Further investigations into the mechanism of the antihypertensive activity of the angiotensin AT1 receptor antagonist, GR138950.

1. The angiotensin AT1 receptor antagonist, GR138950, produces a long-lasting antihypertensive effect in conscious renal artery ligated hypertensive (RALH) rats but this effect does not correlate temporally with its antagonist profile against angiotensin II (AII). In the present experiments we have compared the inhibitory profiles of GR138950 and enalapril, against angiotensin I (AI), with their respective antihypertensive activities. 2. GR138950 (1 mg kg-1, i.a.) and enalapril (3 mg kg-1, i.a.) reduced blood pressure in RALH rats to a similar degree. Maximum reductions in blood pressure occurred approximately 5-24 h and 3-5 h after administration, respectively. The antihypertensive effect of GR138950 lasted for 24-48 h. However, the effect of enalapril lasted for only 5-24 h. 3. In conscious normotensive rats, inhibition of AI-induced pressor responses was maximal 1 h after systemic administration of GR138950 and enalapril. Dose-response curves to AI were displaced to the right, in a parallel manner, 1406 and 102 fold by GR138950 (1 mg kg-1, i.a.) and enalapril (3 mg kg-1 i.a.), respectively. The inhibitory effect of enalapril lasted for < 24 h whereas that of GR138950 lasted for up to 48 h. 4. Contractile responses to AI were extensively inhibited in aortae removed from either RALH rats or normotensive rats, 1 and 5 h after administration of GR138950 (1 mg kg-1, i.a.). Responses were still significantly reduced 24 h after administration but had returned to control levels after 48 h. Enalapril pretreatment (3 mg kg-1, i.a.) did not inhibit contractile responses to AI in aortae isolated from normotensive rats at any time point. 5. These experiments confirm that GR138950 is an effective and long-lasting antihypertensive agent. GR138950 was a more potent and longer lasting antagonist against AI than has previously been found against AII, and the duration of its antihypertensive activity coincides better with its blockade of responses to AI. Blockade of the effects of AII generated locally within the vascular wall might play an important role in the antihypertensive profile of GR138950.