapril- and losartan-treated rats. The high-dose quinapril-treated rats showed markedly reduced
vascular superoxide anion generation compared with the control rats (P<.05). Plasma angiotensin II levels
were unaffected by quinapril treatment but were elevated 7-fold in losartan-treated rats (P <.001 vs. control rats).
The thrombi in the control rats consisted of platelet aggregates, fibrin, and red blood cells.
The intravascular platelet aggregates were much smaller in the quinapril-treated rats (P<.05 vs. control),
but were similar in control and losartan-treated rats. In conclusion, quinapril but not losartan prolongs
time to arterial thrombus formation and results in smaller platelet aggregates in the thrombus. Both quinapril
and losartan decrease platelet aggregation, but only quinapril decreases superoxide anion generation.
This effect on superoxide anion generation as well as mechanisms other than AT1 receptor blockade may underlie
the salutary effect of quinapril on arterial thrombogenesis.
MESH: *Angiotensin-Converting-Enzyme-Inhibitors-pharmacology; *Isoquinolines-pharmacology; *Losartan-pharmacology; *Thrombosis-prevention-and-control
MESH: Angiotensin-II-blood; Blood-Pressure-drug-effects; Dose-Response-Relationship,-Drug; Platelet-Aggregation-drug-effects; Rats-; Rats,-Sprague-Dawley; Superoxides-; Thrombosis-physiopathology
TG: Animal; Comparative-Study; Male; Support,-U.S.-Gov't,-Non-P.H.S.; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: blood; pharmacology; drug-effects; physiopathology; prevention-and-control
RN: 0; 0; 11062-77-4; 11128-99-7; 114798-26-4; 82586-55-8
NM: Angiotensin-Converting-Enzyme-Inhibitors; Isoquinolines; Superoxides; Angiotensin-II; Losartan; quinapril
SB: Index-Medicus
UD: 20010201
AN: 20584489
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 4 of 65 - MEDLINE (R) 2001/01-2001/02
TI: Candesartan cilexetil and renal hemodynamics in hypertensive patients.
AU: Fridman,-K; Wysocki,-M; Friberg,-P; Andersson,-O-K
AD: Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. Katarina.Fridman@astrazeneca.com
SO: Am-J-Hypertens. 2000 Sep; 13(9): 1045-8
IS: 0895-7061
PY: 2000
LA: English
CP: UNITED-STATES
AB: This randomized, double-blind, placebo-controlled crossover study evaluated the effects of
the angiotensin II type 1 (AT1)-receptor blocker candesartan cilexetil on renal blood perfusion and
glomerular filtration in patients with primary hypertension with diastolic blood pressure of 100 to 114 mm Hg.
After a 4-week placebo run-in period, patients were randomized to receive either 16 mg candesartan cilexetil
or placebo once daily for 6 weeks, after which they were switched to the alternative treatment. At the end
of each period, 24 h after the last dose, renal assessments were made and the plasma renin activity, plasma
concentrations of angiotensin II, aldosterone, and catecholamines were measured. Compared with placebo,
candesartan cilexetil significantly reduced mean arterial pressure, by 8 mm Hg (95% confidence interval [CI], 3;12). Renal vascular resistance was significantly reduced by 0.03 mm Hg/mL min(-1) (95% CI, 0.01; 0.06). There was a small nonsignificant increase in renal plasma flow. The filtration fraction fell slightly from 0.24 to 0.22 (95% CI, -0.00, 0.04). As expected, angiotensin II concentrations and plasma renin activity were increased and the aldosterone concentrations were reduced. Catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with 16 mg candesartan cilexetil once daily induced a reduction of renal vascular resistance and a trend toward increased renal plasma flow despite a reduction in mean arterial pressure. Because the glomerular filtration rate was maintained the filtration fraction was reduced, indicating a decreased glomerular capillary pressure.
MESH: *Antihypertensive-Agents-therapeutic-use; *Benzimidazoles-therapeutic-use; *Biphenyl-Compounds-therapeutic-use; *Hypertension-drug-therapy; *Hypertension-physiopathology; *Renal-Circulation-drug-effects
MESH: Adult-; Aged-; Blood-Pressure-drug-effects; Cross-Over-Studies; Double-Blind-Method; Hemodynamics-drug-effects; Hormones-blood; Middle-Age; Receptors,-Angiotensin-antagonists-and-inhibitors; Vascular-Resistance-drug-effects
TG: Female; Human; Male; Support,-Non-U.S.-Gov't
PT: Clinical-Trial; Journal-Article; Randomized-Controlled-Trial
SH: therapeutic-use; drug-effects; blood; drug-therapy; physiopathology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 0; 145040-37-5
NM: Antihypertensive-Agents; Benzimidazoles; Biphenyl-Compounds; Hormones; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; TCV-116
SB: Index-Medicus
UD: 20010111
AN: 20434425
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 5 of 65 - MEDLINE (R) 2001/01-2001/02
TI: Ischemic cardiomyopathy and the cellular renin-angiotensin system.
AU: Anversa,-P; Leri,-A; Li,-B; Liu,-Y; Di-Somma,-S; Kajstura,-J
AD: New York Medical College, Department of Medicine, Valhalla, New York 10595, USA.
SO: J-Heart-Lung-Transplant. 2000 Aug; 19(8 Suppl): S1-11
IS: 1053-2498
PY: 2000
LA: English
CP: UNITED-STATES
AB: BACKGROUND: Ischemic cardiomyopathy produced by non-occlusive coronary artery constriction is characterized by left ventricular failure and right ventricular dysfunction, but whether the local renin-angiotensin system (RAS) is implicated in myocyte dysfunction and cell death remains unclear. METHODS: Changes in single-cell mechanics, the localization of the various constituents of RAS in the myocardium, and the effects of angiotensin II (Ang II) stimulation on myocyte performance and cell death were measured. RESULTS: Chronic ischemia is coupled with alterations in the mechanical properties and calcium (Ca2+) transients of the remaining viable myocytes. The abnormalities in myocyte mechanics consist of depression in peak shortening and velocity of shortening. Moreover, peak systolic Ca2+ is significantly decreased in the cells. In vitro stimulation with Ang II ameliorates myocyte function and systolic Ca2+. Additionally, adult myocytes express genes for renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II receptors. Renin, ACE, and Ang II receptors mRNAs increase under the setting of impaired coronary perfusion. Similarly, the percentage of myocytes containing renin, Ang I, and Ang II increases as well. In vitro studies of neonatal and adult ventricular myocytes indicate that Ang II triggers programmed myocyte cell death and this phenomenon is mediated by activation of the AT1 receptor sub-type. Importantly, the AT1-receptor blocker, losartan, completely inhibits apoptosis. CONCLUSIONS: These multiple observations are consistent with the notion that Ang II may exert 3 separate functions on the heart: (1) stimulation of myocyte hypertrophy, (2) amelioration of myocyte contractile performance, and (3) activation of the suicide program of myocytes.
MESH: *Angiotensin-II-metabolism; *Cardiomyopathy,-Congestive-metabolism; *Myocardial-Ischemia-metabolism; *Myocardium-metabolism; *Renin-Angiotensin-System
MESH: Apoptosis-drug-effects; Cardiomyopathy,-Congestive-etiology; Cardiomyopathy,-Congestive-pathology; Cell-Survival; Cells,-Cultured; Myocardial-Ischemia-pathology; Myocardium-pathology; Rats-; Sensitivity-and-Specificity; Ventricular-Dysfunction,-Left-physiopathology; Ventricular-Dysfunction,-Right-physiopathology
TG: Animal; Human; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article; Review; Review,-Tutorial
SH: metabolism; drug-effects; etiology; pathology; physiopathology
RN: 11128-99-7
NM: Angiotensin-II
CN: HL38132HLNHLBI; HL39902HLNHLBI; HL40561HLNHLBI
SB: Index-Medicus
UD: 20001228
AN: 20468696
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 6 of 65 - MEDLINE (R) 2001/01-2001/02
TI: Intrarenal angiotensin II augmentation in angiotensin II dependent hypertension.
AU: Navar,-L-G; Harrison-Bernard,-L-M
AD: Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
SO: Hypertens-Res. 2000 Jul; 23(4): 291-301
IS: 0916-9636
PY: 2000
LA: English
CP: JAPAN
AB: In several models of angiotensin II (ANG II) dependent hypertension, intrarenal ANG II levels increase to a much greater extent than the circulating levels even though the renal renin levels are decreased. The 2-kidney-1-clip (2K1C) Goldblatt rat model is particularly intriguing because hypertension develops in the presence of an intact kidney which would be expected to maintain sodium balance and protect against hypertension. Although the non-clipped kidney becomes renin depleted, it exhibits enhanced microvascular reactivity and increased tubular fractional sodium reabsorption. The non-clipped kidney ANG II content is either elevated or unchanged and proximal tubular fluid ANG II concentrations are not suppressed compared to the nanomolar concentrations found in normal rats. These results suggest that intrarenal ANG II content can be regulated independently of renal renin content. A similar hypertensive process occurs in rats infused chronically with low doses of ANG II. Renal ANG II content increases over 14 days to a greater extent than the circulating concentrations. Functionally, ANG II infused rats demonstrate reduced sodium excretion and marked suppression of pressure natriuresis. These ANG II dependent influences on kidney function contribute to the maintenance of hypertension. Renal augmentation of ANG II, hypertension, and suppressed sodium excretion are blocked by AT1 receptor blockers. To study the mechanisms responsible for intrarenal ANG II augmentation, we infused a different form of ANG II (Val5 ANG II), that can be separated from endogenous ANG II by HPLC. These results indicated that the increased renal ANG II content was due to accumulation of circulating ANG II in addition to continued production of endogenous ANG II. The renal accumulation of Val5-ANG II was markedly reduced by concomitant treatment with the AT1 receptor blocker, losartan. In addition, we found an unchanged overall ANG II-AT1 receptor protein which probably contributes to the maintained ANG II dependent influences. Collectively, the data support the concept that there is internalization of ANG II through an AT1 receptor mediated process and that some of the internalized ANG II is protected from degradation. The augmented intrarenal ANG II coupled with sustained levels of AT1 receptors contribute to the continued ANG II dependent suppression of renal function and sodium excretion thereby maintaining the hypertension.
MESH: *Angiotensin-II-analogs-and-derivatives; *Angiotensin-II-metabolism; *Hypertension-etiology; *Kidney-metabolism
MESH: Endosomes-metabolism; Hypertension-chemically-induced; Hypertension-metabolism; Intracellular-Membranes-metabolism; Receptors,-Angiotensin-metabolism; Renal-Artery-Obstruction-physiopathology
TG: Animal; Support,-U.S.-Gov't,-P.H.S.
PT: Lectures
SH: analogs-and-derivatives; metabolism; chemically-induced; etiology; physiopathology
RN: 0; 11128-99-7; 53-75-8
NM: Receptors,-Angiotensin; Angiotensin-II; angiotensin-II,-Asp(1)-Val(5)-
SB: Index-Medicus
UD: 20001115
AN: 20367892
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 7 of 65 - MEDLINE (R) 2000
TI: Favourable effects on arterial wave reflection and pulse pressure amplification of adding angiotensin II receptor blockade in resistant hypertension.
AU: Mahmud,-A; Feely,-J
AD: Department of Pharmacology and Therapeutics, Trinity College Dublin and Hypertension Clinic, St. James's Hospital, Dublin 8, Ireland.
SO: J-Hum-Hypertens. 2000 Sep; 14(9): 541-6
IS: 0950-9240
PY: 2000
LA: English
CP: ENGLAND
AB: OBJECTIVE: Angiotensin-converting enzyme (ACE) inhibitors have beneficial effects on arterial compliance and distensibility and favourably modify the arterial pressure waveform in hypertensive patients. The objective of our study was to explore the possible effects of adding an ATII AT1 receptor antagonist to an ACE inhibitor on augmentation pressure, a measure of arterial stiffness, and pulse pressure amplification in patients with poorly controlled essential hypertension. DESIGN AND METHODS: We studied a group of 18 patients with poorly controlled hypertension, despite at least three antihypertensive drugs including an ACE inhibitor, before, at 2 h and 2 weeks following the administration of 80 mg of valsartan, an ATII AT1 receptor antagonist. Haemodynamic responses were measured by cuff sphygmomanometry, arterial pulse-wave analysis and the pulse pressure gradient was calculated as the difference between the brachial pulse pressure (cuff sphygmomanometry) and derived aortic pulse pressure (arterial pulse wave analysis). RESULTS: Blood pressure decreased significantly (P<0.001) and the effect was more pronounced on central (aortic) pulse pressure than peripheral (brachial) pulse pressure. The pulse pressure amplification increased significantly (from 8+/-3 at baseline vs 12+/-7 at 2 h to 14+/-5 mm Hg at 2 weeks, P<0.01) and the augmentation pressure decreased from a baseline value of 21+/-8 to 11+/-7 at 2 h and 10+/-5 at 2 weeks, (P<0.01) following valsartan. CONCLUSION: The results of our study show that in a group of poorly controlled hypertensives, combining an ATII AT1 receptor blocker to an ACE inhibitor induced a significant fall in blood pressure. The decrease in blood pressure was accompanied by a decrease in augmentation pressure in the ascending aorta with a greater decrease in the central pulse pressure than in the peripheral, favourably increasing pulse pressure amplification between central and peripheral arteries. This effect on arterial stiffness and amplification suggests that combined angiotensin II blockade by adding an AT1 receptor blocker to an ACE inhibitor may have more beneficial effects on the blood pressure curve than simple blood pressure reduction.
CM: Comment In: J Hum Hypertens. 2000 Sep;14(9):533-5
MESH: *Angiotensin-Converting-Enzyme-Inhibitors-therapeutic-use; *Antihypertensive-Agents-therapeutic-use; *Arteries-physiopathology; *Blood-Pressure-drug-effects; *Hypertension-drug-therapy; *Hypertension-physiopathology; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Tetrazoles-therapeutic-use; *Valine-analogs-and-derivatives; *Valine-therapeutic-use
MESH: Aged-; Aorta-drug-effects; Aorta-physiopathology; Arteries-drug-effects; Brachial-Artery-drug-effects; Brachial-Artery-physiopathology; Drug-Resistance; Drug-Therapy,-Combination; Heart-Rate-drug-effects; Middle-Age; Pulse-; Regional-Blood-Flow-drug-effects
TG: Female; Human; Male
PT: Journal-Article
SH: therapeutic-use; drug-effects; physiopathology; drug-therapy; antagonists-and-inhibitors; analogs-and-derivatives
RN: 0; 0; 0; 0; 0; 137862-53-4; 7004-03-7
NM: Angiotensin-Converting-Enzyme-Inhibitors; Antihypertensive-Agents; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; valsartan; Valine
SB: Index-Medicus
UD: 20001218
AN: 20438063
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 8 of 65 - MEDLINE (R) 2000
TI: Study on COgnition and Prognosis in the Elderly (SCOPE): baseline characteristics.
