ANGIOTENSIN TYPE-I 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 t wo-stage operation for the implantation of Doppler flow probes and int ravascular catheters to determine the regional haemodynamic profiles o f the angiotensin type 1 receptor antagonists, CV-11974 and EXP 3174. 2. Angiotensin II was given before and up to 24 h after the intravenou s 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 I I causing an equieffective presser response (20-25 mmHg) was smaller i n spontaneously hypertensive rats (6 ng) than in Wistar-Kyoto rats (25 ng) and was associated with marked renal and mesenteric vasoconstrict ion in both groups, CV-11974 (0.1 mg/kg) markedly attenuated the cardi ovascular effects of angiotensin II in spontaneously hypertensive and Wistar-Kyoto rats over the subsequent 6 h. In spontaneously hypertensi ve rats only, CV-11974 by itself caused a progressive fall in mean art erial pressure over 6 h together with a transient increase in renal fl ow (1 h) and a sustained increase in renal conductance over 6 h. Minim al changes occurred in the mesenteric and hindquarters circulations, A ll haemodynamic variables had returned to predrug levels by 24 h. A 10 -fold higher dose of CV-11974 essentially evoked a similar haemodynami c profile, In Wistar-Kyoto rats, CV-11974 did not alter regional haemo dynamics except for causing a small decrease in mean arterial pressure after 4-6 h, 4. In a separate group of spontaneously hypertensive rat s, EXP 3174 caused haemodynamic changes similar to those obtained usin g CV-11974, i.e. there was a progressive reduction in mean arterial pr essure together with a transient increase in renal flow only (90 min), whereas renal conductance was elevated over 6 h. 5. The angiotensin t ype 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 onl y. This action is likely to contribute to the hypotensive action of an giotensin type 1 receptor antagonists in conscious spontaneously hyper tensive rats.