Angiotensin type 1 receptor antagonists CV-11974 and EXP 3174 cause selective renal vasodilatation in conscious spontaneously hypertensive rats.
1. Spontaneously hypertensive rats and Wistar-Kyoto rats underwent a two-stage operation for the implantation of Doppler flow probes and intravascular catheters to determine the regional haemodynamic profiles of the angiotensin type 1 receptor antagonists, CV-11974 and EXP 3174. 2. Angiotensin II was given before and up to 24 h after the intravenous administration of CV-11974 (0.1 and 1.0 mg/kg) and EXP 3174 (1.0 mg/kg) to separate groups of conscious rats. 3. The dose of angiotensin II causing an equieffective pressor response (20-25 mmHg) was smaller in spontaneously hypertensive rats (6 ng) than in Wistar-Kyoto rats (25 ng) and was associated with marked renal and mesenteric vasoconstriction in both groups. CV-11974 (0.1 mg/kg) markedly attenuated the cardiovascular effects of angiotensin II in spontaneously hypertensive and Wistar-Kyoto rats over the subsequent 6 h. In spontaneously hypertensive rats only, CV-11974 by itself caused a progressive fall in mean arterial pressure over 6 h together with a transient increase in renal flow (1 h) and a sustained increase in renal conductance over 6 h. Minimal changes occurred in the mesenteric and hindquarters circulations. All haemodynamic variables had returned to predrug levels by 24 h. A 10-fold higher dose of CV-11974 essentially evoked a similar haemodynamic profile. In Wistar-Kyoto rats, CV-11974 did not alter regional haemodynamics except for causing a small decrease in mean arterial pressure after 4-6 h. 4. In a separate group of spontaneously hypertensive rats, EXP 3174 caused haemodynamic changes similar to those obtained using CV-11974, i.e. there was a progressive reduction in mean arterial pressure together with a transient increase in renal flow only (90 min), whereas renal conductance was elevated over 6 h. 5. The angiotensin type 1 receptor antagonists CV-11974 and EXP 3174 blocked the regional haemodynamic effects of angiotensin II and caused relatively selective renal vasodilatation in conscious spontaneously hypertensive rats only. This action is likely to contribute to the hypotensive action of angiotensin type 1 receptor antagonists in conscious spontaneously hypertensive rats.
Li
X C
XC
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Widdop
R E
RE
D000803:Angiotensin I; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D000803:Angiotensin I; C066026:losartan carboxylic acid; D019808:Losartan; C081643:candesartan