AU: Hansson,-L; Lithell,-H; Skoog,-I; Baro,-F; Banki,-C-M; Breteler,-M; Castaigne,-A; Correia,-M; Degaute,-J-P; Elmfeldt,-D; Engedal,-K; Farsang,-C; Ferro,-J; Hachinski,-V; Hofman,-A; James,-O-F; Krisin,-E; Leeman,-M; de-Leeuw,-P-W; Leys,-D; Lobo,-A; Nordby,-G; Olofsson,-B; Opolski,-G; Prince,-M; Reischies,-F-M
AD: University of Uppsala, Department of Public Health, Clinical Hypertension Research, Sweden.
SO: Blood-Press. 2000; 9(2-3): 146-51
IS: 0803-7051
PY: 2000
LA: English
CP: NORWAY
AB: The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multi-centre, prospective, randomized, double-blind, parallel-group study. The primary objective of SCOPE is to assess the effect of the angiotensin II type 1 (AT1) receptor blocker, candesartan cilexetil 8-16 mg once daily, on major cardiovascular events in elderly patients (70-89 years of age) with mild hypertension (DBP 90-99 and/or SBP 160-179 mmHg). The secondary objectives of the study are to test the hypothesis that antihypertensive therapy can prevent cognitive decline (as measured by the Mini Mental State Examination, MMSE) and dementia, and to assess the effect of therapy on total mortality, myocardial infarction (MI), stroke, renal function, and hospitalization. A total of 4964 patients from 15 participating countries were recruited during the randomization phase of SCOPE, exceeding the target population of 4000. The mean age of the patients at enrolment was 76 years, the ratio of male to female patients was approximately 1:2, and 52% of patients were already being treated with an antihypertensive agent at enrolment. The majority of patients (88%) were educated to at least primary school level. At randomization, mean sitting blood pressure values were SBP 166 mmHg and DBP 90 mmHg, and the mean MMSE score was 28. Previous cardiovascular disease in the study population included myocardial infarction (4%), stroke (4%) and atrial fibrillation (4%). Men, more often than women, had a history of previous MI, stroke and atrial fibrillation. A greater percentage of men were smokers (13% vs 6% in women) and had attended university (11% vs 3% of women). Of the randomized patients, 21% were 80 years of age. In this age group smoking was less common (4% vs 10% for 70-79-year-olds) and fewer had attended university (4% vs 7% for 70-79-year-olds). The incidence of MI was similar in both age groups. However, stroke and atrial fibrillation had occurred approximately twice as frequently in the older patients. The patients' mean age at baseline was similar in the participating countries, and most countries showed the approximate 1:2 ratio for male to female patients. There was also little inter-country variation in terms of mean SBP, DBP or MMSE score. However, there was considerable regional variation in the percentage of patients on therapy prior to enrolment.
MESH: *Aging-psychology; *Antihypertensive-Agents-therapeutic-use; *Benzimidazoles-therapeutic-use; *Biphenyl-Compounds-therapeutic-use; *Cardiovascular-Diseases-prevention-and-control; *Cognition-physiology; *Receptors,-Angiotensin-antagonists-and-inhibitors
MESH: Aged-; Aged,-80-and-over; Cardiovascular-Diseases-epidemiology; Cardiovascular-Diseases-etiology; Cognition-Disorders-prevention-and-control; Dementia-prevention-and-control; Double-Blind-Method; Incidence-; Prognosis-; Risk-Factors; Sex-Characteristics
TG: Female; Human; Male
PT: Clinical-Trial; Journal-Article; Randomized-Controlled-Trial
SH: psychology; therapeutic-use; epidemiology; etiology; prevention-and-control; physiology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 145040-37-5
NM: Antihypertensive-Agents; Benzimidazoles; Biphenyl-Compounds; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; TCV-116
SB: Index-Medicus
UD: 20001218
AN: 20312429
XREC: ABSTRACT (AB)
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Record 9 of 65 - MEDLINE (R) 2000
TI: Angiotensin II type 1 (AT1) receptor blockade in hypertensive women: benefits of candesartan cilexetil versus enalapril or hydrochlorothiazide.
AU: Malmqvist,-K; Kahan,-T; Dahl,-M
AD: Karolinska Institutet Danderyd Hospital, Division of Internal Medicine, Sweden. karin.malmqvist@med.ds.sll.se
SO: Am-J-Hypertens. 2000 May; 13(5 Pt 1): 504-11
IS: 0895-7061
PY: 2000
LA: English
CP: UNITED-STATES
AB: The aim of this large, randomized, double-blind, parallel-group study in hypertensive women was to compare the antihypertensive efficacy and effects on subjective symptoms and quality of life of the new angiotensin II type 1 (AT1) receptor blocker candesartan cilexetil, the angiotensin-converting enzyme inhibitor enalapril, and the diuretic hydrochlorothiazide (HCTZ). Women, aged 40 to 69 years, with a seated diastolic blood pressure (DBP) of 95 to 115 mm Hg, were randomized to candesartan cilexetil, 8 to 16 mg (n = 140), enalapril, 10 to 20 mg (n = 146), or HCTZ, 12.5 to 25 mg (n = 143), for 12 weeks; the higher doses were used if DBP was greater than 90 mm Hg after 6 weeks. Candesartan cilexetil lowered seated blood pressure by 17/11 and 19/11 mm Hg after 6 and 12 weeks of treatment, respectively. This reduction was greater (P < .01) than with enalapril (12/8 and 13/9 mm Hg) or HCTZ (12/7 and 13/8 mm Hg). The proportions of patients with controlled DBP (< 90 mm Hg) after 12 weeks of treatment with candesartan cilexetil, enalapril, or HCTZ were 60%, 51%, and 43%, respectively. Patients experienced less dry cough (P < 0.001) with candesartan cilexetil or HCTZ than with enalapril. No treatment differences were found in the incidence of dizziness and quality of life was well maintained in all groups. Compared with candesartan cilexetil and enalapril, HCTZ increased uric acid and decreased serum potassium (P < .001). In conclusion, candesartan cilexetil reduced blood pressure more effectively and was better tolerated than enalapril or HCTZ in women with mild to moderate hypertension.
MESH: *Angiotensin-Converting-Enzyme-Inhibitors-therapeutic-use; *Antihypertensive-Agents-therapeutic-use; *Benzimidazoles-therapeutic-use; *Biphenyl-Compounds-therapeutic-use; *Enalapril-therapeutic-use; *Hydrochlorothiazide-therapeutic-use; *Hypertension-drug-therapy; *Receptors,-Angiotensin-antagonists-and-inhibitors
MESH: Adult-; Aged-; Blood-Pressure-drug-effects; Diuretics,-Thiazide-therapeutic-use; Double-Blind-Method; Hypertension-blood; Hypertension-psychology; Middle-Age; Quality-of-Life
TG: Comparative-Study; Female; Human; Support,-Non-U.S.-Gov't
PT: Clinical-Trial; Journal-Article; Randomized-Controlled-Trial
SH: therapeutic-use; drug-effects; blood; drug-therapy; psychology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 0; 0; 145040-37-5; 58-93-5; 75847-73-3
NM: Angiotensin-Converting-Enzyme-Inhibitors; Antihypertensive-Agents; Benzimidazoles; Biphenyl-Compounds; Diuretics,-Thiazide; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; TCV-116; Hydrochlorothiazide; Enalapril
SB: Index-Medicus
UD: 20001218
AN: 20284634
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 10 of 65 - MEDLINE (R) 2000
TI: AT1 receptor blockers--cost-effectiveness within the South African context.
AU: Anderson,-A-N; Wessels,-F; Moodley,-I; Kropman,-K
AD: Department of Pharmacy, University of the Witwatersrand, Johannesburg.
SO: S-Afr-Med-J. 2000 May; 90(5): 494-8
IS: 0038-2469
PY: 2000
LA: English
CP: SOUTH-AFRICA
AB: OBJECTIVES: Hypertension is a leading chronic disease in South Africa, Significant mortality results from this condition and from stroke and ischaemic heart disease in which hypertension plays a major role. The objective of this study was to evaluate the evidence for the clinically effective and cost-effective treatment of hypertension, given that the clinician has decided to administer an AT1 receptor blocker. METHODOLOGY: A cost-effectiveness analysis was undertaken from the perspective of the funder of health care in the private sector. A predetermined protocol defined the study scope, the comparators (candesartan, losartan, valsartan and irbesartan) and the inclusion criteria for peer-reviewed data. Data for the clinical efficacy of the comparators, measured as the reduction (mmHg) in sitting diastolic blood pressure (SDBP) achieved, were extracted, statistically assessed and reported. The combinability of the data from different clinical trials was confirmed using analyses of variance. A pharmacoeconomic model was developed by combining these clinical results with South African retail prices and testing the results at a 95% confidence level. RESULTS: Significant difference in clinical effectiveness was found among the comparators, with the following mean reductions in SDBP observed: candesartan 10.57, irbesartan 9.07, losartan 8.89 and valsartan 7.11 mmHg. Candesartan was found to be significantly more effective than losartan. Valsartan was found to be less effective than the other 3 comparators. No significant difference was found between irbesartan and either candesartan or losartan. The reduction in SDBP per R100 spent indicated that candesartan was more cost-effective than the other comparators, among which there were no significant differences. Incremental savings of R5.0 million annually could be achieved by the funders of private health care for every 100,000 successfully treated patients using candesartan. CONCLUSION: Significant differences exist in both the clinical and cost-effectiveness measures used in this study for the comparators. The findings from the analysis will be valuable in decision-making processes for both the funders and providers of health care. This analysis can be enhanced further by the inclusion of additional clinical benefits and long-term health outcomes when the relevant data become available.
MESH: *Angiotensin-Converting-Enzyme-Inhibitors-economics; *Antihypertensive-Agents-economics; *Hypertension-drug-therapy; *Meta-Analysis; *Receptors,-Angiotensin-antagonists-and-inhibitors
MESH: Angiotensin-Converting-Enzyme-Inhibitors-pharmacology; Angiotensin-Converting-Enzyme-Inhibitors-therapeutic-use; Antihypertensive-Agents-pharmacology; Antihypertensive-Agents-therapeutic-use; Cost-Benefit-Analysis; Economics,-Pharmaceutical; Sensitivity-and-Specificity; South-Africa
TG: Comparative-Study; Human; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: economics; pharmacology; therapeutic-use; drug-therapy; antagonists-and-inhibitors
RN: 0; 0; 0
NM: Angiotensin-Converting-Enzyme-Inhibitors; Antihypertensive-Agents; Receptors,-Angiotensin
SB: Index-Medicus
UD: 20001218
AN: 20360279
XREC: ABSTRACT (AB)
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Record 11 of 65 - MEDLINE (R) 2000
TI: Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients.
AU: McInnes,-G-T; O'Kane,-K-P; Istad,-H; Keinanen-Kiukaanniemi,-S; Van-Mierlo,-H-F
AD: University Department of Medicine and Therapeutics Western Infirmary, Glasgow, UK.
SO: J-Hum-Hypertens. 2000 Apr; 14(4): 263-9
IS: 0950-9240
PY: 2000
LA: English
CP: ENGLAND
AB: AIM: To compare candesartan cilexetil and lisinopril in fixed combination with hydrochlorothiazide with respect to antihypertensive efficacy and tolerability. METHODS: This was a double-blind (double-dummy), randomised, parallel group comparison in patients with a mean sitting diastolic blood pressure 95-115 mm Hg on prior antihypertensive monotherapy. Treatments were candesartan cilexetil/hydrochlorothiazide 8/12.5 mg once daily (n = 237) and lisinopril/hydrochlorothiazide 10/12.5 mg once daily (n = 116) for 26 weeks. The primary efficacy variable was change in trough sitting diastolic blood pressure. RESULTS: Changes in mean sitting diastolic blood pressure did not differ significantly between the groups (mean difference 0.5 mm Hg; 95% confidence interval -1.6, 2.7, P = 0.20). No significant differences between the groups was found for other haemodynamic variables (sitting systolic blood pressure, standing blood pressure, sitting/erect heart rate, and proportion of responders and controlled patients). Both drugs were well tolerated but the proportion of patients with at least one adverse event was significantly greater in the lisinopril group (80% vs 69%, P = 0.020). The proportion of patients spontaneously reporting cough (23.1% vs 4.6%) and discontinuing therapy due to adverse events (12.0% vs 5.9%) was also higher in the lisinopril group compared with the candesartan cilexetil group. CONCLUSIONS: The fixed combinations of candesartan cilexetil and hydrochlorothiazide 8/12.5 mg and lisinopril and hydrochlorothiazide 10/12.5 mg once daily are equally effective as antihypertensive agents. The fixed combination containing candesartan cilexetil is better tolerated than that containing lisinopril.
MESH: *Angiotensin-Converting-Enzyme-Inhibitors-therapeutic-use; *Antihypertensive-Agents-therapeutic-use; *Benzimidazoles-therapeutic-use; *Biphenyl-Compounds-therapeutic-use; *Hydrochlorothiazide-administration-and-dosage; *Hypertension-drug-therapy; *Lisinopril-therapeutic-use; *Receptors,-Angiotensin-antagonists-and-inhibitors
MESH: Administration,-Oral; Adult-; Aged-; Aged,-80-and-over; Angiotensin-Converting-Enzyme-Inhibitors-administration-and-dosage; Antihypertensive-Agents-administration-and-dosage; Benzimidazoles-administration-and-dosage; Biphenyl-Compounds-administration-and-dosage; Blood-Pressure-drug-effects; Double-Blind-Method; Drug-Therapy,-Combination; Heart-Rate-drug-effects; Hypertension-metabolism; Hypertension-physiopathology; Lisinopril-administration-and-dosage; Middle-Age; Treatment-Outcome
TG: Comparative-Study; Female; Human; Male; Support,-Non-U.S.-Gov't
PT: Clinical-Trial; Journal-Article; Multicenter-Study; Randomized-Controlled-Trial
SH: administration-and-dosage; therapeutic-use; drug-effects; drug-therapy; metabolism; physiopathology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 0; 145040-37-5; 58-93-5; 83915-83-7
NM: Angiotensin-Converting-Enzyme-Inhibitors; Antihypertensive-Agents; Benzimidazoles; Biphenyl-Compounds; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; TCV-116; Hydrochlorothiazide; Lisinopril
SB: Index-Medicus
UD: 20001218
AN: 20262802
XREC: ABSTRACT (AB)
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Record 12 of 65 - MEDLINE (R) 2000
TI: Dose-dependent effect of angiotensin II on human erythropoietin production.
AU: Freudenthaler,-S-M; Lucht,-I; Schenk,-T; Brink,-M; Gleiter,-C-H
AD: Klinische Pharmakologie, Universitat Gottingen, Germany.
