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

Abstract

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. 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. 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. 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. 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.

Investigation of the inhibitory effect of NG‐nitro‐L‐arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950

“…Despite these ®ndings, it is still apparent that the maximum fall in blood pressure in renal hypertensive rats occurs approximately 5 ± 7 h after administration of GR138950, whereas the maximal blockade of angiotensin AT 1 receptors (as described by the rightward shift of the dosepressor response to A I or A II) occurs at 1 h 1996). Similar observations were made for losartan (Ohlstein et al, 1992) and GR117289 as well as enalapril (Hilditch et al, 1996).…”

“…Although circulatory levels of A II are not elevated in these animals (unlike in RALH rats), the activity of the local vascular renin-angiotensin system is elevated (Inada et al, 1988). Furthermore, there is evidence that the antihypertensive activity of GR138950 in RALH rats is attributable, at least in part, to blockade of locally generated, rather than circulating, A II (Hilditch et al, 1996). In support of this proposal is the ®nding by Xiao and Pang (1994) that vascular smooth muscle cells from adult spontaneously hypertensive rats produce higher amounts of NO than those from corresponding normotensive rats, implying a general activation of inducible NO synthase.…”

“…This mechanism does not explain the ability of L-NAME to inhibit the antihypertensive eects of GR138950 because this compound (like losartan) is devoid of ACE inhibitor activity (Chiu et al, 1989;Hilditch et al, 1996). In this respect, it is interesting to note that L-NAME had a signi®cantly greater inhibitory eect on the antihypertensive response to enalapril compared with that to GR138950 (88+3% vs 63+5%, respectively; P50.01, Student's t test).…”

“…A recent study from our laboratory has shown that the antihypertensive activity of GR138950 in renal hypertensive rats coincides better with its blockade of responses to exogenously administered A I than A II, suggesting that A II generated locally in the vasculature, as well as plasma borne A II, contributes to the cardiovascular pro®le of GR138950 (Hilditch et al, 1996). Despite these ®ndings, it is still apparent that the maximum fall in blood pressure in renal hypertensive rats occurs approximately 5 ± 7 h after administration of GR138950, whereas the maximal blockade of angiotensin AT 1 receptors (as described by the rightward shift of the dosepressor response to A I or A II) occurs at 1 h 1996).…”

“…The enhanced levels of bradykinin result in a NO-dependent vasodilatation which can contribute to the antihypertensive response of ACE inhibitors (Carretero et al, 1981;Carbonell et al, 1988;Bao et al, 1988;Wiemer et al, 1991;Cachofeiro et al, 1992). However, this mechanism does not explain the ability of L-NAME to inhibit the antihypertensive eect of losartan which, like GR138950, is devoid of ACE inhibitor activity (Chiu et al, 1989;Hilditch et al, 1996). The involvement of NO in the response to the angiotensin AT 1 receptor antagonists is implied by this inhibitory action of L-NAME or L-NMMA but relies on the assumption that these compounds selectively inhibit NO synthase.…”