THE ANTIHYPERTENSIVE PROFILE OF THE ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST, GR138950, AND THE INFLUENCE OF POTENTIAL HOMEOSTATIC COMPENSATORY MECHANISMS IN RENAL HYPERTENSIVE RATS

1 The cardiovascular profile of the angiotensin AT(1) receptor antagon ist, GR138950, and the influence of potential compensatory homeostatic mechanisms on this profile, were investigated in renal artery ligated hypertensive (RALH) rats. 2 GR138950 caused a marked reduction in blo od pressure associated with immediate tachycardia in conscious RALH ra ts. The antihypertensive action of GR138950 appeared biphasic; an imme diate fall in blood pressure, which plateaued within 1 h, and which wa s followed by a further slow decline that reached maximum between 5-7 h after administration. 3 The tachycardia caused by GR138950 was atten uated by atenolol and was abolished by combined pretreatment with aten olol and atropine methyl nitrate. However, the antihypertensive profil e of GR138950 was unchanged by these pretreatments. 4 The resting bloo d pressure and the antihypertensive effect of GR138950, in RALH rats, were unaffected by the vasopressin V-1 receptor antagonist, [beta-merc apto-beta,beta-cyclopentamethylene propionyl(1)-w-Me-Tyr(2),Arg(8)]-va sopressin. Thus, vasopressinergic mechanisms are not involved in eithe r maintaining blood pressure in RALH rats, or in compensating for the fall in blood pressure caused by GR138950. 5 In anaesthetized RALH rat s, GR138950 caused a marked fall in blood pressure that was accompanie d by an increase in heart rate along with sustained increases in renal and splanchnic sympathetic nerve activity. 6 In summary, the biphasic fall in blood pressure evoked by GR138950 in RALH rats can not be exp lained on the basis of changes in autonomic control of the heart, alte ration of vasopressin-mediated vasoconstrictor mechanisms or overall s uppression of central sympathetic outflow. Rather, increased vasoconst rictor tone might serve to oppose the initial fall in blood pressure.