SO: Pflugers-Arch. 2000 Apr; 439(6): 838-44
IS: 0031-6768
PY: 2000
LA: English
CP: GERMANY
AB: Current evidence suggests that angiotensin II may be involved in the regulation of renal erythropoietin (EPO) production. The present study assessed the role of angiotensin II (A II) in different doses in the control of EPO production in humans. In a parallel, randomized, placebo-controlled open design, 60 healthy male volunteers received a 6-h intravenous infusion of: placebo (placebo, electrolyte solution), a pressor dose of A II (1-3 microg/min; A II press), a combination of a pressor dose of A II and the selective AT1-receptor blocker losartan, 50 mg (A II press + L), a subpressor dose of A II (0.0375-0.15 microg/min; A II subpress) and a combination of a subpressor dose of A II and losartan (A II subpress + L). A II press treatment resulted in a significant increase of the maximum EPO concentration (CmaxEPO, 41% higher versus placebo) and the amount of EPO produced in 24 h (AUCEPO(0-24 h), 61% larger versus placebo), A II subpress treatment increased CmaxEPO (35% higher versus placebo) and AUC(EPO)(0-24 h) (34% larger versus placebo). A II press + L and A II subpress + L treatments did not significantly increase CmaxEPO and AUCEPO(0-24 h) compared to placebo. A II affects EPO production in a dose-dependent manner. The signal seems to be mediated via AT1-receptors. A II appears to be one modulator EPO production in humans.
MESH: *Angiotensin-II-pharmacology; *Erythropoietin-biosynthesis; *Vasoconstrictor-Agents-pharmacology
MESH: Adolescence-; Adult-; Angiotensin-II-blood; Antihypertensive-Agents-pharmacology; Area-Under-Curve; Dose-Response-Relationship,-Drug; Drug-Combinations; Erythropoietin-blood; Losartan-pharmacology; Osmolar-Concentration; Receptors,-Angiotensin-antagonists-and-inhibitors; Renin-blood; Time-Factors
TG: Human; Male
PT: Clinical-Trial; Journal-Article; Randomized-Controlled-Trial
SH: blood; pharmacology; biosynthesis; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 11096-26-7; 11128-99-7; 114798-26-4; EC 3.4.23.15
NM: Antihypertensive-Agents; Drug-Combinations; Receptors,-Angiotensin; Vasoconstrictor-Agents; Erythropoietin; Angiotensin-II; Losartan; Renin
SB: Index-Medicus
UD: 20001218
AN: 20244946
XREC: ABSTRACT (AB)
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Record 13 of 65 - MEDLINE (R) 2000
TI: Specific angiotensin II receptor blockage improves intestinal perfusion during graded hypovolemia in pigs.
AU: Aneman,-A; Svensson,-M; Broome,-M; Biber,-B; Petterson,-A; Fandriks,-L
AD: Department of Anesthesiology and Intensive Care, Goteborg University, Sweden.
SO: Crit-Care-Med. 2000 Mar; 28(3): 818-23
IS: 0090-3493
PY: 2000
LA: English
CP: UNITED-STATES
AB: OBJECTIVE: To investigate the potential of specific angiotensin II subtype 1 (AT1) receptor blockade to modify the mesenteric hemodynamic response to acute hypovolemia and retransfusion. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University-affiliated animal research laboratory. SUBJECTS: Fasted, anesthetized, ventilated, juvenile domestic pigs of both sexes. INTERVENTIONS: Acute, graded hypovolemia by 20% and 40% of the total estimated blood volume followed by retransfusion in control animals (CTRL; n = 10) and animals pretreated with the AT1 receptor blocker candesartan (CAND; n = 10). MEASUREMENTS AND MAIN RESULTS: Invasive monitoring of arterial and central venous blood pressures, cardiac output, portal venous blood flow, and jejunal mucosal blood flow. Blood gases were repeatedly analyzed to calculate oxygen delivery and consumption. Thirty minutes after each level of hypovolemia at 20% and 40%, cardiac output was decreased in CTRL animals from a baseline of 2.9 +/- 0.1 to 1.8 +/- 0.2 and 1.1 +/- 0.2 L/min, with no differences compared with CAND animals. Cardiac output was restored to 3.0 +/- 0.3 L/min 30 mins after retransfusion in CTRL animals, with no significant intergroup differences. Baseline portal venous blood flow (Q(MES)) and jejunal mucosal perfusion (PU(JEJ)) were greater in CAND animals compared with CTRL animals. During graded hypovolemia, CAND animals maintained Q(MES) and PU(JEJ) at significantly higher levels compared with CTRL animals, particularly after 40% hemorrhage (+221% and + 244%, respectively, relative to the mean values in CTRL animals). The same pattern was observed after retransfusion. Moreover, the calculated mesenteric critical oxygen delivery was significantly greater in CTRL animals (74 mL/min) compared with CAND animals (34 mL/min). No animals died in the CAND group, whereas four animals died during 40% hypovolemia or retransfusion in the CTRL group. CONCLUSIONS: Specific AT1 blockade before acute hypovolemia significantly ameliorated mesenteric and, in particular, jejunal mucosal hypoperfusion. In addition, cardiovascular stability was improved, and mortality in conjunction with acute hypovolemia and retransfusion could be completely avoided. These findings support a fundamental role of the renin-angiotensin system in the mesenteric response to acute hypovolemia and indicate a substantial interventional potential for candesartan in conjunction with circulatory stress.
CM: Comment In: Crit Care Med. 2000 Mar;28(3):898-9
MESH: *Benzimidazoles-therapeutic-use; *Hypovolemia-drug-therapy; *Intestinal-Mucosa-blood-supply; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Splanchnic-Circulation-drug-effects; *Tetrazoles-therapeutic-use
MESH: Acid-Base-Equilibrium-drug-effects; Hemodynamics-drug-effects; Intestinal-Mucosa-drug-effects; Linear-Models; Prospective-Studies; Random-Allocation; Renin-Angiotensin-System-drug-effects; Swine-
TG: Animal; Female; Male; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: drug-effects; therapeutic-use; drug-therapy; blood-supply; antagonists-and-inhibitors
RN: 0; 0; 0; 139481-59-7
NM: Benzimidazoles; Receptors,-Angiotensin; Tetrazoles; CV-11974
SB: Abridged-Index-Medicus; Index-Medicus
UD: 20001218
AN: 20214509
XREC: ABSTRACT (AB)
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Record 14 of 65 - MEDLINE (R) 2000
TI: Roles of tyrosine kinase and protein kinase C in infarct size limitation by repetitive ischemic preconditioning in the rat.
AU: Tanno,-M; Tsuchida,-A; Nozawa,-Y; Matsumoto,-T; Hasegawa,-T; Miura,-T; Shimamoto,-K
AD: Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
SO: J-Cardiovasc-Pharmacol. 2000 Mar; 35(3): 345-52
IS: 0160-2446
PY: 2000
LA: English
CP: UNITED-STATES
AB: In this study, we examined the possibility that infarct-size limitation by repetitive preconditioning (PC) is achieved by activation of both protein kinase C (PKC) and tyrosine kinase. In addition, we assessed whether such kinase activation is triggered by angiotensin II type 1 (AT1) and alpha1-adrenergic receptors and whether sarcolemmal and mitochondrial adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play roles as effectors of cardioprotection in the rat. Under pentobarbital anesthesia, myocardial infarction was induced by 20-min coronary occlusion and 3-h reperfusion in the rat. Infarct size was determined by tetrazolium and expressed as a percentage of area at risk (%IS/AR). PC with one cycle of 5-min ischemia/5-min reperfusion before 20-min ischemia significantly reduced %IS/AR from the control value of 49.4 +/- 2.0 to 35.4 +/- 2.8, and repetitive PC with two cycles of 5-min ischemia/5-min reperfusion further limited %IS/AR to 3.2 +/-0.9. Infarct-size limitation by single-cycle PC was completely abolished by a PKC inhibitor, staurosporine (100 microg/kg; %IS/ AR, 45.7 +/- 5.0). In contrast, the cardioprotection by repetitive PC was only partially blocked by staurosporine (%IS/AR, 19.8 +/- 2.4), another PKC inhibitor, polymyxin B (5 mg/kg; %IS/AR, 16.2 +/- 3.1), or a tyrosine kinase inhibitor, genistein (5 mg/kg; %IS/AR, 21.8 +/- 1.4). However, a combined injection of genistein and staurosporine additively inhibited protection of repetitive PC (%IS/AR, 36.4 +/- 1.7). Staurosporine, polymyxin B, or genistein alone did not modify %IS/AR in nonpreconditioned rat hearts. Infarct-size limitation by repetitive PC was not attenuated by pretreatment with a selective AT1-receptor blocker (CV11974, 10 mg/kg), prazosin (0.6 mg/kg; %IS/AR, 6.4 +/- 3.2 and 1.6 +/- 0.5, respectively). A selective blocker of mitochondrial K(ATP) channels, 5-hydroxydecanoate (3 mg/kg), completely abolished the cardioprotective effect (%IS/AR, 50.8 +/-3.5), but HMR1883 (3 mg/kg), a selective blocker of sarcolemmal K(ATP) channels, failed to inhibit the preconditioning effect (%IS/AR, 4.4 +/- 0.7). These findings suggest that repetition of PC provokes activation of both PKC and tyrosine kinase, leading to enhanced antiinfarct tolerance by opening of mitochondrial but not sarcolemmal K(ATP) channels. It is unlikely that activation of either AT1 or alpha1-adrenergic receptor alone is crucial to trigger preconditioning. Key Words: Tyrosine kinase-Genistein-Angiotensin II-alpha1-Adrenergic receptor-Sarcolemmal K(ATP) channel-Mitochondrial K(ATP) channel.
MESH: *Ischemic-Preconditioning,-Myocardial-methods; *Myocardial-Infarction-physiopathology; *Protein-Kinase-C-physiology; *Protein-Tyrosine-Kinase-physiology
MESH: Analysis-of-Variance; Blood-Pressure-drug-effects; Enzyme-Inhibitors-pharmacology; Genistein-pharmacology; Heart-Rate-drug-effects; Myocardial-Infarction-pathology; Myocardial-Infarction-prevention-and-control; Potassium-Channels-drug-effects; Protein-Kinase-C-antagonists-and-inhibitors; Protein-Tyrosine-Kinase-antagonists-and-inhibitors; Rats-; Rats,-Sprague-Dawley; Receptors,-Adrenergic,-alpha-drug-effects; Staurosporine-pharmacology
TG: Animal; Male
PT: Journal-Article
SH: drug-effects; pharmacology; methods; pathology; physiopathology; prevention-and-control; antagonists-and-inhibitors; physiology
RN: 0; 0; 0; 446-72-0; 62996-74-1; EC 2.7.1.-; EC 2.7.1.112
NM: Enzyme-Inhibitors; Potassium-Channels; Receptors,-Adrenergic,-alpha; Genistein; Staurosporine; Protein-Kinase-C; Protein-Tyrosine-Kinase
SB: Index-Medicus
UD: 20001218
AN: 20173351
XREC: ABSTRACT (AB)
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Record 15 of 65 - MEDLINE (R) 1999 Part B
TI: Differential effects of angiotensin II in the nucleus tractus solitarii of the rat--plausible neuronal mechanism.
AU: Kasparov,-S; Paton,-J-F
AD: Department of Physiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK. sergey.kasparov@bris.ac.uk
SO: J-Physiol. 1999 Nov 15; 521 Pt 1227-38
IS: 0022-3751
PY: 1999
LA: English
CP: ENGLAND
AB: 1. Cellular mechanisms of the actions of angiotensin II (ANGII) within the nucleus of the solitary tract (NTS) were studied using rat brain slices in 78 neurones recorded in the whole-cell configuration. Twenty-nine per cent of cells had an on-going activity and with only one exception these cells responded to tractus solitarii (TS) stimulation with a monophasic excitatory postsynaptic potential (EPSP). In approximately half of the silent cells, TS stimulation evoked an EPSP-inhibitory postsynaptic potential (IPSP) complex. 2. The ANGII (200 or 1000 nM) effect on TS-evoked EPSPs depended on the cell subpopulation. In cells with on-going activity, ANGII (1000 nM) increased evoked EPSP amplitude by +70 +/- 13 % (means +/- s.e.m., n = 5) but reduced it (200 and 1000 nM) in silent cells where both evoked EPSPs and IPSPs were present. ANGII either increased TS-evoked IPSP conductances in cells where they were detectable or revealed an evoked IPSP (200 nM ANGII: IPSP conductance increased from 70 +/- 29 to 241 +/- 34 pS; n = 11). All ANGII effects were prevented by the ANGII type 1 (AT1) receptor blocker losartan. Since 200 nM ANGII did not increase responses to iontophoretically applied GABA, the effect of ANGII on TS-evoked IPSPs may occur presynaptically. 3. The neurokinin type 1 (NK1) receptor antagonist CP-99,994 (5 microM) blocked the ANGII-induced increase in EPSPs but had no effect on TS-evoked IPSP potentiation by ANGII. 4. Thus, ANGII can potentiate both inhibitory and excitatory synaptic transmission within different subpopulations of NTS neurones. Potentiation of evoked EPSPs, but not of IPSPs, involves activation of NK1 receptors. The balance of these actions of ANGII could be reflex specific: for the baroreflex circuitry the inhibitory action might predominate while the peripheral chemoreceptor reflex may be facilitated due to enhanced excitatory transmission.
CM: Erratum In: J Physiol (Lond) 1999 Dec 15;521 Pt 3:761
MESH: *Angiotensin-II-pharmacology; *Solitary-Nucleus-drug-effects; *Solitary-Nucleus-physiology
MESH: Angiotensin-II-administration-and-dosage; Baroreflex-drug-effects; Baroreflex-physiology; Chemoreceptors-drug-effects; Chemoreceptors-physiology; Drug-Interactions; Electric-Stimulation; Excitatory-Postsynaptic-Potentials-drug-effects; Neurons-drug-effects; Neurons-physiology; Patch-Clamp-Techniques; Piperidines-administration-and-dosage; Rats-; Rats,-Sprague-Dawley; Receptors,-Neurokinin-1-antagonists-and-inhibitors; Solitary-Nucleus-cytology; Synaptic-Transmission-drug-effects; Synaptic-Transmission-physiology
TG: Animal; Female; In-Vitro; Male; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: administration-and-dosage; pharmacology; drug-effects; physiology; antagonists-and-inhibitors; cytology
RN: 0; 0; 11128-99-7; 136982-36-0
NM: Piperidines; Receptors,-Neurokinin-1; Angiotensin-II; CP-99994
SB: Index-Medicus
UD: 20001218
AN: 20030131
XREC: ABSTRACT (AB)
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Record 16 of 65 - MEDLINE (R) 1999 Part B
TI: Angiotensin II modulates conducted vasoconstriction to norepinephrine and local electrical stimulation in rat mesenteric arterioles.
