Cardiovascular effects of GR117289, a novel angiotensin AT₁ receptor antagonist

Abstract

1 The effect of GRI 17289, an angiotensin AT, receptor antagonist, on diastolic blood pressure (DBP) was determined in angiotensin-dependent and angiotensin-independent models of hypertension in rats. In addition, the antagonist profile of GRi 17289 at angiotensin AT1 receptors was determined in conscious renal hypertensive rats and conscious normotensive rats, dogs and marmosets. 2 Intra-arterial and oral administration of GRI17289 (0.3-3mgkg-', i.a.; 1-10mgkg-', p.o.) to 6-day left renal artery ligated hypertensive (RALH) rats (DBP> 140 mmHg) produced significant, dose-related reductions in DBP with little apparent effect on heart rate (< 15%). The antihypertensive effect of GRI 17289 developed progressively over several hours and with some doses persisted for 24-48 h after administration. 3 Administration of GRI17289 (1 mg kg-', i.a.) on 5 consecutive days to RALH rats reduced DBP on each day. The antihypertensive effect of GR1 17289 was not cumulative as DBP had almost returned to base-line values, 24 h after administration of each dose. 4 A dose of GRI 17289 (3 mg kg', i.a.), which produced a substantial reduction in DBP (about 70 mmHg) in RALH rats, was administered to rats in which blood pressure was elevated either by unilateral renal artery clipping, sustained infusion of angiotensin II (All), DOCA-salt administration or genetic inbreeding. GR1 17289 reduced DBP in rats in which the renin-angiotensin system was activated by renal artery clipping or All infusion but had little effect in normotensive rats, DOCA-salt rats and SHR. 5 Systemic administration of All to RALH rats and to normotensive rats, dogs and marmosets elicited reproducible pressor responses in all species. Systemic or oral administration of GR1 17289 (3 mg kg-') inhibited the pressor responses produced by All, resulting in parallel, rightward displacements of All dose-response curves. 6 Maximal displacements of All dose-response curves occurred 1 h and 1-7 h after systemic and oral administration, respectively. GR1 17289 produced a 32-246 fold displacement after systemic administration and a 4-12 fold displacement after oral administration. The effect in dogs was short lasting after systemic administration but the effect of GR I17289 lasted for up to 24 h in rats and marmosets and for up to 24 h after oral administration in all species. The antagonist activity appeared specific for angiotensin receptors as GRi17289 did not inhibit pressor responses to phenylephrine or vasopressin. 7 These experiments demonstrate that GRI 17289 reduces blood pressure in conscious hypertensive rats after both systemic and oral administration, and is an effective antagonist at angiotensin AT, receptors in conscious rats, dogs and marmosets.

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

“…Results are shown in Figure 6. Discussion GRI17289 and GR138950 reduce blood pressure in rats in which it is elevated due to activation of the renin-angiotensin system (Hilditch etal., 1993;1995). However, their antagonist profiles against pressor responses produced byAII in conscious hypertensive and normotensive rats do not temporally correlate with their antihypertensive activities.…”

“…However, their antagonist profiles against pressor responses produced byAII in conscious hypertensive and normotensive rats do not temporally correlate with their antihypertensive activities. Previously, in order to explain this disparity, we have suggested that compounds like GRI 17289 and GR138950 might interact with receptors within the central nervous system, or deep within the vascular wall where they might inhibit the contribution made by the local renin-angiotensin system to the regulation of vascular tone 1995). In the present experiments, we have attempted to establish the extent to which blockade of All, generated locally in the vasculature, plays a role in this disparity.…”

“…This, and the fact that the shorter fragments are weak vasoconstrictor agents, makes it unlikely that they contribute much to the pressor response evoked following administration of Al. We have compared the time course over which GR138950 reduced pressor responses evoked by administration of Al with that seen when All was used (Hilditch et al, 1995). In addition, we have evaluated the ability of GR138950 to inhibit vasoconstrictor responses to Al, ex vivo, in aortae removed from hypertensive and normotensive rats at various intervals after dosing with the antagonist.…”

“…GRI38950 and other similar compounds, such as losartan (Akers et al, 1991) and GRI17289 , reduce blood pressure in renal arteryligated hypertensive (RALH) rats but the time course of this effect does not coincide with that of their antagonist profile, against angiotensin II (AII)-induced pressor responses, in either normotensive rats or RALH rats. We have suggested that the antihypertensive activities of these compounds may reflect blockade of AT, receptors at sites additional to those in the vasculature 1995). These could include sites within the central nervous system.…”

“…) is a potent, selective, and specific nonpeptide antagonist at angiotensin AT, receptors in the rabbit isolated aorta, and is also a potent, long-lasting, orally active antihypertensive agent in rats in which blood pressure has been elevated as a result of activation of the renin-angiotensin system (Hilditch et al, 1995). GRI38950 and other similar compounds, such as losartan (Akers et al, 1991) and GRI17289 , reduce blood pressure in renal arteryligated hypertensive (RALH) rats but the time course of this effect does not coincide with that of their antagonist profile, against angiotensin II (AII)-induced pressor responses, in either normotensive rats or RALH rats.…”