AU: Gustafsson,-F; Holstein-Rathlou,-N-H
AD: Department of Medical Physiology, Panum Institute, University of Copenhagen, Denmark. finng@mfi.ku.dk
SO: Cardiovasc-Res. 1999 Oct; 44(1): 176-84
IS: 0008-6363
PY: 1999
LA: English
CP: NETHERLANDS
AB: OBJECTIVE: Localized application of a vasoconstricting agent onto the wall of an arteriole results not only in a local constriction of the vessel, but also in a conducted vasoconstriction which is detectable more than a millimeter upstream and downstream from the application site. We investigated the effect of intravenous infusion of angiotensin II (ANG II), losartan or methoxamine on conducted vasoconstriction to local application of norepinephrine (NE) or local electrical stimulation onto the surface of rat mesenteric arterioles in vivo. METHODS: In anesthetized male Wistar rats (n = 43) NE (0.1 mM) or a local depolarizing current was continuously applied onto mesenteric arterioles using micropipettes. Local and conducted vasoconstriction was measured using videomicroscopy. Conducted responses were measured 200-1000 microns upstream from the application site. RESULTS: Systemic infusion of ANG II (4 ng/min) raised mean arterial blood pressure by 6 +/- 2 mm Hg and increased the conducted but not the local vasoconstrictor response to NE (P < 0.02). Infusion of the alpha 1-agonist methoxamine raised blood pressure to the same extent, but did not change conducted vasoconstriction significantly. Blockade of endogenous ANG II by infusion of the AT1-receptor blocker losartan decreased conducted vasoconstriction to NE (P < 0.03). In parallel with the findings using NE, ANG II increased (P < 0.05) and losartan decreased (P < 0.01) conducted vasoconstriction when local electrical stimulation was used to initiate the conducted vascular response. CONCLUSION: The findings suggest that conducted vasoconstriction to NE and local electrical stimulation in rat mesenteric arterioles are modulated by ANG II, an increase in the plasma levels of ANG II increasing conducted vasoconstriction.
MESH: *Angiotensin-II-pharmacology; *Mesenteric-Arteries-drug-effects; *Norepinephrine-pharmacology; *Vasoconstrictor-Agents-pharmacology
MESH: Adrenergic-alpha-Agonists-pharmacology; Arterioles-drug-effects; Electric-Stimulation; Losartan-pharmacology; Methoxamine-pharmacology; Microscopy,-Video; Rats-; Rats,-Wistar; Receptors,-Angiotensin-drug-effects
TG: Animal; Male; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: pharmacology; drug-effects
RN: 0; 0; 0; 0; 11128-99-7; 114798-26-4; 390-28-3; 51-41-2
NM: Adrenergic-alpha-Agonists; Receptors,-Angiotensin; Vasoconstrictor-Agents; angiotensin-II-type-1-receptor; Angiotensin-II; Losartan; Methoxamine; Norepinephrine
SB: Index-Medicus
UD: 20001218
AN: 20082263
XREC: ABSTRACT (AB)
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Record 17 of 65 - MEDLINE (R) 1999 Part B
TI: Central role of the MAPK pathway in ang II-mediated DNA synthesis and migration in rat vascular smooth muscle cells.
AU: Xi,-X-P; Graf,-K; Goetze,-S; Fleck,-E; Hsueh,-W-A; Law,-R-E
AD: University of California at Los Angeles, School of Medicine, Division of Endocrinology, Diabetes, Los Angeles, CA, USA.
SO: Arterioscler-Thromb-Vasc-Biol. 1999 Jan; 19(1): 73-82
IS: 1079-5642
PY: 1999
LA: English
CP: UNITED-STATES
AB: Angiotensin II (Ang II) promotes vascular smooth muscle cell (VSMC) growth and migration, but the signaling pathways mediating these VSMC behaviors critical to restenosis and atherosclerosis are not completely known. The purpose of the present investigation was to define the role of mitogen-activated protein kinase (MAPK) in Ang II-induced DNA synthesis, migration, and c-fos induction in VSMCs. PD 98059, a synthetic inhibitor of MAPK kinase, or antisense oligodeoxynucleotides (ODNs) to deplete extracellular signal-regulated kinase (ERK)1 and ERK2 MAPKs, were used to inhibit MAPK signaling. PD 98059 at 30 micromol/L reduced Ang II-induced MAPK activity by 69% (P<0.01). Under these conditions, Ang II-induced DNA synthesis was completely inhibited (P<0.01), and Ang II-directed migration was attenuated by 76% (P<0.05). In contrast, induction of c-fos by Ang II was only partially suppressed (58% inhibition, P<0.01). Antisense ODNs against the initiation site of rat ERK1 and ERK2 MAPK mRNAs reduced corresponding protein levels by 63% (P<0.01) and completely inhibited MAPK activation by either Ang II (1 micromol/L) or 10% serum. Antisense ODNs (0.4 micromol/L) completely inhibited Ang II-induced DNA synthesis (P<0.01), decreased migration by 47% (P<0.01), and reduced c-fos induction by 40% (P<0.01 versus control ODN-transfected VSMCs). The Ang II type 1 (AT1)-receptor blocker irbesartan completely blocked DNA synthesis, migration, MAPK activation, and c-fos induction by Ang II in VSMCs. These results demonstrate that activation of MAPK plays a crucial role in Ang II-directed migration and DNA synthesis through the AT1 receptor. In contrast, Ang II-mediated c-fos induction and migration were only partially inhibited by either antisense ODNs or PD 98059, suggesting that other pathways in addition to the MAPK pathway may be involved in these actions of Ang II. We conclude that MAPK is a critical regulatory factor for Ang II-mediated migration and growth in VSMCs. Ang II-induced DNA synthesis showed a stronger MAPK dependence than did Ang II-directed migration or c-fos induction.
MESH: *Angiotensin-II-pharmacology; *Ca2+-Calmodulin-Dependent-Protein-Kinase-metabolism; *Cell-Movement-drug-effects; *DNA-biosynthesis; *Muscle,-Smooth,-Vascular-cytology; *Muscle,-Smooth,-Vascular-metabolism
MESH: Ca2+-Calmodulin-Dependent-Protein-Kinase-antagonists-and-inhibitors; Ca2+-Calmodulin-Dependent-Protein-Kinase-genetics; Enzyme-Activation; Enzyme-Inhibitors-pharmacology; Flavones-pharmacology; Oligodeoxyribonucleotides,-Antisense-pharmacology; Proto-Oncogene-Proteins-c-fos-biosynthesis; RNA,-Messenger-metabolism; Rats-; Rats,-Sprague-Dawley; Receptors,-Angiotensin-physiology; Signal-Transduction-drug-effects; p42-MAP-Kinase
TG: Animal; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: pharmacology; antagonists-and-inhibitors; genetics; metabolism; drug-effects; biosynthesis; cytology; physiology
RN: 0; 0; 0; 0; 0; 0; 0; 0; 11128-99-7; 9007-49-2; EC 2.7.10.-; EC 2.7.10.-; EC 2.7.10.-
NM: Enzyme-Inhibitors; Flavones; Oligodeoxyribonucleotides,-Antisense; PD-98059; Proto-Oncogene-Proteins-c-fos; RNA,-Messenger; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; Angiotensin-II; DNA; Ca(2+)-Calmodulin-Dependent-Protein-Kinase; extracellular-signal-regulated-kinase-1; p42-MAP-Kinase
CN: RO1HL58328HLNHLBI
SB: Index-Medicus
UD: 20001218
AN: 99106025
XREC: ABSTRACT (AB)
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Record 18 of 65 - MEDLINE (R) 1999 Part B
TI: Molecular mechanisms of angiotensin II receptor internalization.
AU: Hunyady,-L
AD: Department of Physiology, Semmelweis University of Medicine, Budapest, Hungary. Hunyady@puskin.sote.hu
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S47-56
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Angiotensin II (AngII) initiates cellular responses by activation of type I (AT1) and type 2 (AT2) angiotensin receptors. Both AT1 and AT1 receptors have seven transmembrane structures characteristic of G protein-coupled receptors, but only the AT1 receptor undergoes rapid internalization upon agonist binding. In addition to the agonist hormone, the peptide antagonist [Sar1,Ile8]AngII can also induce internalization of the AT1a receptor expressed in mammalian cell lines, but the nonpeptide AT1 receptor blocker losartan does not internalize. AT1 receptor internalization occurs via clathrin-coated pits, but there is evidence that, in contrast to the internalization of other G protein-coupled receptors, the internalization of the AT1 receptor is independent of dynamin and beta-arrestin. Mutagenesis studies demonstrated that AT1 receptor internalization requires two regions in the cytoplasmic tail of the receptor, but it is independent of G protein activation. The dependence of AT1 receptor internalization on the presence of a serine-threonine-rich region suggests that phosphorylation of the receptor tail may regulate the internalization process. The possible role of AT1 receptor internalization in sustained signal generation has been suggested, but its relationship to nuclear AngII receptors is not completely understood.
MESH: *Angiotensin-II-metabolism; *Receptors,-Angiotensin-metabolism
MESH: Amino-Acid-Sequence; Arrestin-metabolism; Cells,-Cultured; Clathrin-metabolism; Endocytosis-; GTP-Binding-Proteins-metabolism; Molecular-Sequence-Data; Phosphorylation-; Receptors,-Angiotensin-chemistry; Signal-Transduction
TG: Animal; Support,-Non-U.S.-Gov't
PT: Journal-Article; Review; Review,-Tutorial
SH: metabolism; chemistry
RN: 0; 0; 0; 0; 0; 11128-99-7; EC 3.6.1.-
NM: Arrestin; Clathrin; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; angiotensin-II-type-2-receptor; Angiotensin-II; GTP-Binding-Proteins
SB: Index-Medicus
UD: 20001218
AN: 99107158
XREC: ABSTRACT (AB)
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Record 19 of 65 - MEDLINE (R) 1999 Part A
TI: Insulin resistance in adipocytes from spontaneously hypertensive rats: effect of long-term treatment with enalapril and losartan.
AU: Caldiz,-C-I; de-Cingolani,-G-E
AD: Center of Cardiovascular Research, School of Medicine, National University of La Plata, Argentina.
SO: Metabolism. 1999 Aug; 48(8): 1041-6
IS: 0026-0495
PY: 1999
LA: English
CP: UNITED-STATES
AB: Insulin responsiveness was studied in isolated adipocytes from the normotensive Wistar Kyoto (WKY) rat and the spontaneously hypertensive rat (SHR). The effect of insulin (0.1 to 5 nmol/L) on glucose uptake (glucose transport and lipogenesis) was measured, and the maximal effect of insulin (Emax) and the dose of insulin required to elicit 50% of the maximal response (EC50) were calculated. A diminished Emax on lipogenesis without changes in the EC50 was detected in SHRs. The Emax was 0.49 +/- 0.09 (SHR) and 1.16 +/- 0.14 (WKY) micromol/10(5) cells (P < .05), and the EC50 was 0.13 +/- 0.03 and 0.11 +/- 0.02 nmol/L for WKY and SHR, respectively. Similar results were obtained when measuring insulin-stimulated glucose transport. A 30-day long-term treatment with enalapril (20 mg/kg/d) normalized insulin responsiveness in adipocytes from SHRs. The effect of enalapril was suppressed when SHRs were pretreated with enalapril and 150 microg/kg/d of the bradykinin (BK) B2-receptor blocker Hoe 140. Pretreatment with losartan (40 mg/kg/d) did not improve insulin action in the SHR. Since these results were obtained with isolated cells in which glucose availability was not a function of blood flow, and the effect of insulin in the SHR was improved by pretreatment with an angiotensin-converting enzyme (ACE) inhibitor but not with the AT1-receptor blocker, it appears that the insulin resistance linked to the hypertension is not related to changes in blood flow.
MESH: *Adipocytes-metabolism; *Antihypertensive-Agents-pharmacology; *Enalapril-pharmacology; *Hypertension-metabolism; *Insulin-Resistance; *Losartan-pharmacology
MESH: Adipocytes-drug-effects; Antihypertensive-Agents-therapeutic-use; Biological-Transport; Enalapril-therapeutic-use; Glucose-metabolism; Hypertension-drug-therapy; Losartan-therapeutic-use; Rats-; Rats,-Inbred-SHR; Rats,-Inbred-WKY
TG: Animal; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: drug-effects; metabolism; pharmacology; therapeutic-use; drug-therapy
RN: 0; 114798-26-4; 50-99-7; 75847-73-3
NM: Antihypertensive-Agents; Losartan; Glucose; Enalapril
SB: Index-Medicus
UD: 20001218
AN: 99387327
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 20 of 65 - MEDLINE (R) 1999 Part A
TI: Valsartan/hydrochlorothiazide.
AU: Langtry,-H-D; McClellan,-K-J
AD: Adis International Limited, Auckland, New Zealand.
SO: Drugs. 1999 May; 57(5): 751-5; discussion 756-8
IS: 0012-6667
PY: 1999
LA: English
CP: NEW-ZEALAND
AB: Valsartan/hydrochlorothiazide (HCTZ) combines an angiotensin II AT1 receptor blocker with a thiazide diuretic to produce additive blood pressure reductions without major effects on heart rate. HCTZ did not significantly alter valsartan pharmacokinetics; during combination therapy, HCTZ pharmacokinetics differed from those seen with HCTZ monotherapy. In clinical trials in patients with essential hypertension, adding HCTZ 12.5 or 25 mg/day to valsartan 80 mg/day resulted in a greater blood pressure reduction than increasing the valsartan dosage from 80 to 160 mg/day. The valsartan/HCTZ combination was generally more effective than either drug given alone. Efficacy of the combination was maintained during up to 3 years of treatment. Valsartan/HCTZ was well tolerated in both short and long term trials. The most common adverse events were dizziness, headache and fatigue. The overall incidence of adverse events with the combination was similar to that with placebo. HCTZ-induced hypokalaemia was less common during combination therapy.
MESH: *Antihypertensive-Agents-pharmacology; *Hydrochlorothiazide-pharmacology; *Hypertension-drug-therapy; *Tetrazoles-pharmacology; *Valine-analogs-and-derivatives
MESH: Antihypertensive-Agents-pharmacokinetics; Clinical-Trials; Drug-Combinations; Heart-Rate-drug-effects; Hydrochlorothiazide-pharmacokinetics; Tetrazoles-pharmacokinetics; Valine-pharmacokinetics; Valine-pharmacology
TG: Human
PT: Journal-Article; Review; Review,-Tutorial
SH: pharmacokinetics; pharmacology; drug-effects; drug-therapy; analogs-and-derivatives
RN: 0; 0; 0; 137862-53-4; 58-93-5; 7004-03-7
NM: Antihypertensive-Agents; Drug-Combinations; Tetrazoles; valsartan; Hydrochlorothiazide; Valine
SB: Index-Medicus
UD: 20001218
AN: 99279740
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 21 of 65 - MEDLINE (R) 1999 Part A
TI: Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal angiotensin II concentrations.
AU: Verhagen,-A-M; Braam,-B; Boer,-P; Grone,-H-J; Koomans,-H-A; Joles,-J-A
AD: Department of Nephrology, University Hospital Utrecht, The Netherlands.
SO: Kidney-Int. 1999 Jul; 56(1): 222-31
IS: 0085-2538
PY: 1999
LA: English
CP: UNITED-STATES
AB: BACKGROUND: Chronic nitric oxide synthase (NOS) inhibition results in hypertension, proteinuria, and renal morphological changes. Continuous angiotensin II (Ang II) blockade prevents these effects, suggesting an essential role of Ang II. However, it is not known whether renal Ang II concentrations are primarily increased or whether the scarcity of NO allows normal concentrations of Ang II to cause these detrimental effects. Therefore, we measured renal Ang II concentrations before and during the development of renal damage. METHODS: Group 1 served as controls. Groups 2 through 5 received the NOS inhibitor Nomega-nitro-L-arginine (L-NNA; 40 mg/kg/day) for 4, 7, 14, and 21 days, respectively. Systolic blood pressure (SBP), proteinuria, glomerular filtration rate (GFR), and renal and blood Ang II were measured. In a separate experiment, rats were treated with L-NNA + the Ang II AT1 receptor blocker losartan to determine the functional effects of endogenous Ang II during chronic NOS inhibition. RESULTS: L-NNA treatment resulted in an increase in SBP from day 4 (161 +/- 4 vs. 135 +/- 4 mm Hg in control, P < 0.05) to day 21 (230 +/- 9 mm Hg). GFR was decreased from day 4 (1.9 +/- 0.2 vs. 2.5 +/- 0.2 ml/min in control, P < 0.05) to day 21 (1.2 +/- 0.2 ml/min). Proteinuria was increased from day 14 (85 +/- 14 vs. 6 +/- 1 mg/day in control, P < 0.05) to day 21 (226 +/- 30 mg/day). L-NNA treatment during four days resulted in a significant decrease in renal Ang II (183 +/- 32 vs. 454 +/- 40 fmol/g in control, P < 0.05). On day 7, 14, and 21, renal Ang II was not significantly different from the control. Blood Ang II was not significantly different from the control on days 4, 7, and 14 but was significantly increased after 21 days of L-NNA treatment (215 +/- 35 vs. 78 +/- 13 fmol/ml in control, P < 0.05). Ang II type-1 (AT1) receptor blockade prevented the severe renal injury and hypertension induced by chronic NOS inhibition. CONCLUSIONS: Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal Ang II concentrations. This suggests that the detrimental effects of endogenous Ang II are increased during chronic NOS inhibition. Thus, when NO levels are low, normal Ang II concentrations can cause renal injury and hypertension.
MESH: *Angiotensin-II-metabolism; *Kidney-drug-effects; *Kidney-pathology; *Losartan-pharmacology; *Nitric-Oxide-Synthase-antagonists-and-inhibitors; *Receptors,-Angiotensin-antagonists-and-inhibitors
MESH: Angiotensin-II-blood; Blood-Pressure-drug-effects; Enzyme-Inhibitors-pharmacology; Kidney-metabolism; Kidney-physiopathology; Nitroarginine-pharmacology; Osmolar-Concentration; Rats-; Rats,-Sprague-Dawley; Time-Factors
TG: Animal; Male; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: blood; metabolism; drug-effects; pharmacology; pathology; physiopathology; antagonists-and-inhibitors
RN: 0; 0; 0; 11128-99-7; 114798-26-4; 2149-70-4; EC 1.14.13.39
NM: Enzyme-Inhibitors; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; Angiotensin-II; Losartan; Nitroarginine; Nitric-Oxide-Synthase
SB: Index-Medicus
UD: 20001218
AN: 99340510
XREC: ABSTRACT (AB)
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Record 22 of 65 - MEDLINE (R) 1999 Part A
TI: Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction.
AU: Zhang,-W; Huang,-B-S; Leenen,-F-H
AD: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
SO: Am-J-Physiol. 1999 May; 276(5 Pt 2): H1608-15
IS: 0002-9513
PY: 1999
LA: English
CP: UNITED-STATES
AB: Blockade of brain "ouabain" prevents the sympathetic hyperactivity and impairment of baroreflex function in rats with congestive heart failure (CHF). Because brain "ouabain" may act by activating the brain renin-angiotensin system (RAS), the aim of the present study was to assess whether chronic treatment with the AT1-receptor blocker losartan given centrally normalizes the sympathetic hyperactivity and impairment of baroreflex function in Wistar rats with CHF postmyocardial infarction (MI). After left coronary artery ligation (2 or 6 wk), rats received either intracerebroventricular losartan (1 mg. kg-1. day-1, CHF-Los) or vehicle (CHF-Veh) by osmotic minipumps. To assess possible peripheral effects of intracerebroventricular losartan, one set of CHF rats received the same rate of losartan subcutaneously. Sham-operated rats served as control. After 2 wk of treatment, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) at rest and in response to air-jet stress and intracerebroventricular injection of the alpha2-adrenoceptor-agonist guanabenz were measured in conscious animals. Arterial baroreflex function was evaluated by ramp changes in MAP. Compared with sham groups, CHF-Veh groups showed impaired arterial baroreflex control of HR and RSNA, increased sympathoexcitatory and pressor responses to air-jet stress, and increased sympathoinhibitory and hypotensive responses to guanabenz. The latter is consistent with decreased activity in sympathoinhibitory pathways. Chronic intracerebroventricular infusion of losartan largely normalized these abnormalities. In CHF rats, the same rate of infusion of losartan subcutaneously was ineffective. In sham-operated rats, losartan intracerebroventricularly or subcutaneously did not affect sympathetic activity. We conclude that the chronic increase in sympathoexcitation, decrease in sympathoinhibition, and desensitized baroreflex function in CHF all appear to depend on the brain RAS, since this whole pattern of changes can be normalized by chronic central AT1-receptor blockade with losartan.
MESH: *Brain-metabolism; *Myocardial-Infarction-physiopathology; *Renin-Angiotensin-System-physiology; *Sympathetic-Nervous-System-metabolism
MESH: Angiotensin-II-pharmacology; Antihypertensive-Agents-pharmacology; Baroreflex-drug-effects; Baroreflex-physiology; Blood-Pressure-drug-effects; Brain-blood-supply; Cardiotonic-Agents-pharmacology; Enzyme-Inhibitors-pharmacology; Guanabenz-pharmacology; Heart-Failure,-Congestive-physiopathology; Heart-Rate-drug-effects; Injections,-Intraventricular; Losartan-pharmacology; Nitroprusside-pharmacology; Ouabain-pharmacology; Phenylephrine-pharmacology; Rats-; Rats,-Wistar; Receptors,-Angiotensin-antagonists-and-inhibitors; Stress-physiopathology; Sympathetic-Nervous-System-blood-supply; Sympathetic-Nervous-System-chemistry
TG: Animal; Male; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: pharmacology; drug-effects; physiology; blood-supply; metabolism; physiopathology; antagonists-and-inhibitors; chemistry
RN: 0; 0; 0; 0; 0; 11128-99-7; 114798-26-4; 15078-28-1; 5051-62-7; 59-42-7; 630-60-4
NM: Antihypertensive-Agents; Cardiotonic-Agents; Enzyme-Inhibitors; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; Angiotensin-II; Losartan; Nitroprusside; Guanabenz; Phenylephrine; Ouabain
SB: Index-Medicus
UD: 20001218
AN: 99261972
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 23 of 65 - MEDLINE (R) 1999 Part A
TI: Effects of AT1-receptor blockade on progression of left ventricular dysfunction in dogs with heart failure.
AU: Tanimura,-M; Sharov,-V-G; Shimoyama,-H; Mishima,-T; Levine,-T-B; Goldstein,-S; Sabbah,-H-N
AD: Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit 48202, Michigan, USA.
SO: Am-J-Physiol. 1999 Apr; 276(4 Pt 2): H1385-92
IS: 0002-9513
PY: 1999
LA: English
CP: UNITED-STATES
AB: The objective of the present study was to determine the effects of early long-term monotherapy with the angiotensin II AT1-receptor antagonist valsartan on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure (HF). Studies were performed in 30 dogs with moderate HF produced by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction was 30-40%. Two weeks after the last embolization, dogs were randomized to 3 mo of oral therapy with low-dose valsartan (400 mg twice daily, n = 10), to high-dose valsartan (800 mg twice daily, n = 10), or to no treatment at all (control, n = 10). Treatment with valsartan significantly reduced mean aortic pressure and LV end-diastolic pressure compared with control. In untreated dogs, LV ejection fraction decreased (37 +/- 1 vs. 29 +/- 1%, P = 0.001) and end-systolic volume (ESV) and end-diastolic volume (EDV) increased (81 +/- 5 vs. 92 +/- 5 ml, P < 0.001; 51 +/- 3 vs. 65 +/- 3 ml, P = 0.001, respectively) after 3 mo of follow-up compared with those levels before follow-up. In dogs treated for 3 mo with low-dose valsartan, ejection fraction was preserved (37 +/- 1 vs. 38 +/- 2%, pretreatment vs. posttreatment) as was ESV but not EDV. In dogs treated for 3 mo with high-dose valsartan, ejection fraction decreased (35 +/- 1 vs. 31 +/- 2%, P = 0.02) and ESV and EDV increased in a manner comparable to those levels in controls. Valsartan had no significant effects on cardiomyocyte hypertrophy or on the extent of interstitial fibrosis. We conclude that, for dogs with moderate HF, early long-term therapy with the AT1-receptor blocker valsartan decreases preload and afterload but has only limited benefits in attenuating the progression of LV dysfunction and chamber remodeling.
MESH: *Cardiac-Output,-Low-physiopathology; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Ventricular-Dysfunction,-Left-physiopathology
MESH: Cardiac-Output,-Low-drug-therapy; Cardiac-Output,-Low-pathology; Disease-Progression; Dogs-; Dose-Response-Relationship,-Drug; Tetrazoles-therapeutic-use; Valine-analogs-and-derivatives; Valine-therapeutic-use; Ventricular-Dysfunction,-Left-drug-therapy; Ventricular-Dysfunction,-Left-pathology; Ventricular-Remodeling-drug-effects
TG: Animal; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: drug-therapy; pathology; physiopathology; antagonists-and-inhibitors; therapeutic-use; analogs-and-derivatives; drug-effects
RN: 0; 0; 0; 137862-53-4; 7004-03-7
NM: Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; valsartan; Valine
CN: HL4909004HLNHLBI
SB: Index-Medicus
UD: 20001218
AN: 99216222
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 24 of 65 - MEDLINE (R) 1999 Part A
TI: Resetting of exaggerated tubuloglomerular feedback activity in acutely volume-expanded young SHR.
AU: Brannstrom,-K; Arendshorst,-W-J
AD: Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545, USA.
SO: Am-J-Physiol. 1999 Mar; 276(3 Pt 2): F409-16
IS: 0002-9513
PY: 1999
LA: English
CP: UNITED-STATES
AB: One purpose of the present study was to evaluate the ability of 7-wk-old spontaneously hypertensive rats (SHR) to reset tubuloglomerular feedback (TGF) activity in response to acute volume expansion (VE). Second, we evaluated the contribution of ANG II, via its action on AT1 receptors, to TGF control of glomerular function during VE. TGF was assessed by micropuncture methods and proximal tubular stop-flow pressure (SFP) determinations in SHR, Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD). During euvolemia SHR exhibited enhanced TGF activity. In the same animals acute VE was achieved by infusion of saline (5 ml. h-1. 100 g body wt-1). VE led to resetting of TGF in all three strains. Maximal SFP responses, elicited by a 30-40 nl/min loop of Henle perfusion rate, decreased from 19 to 12 mmHg in SHR and, on average, from 11 to 5 mmHg in WKY and SD (P < 0.001). Tubular flow rate producing a half-maximal response (turning point) shifted to higher flow rates during VE, from 12 to 14 nl/min in SHR and from 15 to 19 nl/min in WKY. Administration of the AT1 receptor blocker candesartan (0.05 mg/kg iv) during sustained VE decreased TGF-mediated reductions in SFP in SHR and slightly increased the turning point in WKY. Nevertheless, other parameters of TGF activity were unaffected by AT1 receptor blockade. In conclusion, young SHR possess the ability to reset TGF activity in response to VE to a degree similar to compensatory adjustments in WKY. However, TGF remains enhanced in SHR during VE. ANG II and its action on AT1 receptors are in part responsible for the exaggerated SFP responses in young SHR during VE.
MESH: *Kidney-Glomerulus-physiology; *Kidney-Tubules-physiology; *Plasma-Substitutes-pharmacology; *Rats,-Inbred-SHR-physiology
MESH: Angiotensin-II-physiology; Benzimidazoles-pharmacology; Feedback-; Loop-of-Henle-physiology; Perfusion-; Pressure-; Punctures-; Rats-; Rats,-Inbred-WKY; Rats,-Sprague-Dawley; Receptors,-Angiotensin-antagonists-and-inhibitors; Receptors,-Angiotensin-physiology; Sodium-Chloride-pharmacology; Tetrazoles-pharmacology
TG: Animal; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: physiology; pharmacology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 11128-99-7; 139481-59-7; 7647-14-5
NM: Benzimidazoles; Plasma-Substitutes; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; Angiotensin-II; CV-11974; Sodium-Chloride
CN: HL02334HLNHLBI
SB: Index-Medicus
UD: 20001218
AN: 99170605
XREC: ABSTRACT (AB)
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Record 25 of 65 - MEDLINE (R) 1999 Part A
TI: AT1 calcium signaling in renal vascular smooth muscle cells.
AU: Iversen,-B-M; Arendshorst,-W-J
AD: Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, USA. Bjarne.Iversen@meda.uib.no
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S84-9
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Experiments were conducted to gain insight into calcium signaling mechanisms triggered by angiotensin II (AngII) stimulation in vascular smooth muscle cells (SMC) freshly isolated from preglomerular vessels of normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Cytosolic calcium concentration ([Ca2+]i) was measured using ratiometric Fura-2 fluorescence and a microscope-based photometer. Vascular SMC from preglomerular vessels were isolated and dispersed using an iron oxide-sieving method combined with collagenase treatment. AngII produced rapid increases in [Ca2+]i that remained elevated for the duration of continued stimulation. The same pattern of time response was observed in WKY and in SHR. AngII elicited dose-dependent increases in [Ca2+]i in groups of individual preglomerular arteriolar SMC from both strains. AngII (10(-10) M) induced an increase from baseline levels in WKY and SHR (37+/-9 and 32+/-13 nM; P < 0.05). In response to 10(-6) M AngII, steady-state responses were 165+/-30 and 170+/-35 nM (P < 0.01). The responses did not differ between strains (P > 0.4). The effects of AngII were inhibited by 88% by the AT1 receptor blocker candesartan in renal SMC. In SMC pretreated with calcium-free medium, baseline [Ca2+]i fell by about 60 nM. Thereafter, AngII did not elicit any [Ca2+]i response either in WKY or in SHR when calcium entry was prevented. Also, after prestimulation by AngII, a calcium-free solution completely reversed the effects of AngII. This study shows that AngII acts through AT1 receptors to stimulate [Ca2+]i by a predominant action on calcium entry with no evidence for calcium mobilization. Other studies have demonstrated that calcium entry in these SMC is mediated by voltage-gated, L-type entry channels sensitive to dihydropyridine agents. No strain differences were noted between the actions of AngII on individual renal SMC from SHR and normotensive control animals.
MESH: *Calcium-Signaling; *Kidney-Glomerulus-blood-supply; *Muscle,-Smooth,-Vascular-metabolism; *Receptors,-Angiotensin-metabolism
MESH: Angiotensin-II-pharmacology; Benzimidazoles-pharmacology; Calcium-metabolism; Cells,-Cultured; Egtazic-Acid; Rats-; Rats,-Inbred-SHR; Rats,-Inbred-WKY; Receptors,-Angiotensin-antagonists-and-inhibitors; Tetrazoles-pharmacology
TG: Animal; Male
PT: Journal-Article
SH: pharmacology; metabolism; blood-supply; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 11128-99-7; 139481-59-7; 67-42-5; 7440-70-2
NM: Benzimidazoles; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; Angiotensin-II; CV-11974; Egtazic-Acid; Calcium
SB: Index-Medicus
UD: 20001218
AN: 99107163
XREC: ABSTRACT (AB)
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Record 26 of 65 - MEDLINE (R) 1999 Part A
TI: Mesangial AT1 receptors: expression, signaling, and regulation.
AU: Ardaillou,-R; Chansel,-D; Chatziantoniou,-C; Dussaule,-J-C
AD: Institut National de la Sante et de la Recherche Medicale U 489, Hopital Tenon, Paris, France. raymond.ardaillou@tnn.ap-hop-paris.fr
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S40-6
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Mesangial cells are one of the main targets of angiotensin II (AngII) in the renal cortex. AngII receptors on mesangial cells are of high affinity (nanomolar range). They belong to the AT1 subtype as shown by the inhibitory effect of AT1 antagonists on [125I]-Sar1, Ala8 AngII binding and on all of the biologic effects mediated by AngII, such as cytosolic calcium stimulation, inositol phosphate formation, prostaglandin production, and cell contraction. AngII also exerts long-term effects on mesangial cells, including stimulation of cell growth and synthesis of a variety of proteins, essentially the components of the extracellular matrix (collagen, fibronectin) and the type 1 inhibitor of plasminogen activator. These effects are mediated, at least in part, by autocrine products, in particular endothelin, platelet-derived growth factor, and transforming growth factor-beta, whose synthesis is enhanced by AngII. Treatment by an AT1 receptor blocker of mice with experimental nephritis inhibits activation of type I collagen alpha2 chain promoter and prevents the development of glomerulosclerosis. AngII receptors in rat mesangial cells are equally distributed between the AT1A and AT1B isoforms. Treatment of these cells by AngII or losartan, an AT1 receptor blocker, has no effect on AT1A and AT1B receptor mRNA expression, whereas candesartan, another AT1 receptor blocker, increases and dexamethasone decreases this expression.
MESH: *Angiotensin-II-pharmacology; *Glomerular-Mesangium-metabolism; *Receptors,-Angiotensin-biosynthesis
MESH: Benzimidazoles-pharmacology; Binding,-Competitive; Cells,-Cultured; Gene-Expression-Regulation; Losartan-pharmacology; Receptors,-Angiotensin-antagonists-and-inhibitors; Signal-Transduction; Tetrazoles-pharmacology
TG: Animal; Human
PT: Journal-Article; Review; Review,-Tutorial
SH: pharmacology; metabolism; antagonists-and-inhibitors; biosynthesis
RN: 0; 0; 0; 0; 11128-99-7; 114798-26-4; 139481-59-7
NM: Benzimidazoles; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; Angiotensin-II; Losartan; CV-11974
SB: Index-Medicus
UD: 20001218
AN: 99107157
XREC: ABSTRACT (AB)
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Record 27 of 65 - MEDLINE (R) 1999 Part A
TI: Candesartan: a new-generation angiotensin II AT1 receptor blocker: pharmacology, antihypertensive efficacy, renal function, and renoprotection.
AU: Morsing,-P
AD: CV Pharmacology, Preclinical R&D, Astra Hassle AB, Molndal, Sweden. peter.morsing@hassle.se.astra.com
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S248-54
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Candesartan, which is the active compound formed during adsorption of candesartan cilexetil, is one of the new generation of angiotensin II AT1 receptor blockers. Candesartan is an insurmountable blocker with a slow dissociation from the AT1 receptor, and it has been shown to effectively reduce BP in humans and in a variety of genetic and experimental models of hypertension. Possible mechanisms for a better effect in BP reduction compared with losartan may be the insurmountable characteristics of binding or more pronounced renal effects, but these need further evaluation. Candesartan has favorable effects on renal function demonstrated in both humans and animals, and has also been shown to protect the kidney in several models of renal injury. The beneficial effects exerted by candesartan could even be demonstrated in experimental models of hypertension in which BP is affected little, if at all. The renoprotective effects have been observed in the regulation of gene expression, as well as in biochemical and histologic evaluations.
MESH: *Antihypertensive-Agents-pharmacology; *Kidney-drug-effects; *Receptors,-Angiotensin-antagonists-and-inhibitors
MESH: Benzimidazoles-pharmacokinetics; Benzimidazoles-pharmacology; Biphenyl-Compounds-pharmacology; Disease-Models,-Animal; Hemodynamics-drug-effects; Hypertension-drug-therapy; Hypertension-physiopathology; Kidney-physiopathology; Losartan-pharmacology; Tetrazoles-pharmacokinetics; Tetrazoles-pharmacology
TG: Animal; Comparative-Study; Human
PT: Journal-Article; Review; Review,-Tutorial
SH: pharmacology; pharmacokinetics; drug-effects; drug-therapy; physiopathology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 0; 114798-26-4; 138402-11-6; 139481-59-7; 145040-37-5
NM: Antihypertensive-Agents; Benzimidazoles; Biphenyl-Compounds; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; Losartan; irbesartan; CV-11974; TCV-116
SB: Index-Medicus
UD: 20001218
AN: 99107191
XREC: ABSTRACT (AB)
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Record 28 of 65 - MEDLINE (R) 1999 Part A
TI: Coinhibition of immune and renin-angiotensin systems reduces the pace of glomerulosclerosis in the rat remnant kidney.
AU: Hamar,-P; Peti-Peterdi,-J; Razga,-Z; Kovacs,-G; Heemann,-U; Rosivall,-L
AD: Department of Pathophysiology, International Nephrological Research and Training Center, Semmelweis University, Budapest, Hungary. hampet@net.sote.hu
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S234-8
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: The development of progressive glomerulosclerosis (GS) has been attributed to a number of humoral and hemodynamic factors, however, neither the exact pathomechanism nor the prevention and treatment have been clearly established. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenetic factors. According to our working hypothesis, a combination therapy with the inhibition of RAS and IL-2 system may be more potent in the prevention of the progression of GS than a monotherapy. After 5/6 subtotal nephrectomy, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT1 receptor blocker candesartan cilexetil (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined regularly, and at week 16, systolic BP, plasma total cholesterol, and triglyceride (TG) levels were measured and kidneys were harvested for morphologic and immunohistochemical analysis. Combination therapy was more effective (proteinuria: CA + T: 29.3+/-12.8 mg/24 h, E + T: 31.3+/-13.0 mg/24 h; GS: CA + T: 10.7+/-4.1%, E + T: 8.3+/-4.6%, P < 0.01) than monotherapy (proteinuria: T: 49.3+/-17.3 mg/24 h, CA: 53.2+/-18.1 mg/24 h, E: 51.1+/-26.6 mg/24 h; GS: T: 10.9+/-4.4%, CA: 23.8+/-4%, E: 14.2+/-5.3%, P < 0.05, with control values of proteinuria: 77.6+/-27.1 mg/24 h and GS: 28+/-2.9%). The number of infiltrating ED-1 (rat macrophage marker) macrophages (T: 161.5+/-51.2 cells/field of view, CA: 203.6+/-102.3, E: 178.6+/-35.3, CA + T: 140.2+/-63.2, E + T:128.2+/-75.6), and CD-5+ (rat T cell marker) T lymphocytes (CA + T: 261.5+/-103.6, E + T: 236+/-94.8) was significantly reduced by the treatment protocols (controls: ED-1: 356+/-100, CD-5: 482.9+/-154.5). These results indicate that an inhibition of RAS either with angiotensin-converting enzyme or AT1 receptor blockade, together with the inhibition of IL-2 synthesis, is more effective in the prevention of GS than a single treatment alone.
MESH: *Antihypertensive-Agents-therapeutic-use; *Glomerulosclerosis,-Focal-drug-therapy; *Immunosuppressive-Agents-therapeutic-use; *Kidney-drug-effects
MESH: Benzimidazoles-therapeutic-use; Blood-Pressure-drug-effects; Cholesterol-blood; Disease-Models,-Animal; Enalapril-therapeutic-use; Glomerulosclerosis,-Focal-blood; Glomerulosclerosis,-Focal-urine; Immune-System-drug-effects; Interleukin-2-biosynthesis; Kidney-immunology; Kidney-metabolism; Nephrectomy-; Proteinuria-urine; Rats-; Rats,-Wistar; Renin-Angiotensin-System-drug-effects; Tacrolimus-therapeutic-use; Tetrazoles-therapeutic-use; Triglycerides-blood
TG: Animal; Male; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: therapeutic-use; drug-effects; blood; drug-therapy; urine; biosynthesis; immunology; metabolism
RN: 0; 0; 0; 0; 0; 0; 109581-93-3; 139481-59-7; 57-88-5; 75847-73-3
NM: Antihypertensive-Agents; Benzimidazoles; Immunosuppressive-Agents; Interleukin-2; Tetrazoles; Triglycerides; Tacrolimus; CV-11974; Cholesterol; Enalapril
SB: Index-Medicus
UD: 20001218
AN: 99107188
XREC: ABSTRACT (AB)
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Record 29 of 65 - MEDLINE (R) 1999 Part A
TI: Angiotensin II stimulates macula densa basolateral sodium/hydrogen exchange via type 1 angiotensin II receptors.
AU: Bell,-P-D; Peti-Peterdi,-J
AD: Nephrology Research and Training Center, Department of Medicine, University of Alabama at Birmingham, 35294, USA. dbell@nrtc.dom.uab.edu
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S225-9
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Angiotensin II (AngII) enhances tubuloglomerular feedback responses and is considered to be a specific modulator of feedback activity. The sites at which AngII interacts with the signal transmission process remain unknown. In certain renal epithelia, AngII stimulates Na/H exchange activities. Evidence for the regulation of macula densa apical Na/H exchange by AngII was recently reported. Because macula densa cells also express a basolateral Na/H exchanger, the possibility that AngII stimulates this exchanger activity was investigated. In preparations of isolated perfused thick ascending limb with attached glomerulus dissected from rabbit kidney, the intracellular pH (pHi) of macula densa cells was measured with fluorescence microscopy using 2',7'-bis(2-carboxyethyl)-5-(and -6)carboxyfluorescein. Perfusion and bathing solutions were iso-osmotic Cl-free Ringer's solutions modified using N-methyl-D-glucamine and cyclamate as the Na and Cl substitutes, respectively. Control pHi, during perfusion with 0 mM Na and 150 mM Na in the bath, averaged 7.21+/-0.07 (n=10). Removal of Na from the bath (i.e., basolateral solution) decreased pHi by 0.39+/-0.06 units (n=5, P < 0.01). Addition of 10(-9) M AngII to the bath resulted in a significant increase in the Na-dependent acid load. This increase in Na-dependent cell acidification was completely blocked by coadministration of the AngII type 1 (AT1) receptor blocker candesartan (10(-8) M). In addition, AngII increased the rate of pHi recovery from the acid load induced by readdition of bath Na. This stimulatory effect of AngII was also completely reversed by coadministration of the AT1 receptor blocker candesartan. These results indicate that AngII stimulates macula densa basolateral Na/H exchange via AT1 receptors and therefore may affect tubuloglomerular feedback signal transmission, at least in part, through direct effects on macula densa transport processes.
MESH: *Angiotensin-II-pharmacology; *Kidney-Glomerulus-drug-effects; *Receptors,-Angiotensin-drug-effects; *Sodium-Hydrogen-Antiporter-metabolism
MESH: Benzimidazoles-pharmacology; Hydrogen-Ion-Concentration; Kidney-Glomerulus-metabolism; Rabbits-; Receptors,-Angiotensin-antagonists-and-inhibitors; Signal-Transduction-drug-effects; Sodium-Hydrogen-Antiporter-biosynthesis; Tetrazoles-pharmacology
TG: Animal; In-Vitro; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: pharmacology; drug-effects; metabolism; antagonists-and-inhibitors; biosynthesis
RN: 0; 0; 0; 0; 0; 11128-99-7; 139481-59-7
NM: Benzimidazoles; Receptors,-Angiotensin; Sodium-Hydrogen-Antiporter; Tetrazoles; angiotensin-II-type-1-receptor; Angiotensin-II; CV-11974
CN: NIDDK32032DKNIDDK
SB: Index-Medicus
UD: 20001218
AN: 99107186
XREC: ABSTRACT (AB)
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Record 30 of 65 - MEDLINE (R) 1999 Part A
TI: Effects of candesartan on angiotensin II-induced renal vasoconstriction in rats and mice.
AU: Ruan,-X; Purdy,-K-E; Oliverio,-M-I; Coffman,-T-M; Arendshorst,-W-J
AD: University of North Carolina at Chapel Hill, 27599-7545, USA.
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S202-7
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: This study determined the inhibitory effect of the angiotensin II (AngII) type I (AT1) receptor blocker candesartan on renal vascular reactivity in vivo. Reactivity to AngII before and during candesartan administration was assessed by measuring (by electromagnetic or ultrasonic flowmetry) renal blood flow responses to AngII in rats and mice. AngII produced greater renal vasoconstriction in 7-wk-old, spontaneously hypertensive rats than in Wistar-Kyoto rats. After indomethacin treatment, AngII (2 ng) produced 40% reductions in renal blood flow in both rat strains, without affecting systemic arterial pressure. Coadministration of candesartan blocked AngII effects in a dose-dependent manner, with similar levels of inhibition in spontaneously hypertensive rats and Wistar-Kyoto rats; maximal inhibition was 80%. In rats that had been pretreated (for 30 min) with intravenous candesartan, AngII-induced renal vasoconstriction was inhibited dose dependently up to 98%. To evaluate receptor subtype mediation, responses were compared in mice with or without the AT1A receptor (deleted by gene targeting). Intrarenal AngII (1 ng) caused a 32% reduction of renal blood flow in wild-type mice and an 8% reduction of renal blood flow in AT1A receptor-knockout mice. Ten nanograms of AngII were required to elicit 20% renal vasoconstriction in these mutant mice. Concurrent injection of candesartan caused dose-dependent inhibition of AngII up to 80%. The candesartan IC50 values for percentage changes in renal blood flow did not differ in the two groups of mice. These studies establish that candesartan is an effective, highly selective, AT1 receptor blocker, inhibiting renal vasoconstriction in rodents in a concentration- and time-dependent manner. Candesartan effectively blocks AT1A and AT1B receptors in renal resistance vessels of rodents, with similar efficacies in rats and mice.
MESH: *Angiotensin-II-antagonists-and-inhibitors; *Benzimidazoles-pharmacology; *Kidney-drug-effects; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Tetrazoles-pharmacology
MESH: Angiotensin-II-administration-and-dosage; Benzimidazoles-therapeutic-use; Dose-Response-Relationship,-Drug; Hypertension-drug-therapy; Hypertension-genetics; Kidney-blood-supply; Mice-; Mice,-Knockout; Rats-; Rats,-Inbred-SHR; Rats,-Inbred-WKY; Receptors,-Angiotensin-genetics; Regional-Blood-Flow-drug-effects; Renal-Artery; Tetrazoles-therapeutic-use; Time-Factors; Vasoconstriction-drug-effects
TG: Animal; Comparative-Study; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: administration-and-dosage; antagonists-and-inhibitors; pharmacology; therapeutic-use; drug-therapy; genetics; blood-supply; drug-effects
RN: 0; 0; 0; 0; 11128-99-7; 139481-59-7
NM: Benzimidazoles; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; Angiotensin-II; CV-11974
CN: HL02334HLNHLBI
SB: Index-Medicus
UD: 20001218
AN: 99107182
XREC: ABSTRACT (AB)
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Record 31 of 65 - MEDLINE (R) 1999 Part A
TI: Renal responses of the nonclipped kidney of two-kidney/one-clip Goldblatt hypertensive rats to type 1 angiotensin II receptor blockade with candesartan.
AU: Cervenka,-L; Navar,-L-G
AD: Tulane University School of Medicine, Department of Physiology, New Orleans, Louisiana 70112, USA.
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S197-201
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Recent studies with normal rats indicated that systemic administration of the angiotensin II (AngII) type 1 (AT1) receptor blocker candesartan elicited divergent renal hemodynamic and excretory responses depending on the magnitude of associated decreases in mean arterial pressure. To evaluate the responses to candesartan in hypertensive rats, experiments were performed 25 d after unilateral renal arterial constriction with a 0.25-mm clip. The rats were anesthetized and prepared for acute clearance experiments. Control arterial pressure responses to a bolus AngII dose (50 ng) averaged 35+/-7 mmHg; the control decreases in cortical renal blood flow (RBF), measured with laser Doppler flowmetry, were 58+/-9%. The vasoconstrictor responses to AngII were abolished by candesartan doses of 1 and 0.1 mg/kg. Treatment with 0.01 mg/kg candesartan attenuated the arterial pressure responses but did not prevent the cortical RBF decreases. The highest dose of candesartan (1 mg/kg) elicited rapid reductions in arterial pressure (from 154+/-5 to 122+/-9 mmHg), leading to associated decreases in RBF (from 5.5+/-0.2 to 4.6+/-0.4 ml/min x g) and sodium excretion (from 0.4+/-0.1 to 0.2+/-0.1 microEq/min x g). The 0.1 mg/kg dose of candesartan led to gradual reductions in arterial pressure (from 155+/-5 to 140+/-5 mmHg), and there were significant increases in RBF (from 5.4+/-0.2 to 6.8+/-0.4 ml/min x g) and decreases in renal vascular resistance. However, this dose still decreased urine flow and sodium excretion. In contrast, when candesartan was administered at 0.01 mg/kg, a dose that did not significantly decrease arterial pressure, there were significant increases in RBF (26+/-11%) and urine flow (43+/-19%) and proportionately greater increases in sodium excretion (284+/-89%) and fractional sodium excretion (351+/-99%). These data demonstrate the divergent renal hemodynamic and sodium excretory responses to AT1 receptor blockade in hypertensive rats, depending on the magnitude of decreases in arterial pressure. The lower candesartan dose, which did not cause hypotension, elicited substantial increases in RBF and proportionally much greater increases in sodium excretion, revealing the direct renal vasodilation and natriuretic effects of AT1 receptor blockade.
MESH: *Benzimidazoles-therapeutic-use; *Hypertension,-Renal-drug-therapy; *Kidney-drug-effects; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Tetrazoles-therapeutic-use
MESH: Angiotensin-II-pharmacology; Blood-Pressure-drug-effects; Dose-Response-Relationship,-Drug; Glomerular-Filtration-Rate; Hypertension,-Renal-urine; Rats-; Rats,-Sprague-Dawley; Regional-Blood-Flow-drug-effects; Sodium-urine; Time-Factors; Vasodilation-
TG: Animal; Male; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: pharmacology; therapeutic-use; drug-effects; drug-therapy; urine; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 11128-99-7; 139481-59-7; 7440-23-5
NM: Benzimidazoles; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; Angiotensin-II; CV-11974; Sodium
CN: HL26371HLNHLBI
SB: Index-Medicus
UD: 20001218
AN: 99107181
XREC: ABSTRACT (AB)
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Record 32 of 65 - MEDLINE (R) 1999 Part A
TI: Renin-angiotensin system dependence of renal hemodynamics in mice.
AU: Traynor,-T-R; Schnermann,-J
AD: Department of Physiology, The University of Michigan, Ann Arbor, USA.
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S184-8
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Renin secretion from isolated, perfused, thick ascending limb/glomerulus preparations from mice, under baseline conditions, has been found to be approximately 10-fold higher than that observed with the same preparations from rabbits. Higher renin secretion rates appear to be accompanied by higher plasma renin activities in mice, compared with rats, rabbits, or humans. Experiments were performed to determine the extent of the renin-angiotensin system dependence of renal hemodynamics in mice. Administration of the type 1 angiotensin II (AT1) receptor blocker candesartan (10 mg/kg) to untreated control mice increased renal blood flow by 55% (from 1.8+/-0.2 to 2.8+/-0.2 ml/min) and decreased renal vascular resistance by 42% (from 55+/-7.5 to 31.8+/-2.3 mmHg x min/ml). Similarly, acute extracellular volume expansion increased renal blood flow by 84% and reduced renal vascular resistance by 48%. In mice with null mutations in either the AT1 receptor or the angiotensin-converting enzyme gene, renal vascular resistance was significantly lower than in wild-type mice. Tubuloglomerular feedback, which is an angiotensin II-dependent vasoconstrictor response, was found to be abolished in both strains of knockout mice. Acute AT1 receptor blockade by candesartan reduced tubuloglomerular feedback responses to a flow rate step change of 0 to 30 nl/min by approximately 80% (from 6.1+/-1.4 to 1.3+/-0.4 mmHg). Candesartan increased the steady-state autoregulatory index from 0.19 to 0.55 (in a pressure interval of 90 to 100 mmHg), suggesting reduced efficiency of steady-state autoregulation. These results indicate that the renin-angiotensin system exerts tonic control over renal vascular resistance in mice to a greater extent than previously observed in other mammalian species.
MESH: *Benzimidazoles-pharmacology; *Hemodynamics-physiology; *Kidney-Glomerulus-physiology; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Renin-Angiotensin-System-physiology; *Tetrazoles-pharmacology
MESH: Glomerular-Filtration-Rate-drug-effects; Hemodynamics-drug-effects; Homeostasis-drug-effects; Kidney-Glomerulus-drug-effects; Mice-; Mice,-Knockout; Mutation-; Peptidyl-Dipeptidase-A-genetics; Receptors,-Angiotensin-genetics; Renin-analysis; Renin-secretion; Renin-Angiotensin-System-drug-effects; Vascular-Resistance-drug-effects
TG: Animal; Comparative-Study; In-Vitro; Male; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: pharmacology; drug-effects; physiology; genetics; antagonists-and-inhibitors; analysis; secretion
RN: 0; 0; 0; 0; 139481-59-7; EC 3.4.15.1; EC 3.4.23.15
NM: Benzimidazoles; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; CV-11974; Peptidyl-Dipeptidase-A; Renin
CN: DK09489DKNIDDK; DK37448DKNIDDK; DK40042DKNIDDK
SB: Index-Medicus
UD: 20001218
AN: 99107179
XREC: ABSTRACT (AB)
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Record 33 of 65 - MEDLINE (R) 1999 Part A
TI: Candesartan cilexetil protects against loss of autoregulatory efficiency in angiotensin II-infused rats.
AU: Inscho,-E-W; Imig,-J-D; Deichmann,-P-C; Cook,-A-K
AD: Tulane University School of Medicine, New Orleans, Louisiana 70112, USA. einscho@mailhost.tcs.tulane.edu
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S178-83
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Renal autoregulatory efficiency is compromised in angiotensin-II (AngII)-dependent Goldblatt hypertension. The current studies were performed to assess renal autoregulatory capability in AngII-infused hypertensive rats and to determine the effect of chronic candesartan cilexetil treatment on autoregulatory behavior. Rats received chronic infusion of AngII (60 ng/min) or vehicle via an osmotic minipump implanted subcutaneously in the dorsum of the neck. Selected rats received the novel AT1 receptor blocker candesartan cilexetil (1.0 mg/kg per d) in the drinking water. Systolic BP averaged 118+/-1 mmHg (n=34) before pump implantation. Chronic AngII infusion for 6 d increased arterial pressure to 151+/-4 mmHg. Candesartan cilexetil administration prevented the AngII-dependent increase in systolic BP. Microvascular autoregulation experiments were performed in vitro using the blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Renal perfusion pressure was set at 100 mmHg during the control period before being decreased to 65 mmHg. Afferent arteriolar diameter was measured continuously as the perfusion pressure was increased from 65 mmHg to 170 mmHg in 15-mmHg increments. Afferent arteriolar diameter in sham-treated rats was 120% of control at a perfusion pressure of 65 mmHg and decreased to 76% of the control diameter at 170 mmHg (n=6). This behavior is consistent with normal autoregulatory behavior. Arterioles from rats receiving chronic infusion of AngII exhibited compromised renal microvascular autoregulatory efficiency. Afferent arteriolar diameter in AngII-treated kidneys varied from 103 to 100% (n=6) of the control diameter over the same pressure range of 65 to 170 mmHg. This blunting of autoregulatory behavior was prevented by AT1 receptor blockade. In animals receiving AngII + candesartan cilexetil, stepwise changes in perfusion pressure elicited changes in afferent arteriolar diameter between 120 and 84% after 6 d of treatment (n=6). These data suggest that chronic elevations in circulating AngII and/or the associated increase in arterial pressure impairs renal autoregulatory capability. Furthermore, inhibition of AT1 receptors with candesartan cilexetil provides protection against AngII-mediated increases in arterial pressure and prevents the associated deterioration of renal autoregulatory responsiveness.
MESH: *Benzimidazoles-therapeutic-use; *Biphenyl-Compounds-therapeutic-use; *Hypertension-drug-therapy; *Kidney-drug-effects; *Receptors,-Angiotensin-antagonists-and-inhibitors
MESH: Angiotensin-II; Blood-Pressure-drug-effects; Homeostasis-drug-effects; Hypertension-chemically-induced; Hypertension-urine; Kidney-blood-supply; Kidney-physiology; Rats-; Rats,-Sprague-Dawley; Vasoconstriction-
TG: Animal; Male; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PT: Journal-Article
SH: therapeutic-use; drug-effects; chemically-induced; drug-therapy; urine; blood-supply; physiology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 11128-99-7; 145040-37-5
NM: Benzimidazoles; Biphenyl-Compounds; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; Angiotensin-II; TCV-116
CN: DK44628DKNIDDK
SB: Index-Medicus
UD: 20001218
AN: 99107178
XREC: ABSTRACT (AB)
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Record 34 of 65 - MEDLINE (R) 1999 Part A
TI: Effects of candesartan on the renin system in conscious rats.
AU: Wagner,-C; Kurtz,-A
AD: Institut fur Physiologie der Universitat Regensburg, Germany.
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S169-71
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: This study aimed to assess and to compare the effects of cadesartan cilexetil on the renin system in rats. Male Sprague Dawley rats were orally treated either with the angiotensin-converting enzyme inhibitor ramipril (7.5 mg/kg per d), with the established AngII-AT1 receptor blocker losartan (40 mg/kg per d), or with candesartan cilexetil (1 mg/kg per d) for 3 d, and the effects of these treatments on plasma renin activity, renal renin mRNA levels, and adrenal levels of AngII-AT1a and AngII-AT1b receptor mRNA were determined. It was found that all drugs led to very similar increases in plasma renin activity and renin mRNA levels and to rather similar decreases in adrenal AngII-AT1b receptor mRNA levels. It is concluded therefore that the effects of candesartan on the renin system in vivo are not different from those obtained with angiotensin-converting enzyme inhibition or with the AngII-AT1 receptor blocker losartan.
MESH: *Benzimidazoles-pharmacology; *Biphenyl-Compounds-pharmacology; *Renin-blood; *Renin-Angiotensin-System-drug-effects
MESH: Adrenal-Glands-drug-effects; Adrenal-Glands-metabolism; Angiotensin-Converting-Enzyme-Inhibitors-pharmacology; Losartan-pharmacology; RNA,-Messenger-biosynthesis; Ramipril-pharmacology; Rats-; Rats,-Sprague-Dawley; Receptors,-Angiotensin-biosynthesis
TG: Animal; Comparative-Study; Male
PT: Journal-Article
SH: drug-effects; metabolism; pharmacology; biosynthesis; blood
RN: 0; 0; 0; 0; 0; 0; 0; 114798-26-4; 145040-37-5; 87333-19-5; EC 3.4.23.15
NM: Angiotensin-Converting-Enzyme-Inhibitors; Benzimidazoles; Biphenyl-Compounds; RNA,-Messenger; Receptors,-Angiotensin; angiotensin-II-type-1-receptor; angiotensin-II-type-2-receptor; Losartan; TCV-116; Ramipril; Renin
SB: Index-Medicus
UD: 20001218
AN: 99107176
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 35 of 65 - MEDLINE (R) 1999 Part A
TI: The effects of candesartan on human AT1 receptor-expressing Chinese hamster ovary cells.
AU: Vauquelin,-G; Fierens,-F-L; De-Backer,-J-P; Vanderheyden,-P-M
AD: Department of Molecular and Biochemical Pharmacology, Institute of Molecular Biology, Free University of Brussels (VUB), Sint-Genesius Rode, Belgium. gvauquel@vub.ac.be
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S15-7
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: Chinese hamster ovary cells expressing the cloned human angiotensin II receptor of the AT1 subtype (CHO-AT1 cells) were used as an 'in vitro" model system to investigate the action mechanism of the nonpeptide AT1 receptor blocker candesartan. In the presence of 10 mM LiCl, angiotensin II causes a long-lasting increase in the production of inositol phosphates in these cells. This effect is dose-dependent with half-maximal stimulation (EC50) at 3 nM angiotensin II. Pre-incubation of the cells for 30 min at 37 degrees C with candesartan decreases the maximal response to angiotensin II by up to 90%, with a half-maximal decrease at 0.5 nM candesartan. At this concentration, candesartan only produces a slight rightward shift of the angiotensin II dose-response curve. Recovery experiments on CHO-AT1 cells reveal that the inhibitory effect of candesartan is only slowly reversed after removal of the blocker. The insurmountable effect of candesartan can therefore be ascribed to its long-lasting inhibition of the AT1 receptor.
MESH: *Antihypertensive-Agents-pharmacology; *Benzimidazoles-pharmacology; *CHO-Cells-drug-effects; *Receptors,-Angiotensin-biosynthesis; *Tetrazoles-pharmacology
MESH: Angiotensin-II-antagonists-and-inhibitors; Angiotensin-II-pharmacology; CHO-Cells-metabolism; Dose-Response-Relationship,-Drug; Hamsters-; Inositol-Phosphates-biosynthesis; Lithium-Chloride; Receptors,-Angiotensin-genetics; Transfection-
TG: Animal; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: antagonists-and-inhibitors; pharmacology; drug-effects; metabolism; biosynthesis; genetics
RN: 0; 0; 0; 0; 0; 0; 11128-99-7; 139481-59-7; 7447-41-8
NM: Antihypertensive-Agents; Benzimidazoles; Inositol-Phosphates; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; Angiotensin-II; CV-11974; Lithium-Chloride
SB: Index-Medicus
UD: 20001218
AN: 99107153
XREC: ABSTRACT (AB)
--------------------------------------------------------------------------------
Record 36 of 65 - MEDLINE (R) 1999 Part A
TI: Effects of the angiotensin AT1 receptor blocker candesartan on myocardial ischemic/reperfusion injury.
AU: Shimizu,-M; Sjoquist,-P-O; Wang,-Q-D; Ryden,-L
AD: Department of Cardiology, Karolinska Hospital, Stockholm, Sweden.
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S137-42
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: The effect of the insurmountable angiotensin II AT1 receptor blocker candesartan on ischemic/reperfusion injury was investigated in isolated rat hearts and in anesthetized pigs. The possible additive effect of candesartan on the cardioprotection by a calcium antagonist and a lipid peroxidation inhibitor was also studied. In Langendorff-perfused rat hearts, candesartan, in a dose-related manner, improved left ventricular functional recovery and reduced the no-reflow area following global ischemia and reperfusion. A similar degree of cardioprotection by candesartan (10 nM) and an equipotent concentration of another AT1 receptor blocker losartan (3 microM) was observed when ischemia was begun immediately after drug pretreatment. When a washout period was implemented between pretreatment and ischemia, the protective effect of candesartan, but not that of losartan, remained, suggesting that candesartan may provide a more efficient cardioprotection than losartan. In anesthetized pigs subjected to 45 min of coronary artery occlusion followed by 240 min of reperfusion, local coronary venous retroinfusion (0.042, 0.42, and 4.2 microM) of candesartan starting just before reperfusion improved, in a dose-related manner, the recovery of myocardial segment shortening (sonomicrometer) and reduced infarct size without persistent effect on regional myocardial blood flow (microspheres). A combination of candesartan, felodipine, and the lipid peroxidation inhibitor H290/51 produced a more pronounced infarct limitation than each of these agents alone. In conclusion, candesartan exerts a cardioprotective effect, via a local mechanism within the ischemic myocardium. A combination of drugs with different pharmacologic profiles may provide a better cardioprotection in the setting of myocardial ischemic/reperfusion compared with each individual compound.
MESH: *Benzimidazoles-therapeutic-use; *Myocardial-Ischemia-drug-therapy; *Myocardial-Reperfusion-Injury-drug-therapy; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Tetrazoles-therapeutic-use
MESH: Antioxidants-therapeutic-use; Calcium-Channel-Blockers-therapeutic-use; Drug-Therapy,-Combination; Felodipine-therapeutic-use; Hemodynamics-drug-effects; Indoles-therapeutic-use; Losartan-therapeutic-use; Myocardial-Ischemia-pathology; Rats-; Rats,-Sprague-Dawley; Swine-
TG: Animal; Comparative-Study; Female; In-Vitro; Male; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: therapeutic-use; drug-effects; drug-therapy; pathology; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 0; 0; 0; 114798-26-4; 139481-59-7; 72509-76-3
NM: Antioxidants; Benzimidazoles; Calcium-Channel-Blockers; H290-51; Indoles; Receptors,-Angiotensin; Tetrazoles; angiotensin-II-type-1-receptor; Losartan; CV-11974; Felodipine
SB: Index-Medicus
UD: 20001218
AN: 99107172
XREC: ABSTRACT (AB)
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Record 37 of 65 - MEDLINE (R) 1999 Part A
TI: Normalizing the expression of nitric oxide synthase by low-dose AT1 receptor antagonism parallels improved vascular morphology in hypertensive rats.
AU: Bennai,-F; Morsing,-P; Paliege,-A; Ketteler,-M; Mayer,-B; Tapp,-R; Bachmann,-S
AD: Institut fur Anatomie, Charite, Humboldt Universitat, Berlin, Germany.
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S104-15
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: In essential hypertension, stroke and kidney damage may result from an impaired interaction of vasoregulatory systems. Stroke-prone spontaneously hypertensive rats (SHRSP) were studied to analyze the effects of a low-dose treatment of the angiotensin II type 1 receptor (AT1) blocker candesartan cilexetil on the expression of nitric oxide synthases (NOS) and on vascular structure. Both treated and untreated SHRSP were kept on a stroke-promoting dietary regimen, and compared with Wistar Kyoto rats (WKY). Early mortality of untreated SHRSP was prevented by the treatment. In untreated SHRSP, cerebral intraparenchymal vessels of the parietal lobe showed lesions of the vascular wall and its periphery, such as proteinaceous deposits, perivascular dilated spaces, increase in phagocytic cells, and decreased actin immunostaining. Renal lesions were more pronounced comprising arteriolar occlusion, extensive loss of actin, increased alpha1(IV) collagen expression, and glomerular sclerotic as well as tubulointerstitial lesions. Beneficial effects of the AT1 blockade were more pronounced in brain than in kidney. Activity profile of NOS showed increased NADPH diaphorase staining in media and endothelium of SHRSP; endothelial NOS3 immunoreactivity was decreased, but instead, inducible NOS2 increased in untreated SHRSP. These changes were largely prevented in the treated group. NOS activity in macula densa cells was unchanged, whereas afferent arteriolar renin levels were increased in untreated SHRSP. Results demonstrate an effective reduction of hypertensive vascular changes with a nonpressor dose of candesartan. A "role switch" of vascular NOS in hypertension from physiologic NOS3 toward deleterious NOS2 is suggested, and its prevention by the AT1 blocker points to an angiotensin II-dependent, nitric oxide-mediated pathway that may impair endothelial function and aggravate defects of the blood-brain barrier and kidney structures.
MESH: *Benzimidazoles-pharmacology; *Brain-drug-effects; *Kidney-drug-effects; *Microcirculation-drug-effects; *Nitric-Oxide-Synthase-biosynthesis; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Tetrazoles-pharmacology
MESH: Arterioles-drug-effects; Arterioles-enzymology; Arterioles-ultrastructure; Benzimidazoles-therapeutic-use; Blood-Pressure; Body-Weight; Brain-blood-supply; Brain-enzymology; Cerebrovascular-Disorders-etiology; Hypertension-drug-therapy; Kidney-blood-supply; Kidney-enzymology; Microcirculation-enzymology; Microcirculation-ultrastructure; NADPH-Dehydrogenase; Nitric-Oxide-Synthase-analysis; Rats-; Rats,-Inbred-SHR; Rats,-Inbred-WKY; Sodium,-Dietary; Tetrazoles-therapeutic-use
TG: Animal; Comparative-Study; Support,-Non-U.S.-Gov't
PT: Journal-Article
SH: drug-effects; enzymology; ultrastructure; pharmacology; therapeutic-use; blood-supply; etiology; drug-therapy; analysis; biosynthesis; antagonists-and-inhibitors
RN: 0; 0; 0; 0; 0; 139481-59-7; EC 1.14.13.-; EC 1.14.13.-; EC 1.14.13.39; EC 1.6.99.1
NM: Benzimidazoles; Receptors,-Angiotensin; Sodium,-Dietary; Tetrazoles; angiotensin-II-type-1-receptor; CV-11974; endothelial-constitutive-nitric-oxide-synthase; inducible-nitric-oxide-synthase; Nitric-Oxide-Synthase; NADPH-Dehydrogenase
SB: Index-Medicus
UD: 20001218
AN: 99107168
XREC: ABSTRACT (AB)
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Record 38 of 65 - MEDLINE (R) 1999 Part A
TI: Analysis of the effects of candesartan on responses to angiotensin II in the hindquarters vascular bed of the cat.
AU: Champion,-H-C; Bivalacqua,-T-J; Lambert,-D-G; McNamara,-D-B; Kadowitz,-P-J
AD: Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA. champion@mailhost.tcs.tulane.edu
SO: J-Am-Soc-Nephrol. 1999 Jan; 10 Suppl 11S101-3
IS: 1046-6673
PY: 1999
LA: English
CP: UNITED-STATES
AB: The effects of the nonpeptide angiotensin II (AngII) AT1 receptor blocker candesartan on responses to AngII were investigated in the hindquarters vascular bed of the cat. Under constant-flow conditions, injections of AngII into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Candesartan in a dose of 3 microg/kg intravenously (i.v.) decreased vasoconstrictor responses to AngII in a surmountable manner. At doses of 30 and 300 microg/kg i.v., candesartan shifted the dose-response curve to AngII to the right in an insurmountable manner, indicating an insurmountable blockade of AT1 receptors. The inhibitory effects of the larger doses of candesartan on responses to AngII were long in duration, and the AT1 receptor blocker had little effect on baseline pressures. Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2alpha, vasopressin, BAY K8644; biphasic responses to endothelin-1; or on vasodilator responses to acetylcholine, albuterol, or levcromakalim. These results indicate that candesartan is a potent and selective angiotensin AT1 receptor blocker that can induce both surmountable and insurmountable AT1 receptor blockade and provide support for the hypothesis that there are "spare" AT1 receptors in the hindquarters vascular bed of the cat.
MESH: *Angiotensin-II-pharmacology; *Benzimidazoles-pharmacology; *Receptors,-Angiotensin-antagonists-and-inhibitors; *Tetrazoles-pharmacology
MESH: Angiotensin-II-antagonists-and-inhibitors; Blood-Pressure-drug-effects; Cats-; Dose-Response-Relationship,-Drug; Hindlimb-blood-supply; Time-Factors; Vasoconstrictor-Agents-pharmacology; Vasodilator-Agents-pharmacology
TG: Animal; Comparative-Study; Female; Male
PT: Journal-Article
SH: antagonists-and-inhibitors; pharmacology; drug-effects; blood-supply
RN: 0; 0; 0; 0; 0; 0; 11128-99-7; 139481-59-7
NM: Benzimidazoles; Receptors,-Angiotensin; Tetrazoles; Vasoconstrictor-Agents; Vasodilator-Agents; angiotensin-II-type-1-receptor; Angiotensin-II; CV-11974
SB: Index-Medicus
UD: 20001218
AN: 99107167
XREC: ABSTRACT (AB)
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Record 39 of 65 - MEDLINE (R) 1999 Part A
TI: Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth.
AU: Akishita,-M; Ito,-M; Lehtonen,-J-Y; Daviet,-L; Dzau,-V-J; Horiuchi,-M
AD: Cardiovascular Research, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
SO: J-Clin-Invest. 1999 Jan; 103(1): 63-71
IS: 0021-9738
PY: 1999
LA: English
CP: UNITED-STATES
AB: Angiotensin II type 2 (AT2) receptor is abundantly expressed in vascular smooth muscle cells (VSMC) of the fetal vasculature during late gestation (embryonic day 15-20), during which the blood vessels undergo remodeling. To examine directly the influence of AT2 receptor expression in the developmental biology of VSMC, we studied cultures of VSMC from fetal and postnatal wild-type (Agtr2(+)) and AT2 receptor null (Agtr2(-)) mice. Consistent with in vivo data, AT2 receptor binding in cultured Agtr2(+) VSMC increased by age, peaking at embryonic day 20, and decreased dramatically after birth. Angiotensin II-induced growth in Agtr2(+) VSMC (embryonic day 20) was increased by the AT2 receptor blocker PD123319, indicating that the AT2 receptors are functional and exert an antigrowth effect in Agtr2(+) VSMC. Growth of VSMC in response to serum decreased age dependently and was higher in Agtr2(-) than in Agtr2(+), inversely correlating with AT2 receptor expression. However, serum-induced growth in Agtr2(+) and Agtr2(-) VSMC and the exaggerated Agtr2(-) VSMC growth was maintained even in the presence of PD123319 or losartan, an AT1 receptor blocker. Moreover, Agtr2(-) VSMC showed greater growth responses to platelet-derived growth factor and basic fibroblast growth factor, indicating that Agtr2(-) cells exhibit a generalized exaggerated growth phenotype. We studied the mechanism responsible for this phenotype and observed that extracellular signal-regulated kinase (ERK) activity was higher in Agtr2(-) VSMC at baseline and also in response to serum. ERK kinase inhibitor PD98059 inhibited both growth and ERK phosphorylation dose-dependently, while the regression lines between growth and ERK phosphorylation were identical in Agtr2(+) and Agtr2(-) VSMC, suggesting that increased ERK activity in Agtr2(-) VSMC is pivotal in the growth enhancement. Furthermore, the difference in ERK phosphorylation between Agtr2(+) and Agtr2(-) was abolished by vanadate but not by okadaic acid, implicating tyrosine phosphatase in the difference in ERK activity. These results suggest that the AT2 receptor expression during the fetal vasculogenesis influences the growth phenotype of VSMC via the modulation of ERK cascade.
MESH: *Blood-Vessels-growth-and-development; *Ca2+-Calmodulin-Dependent-Protein-Kinase-metabolism; *Gene-Expression-Regu