CARDIOVASCULAR EFFECTS OF GR117289, A NOVEL ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST

1 The effect of GR117289, an angiotensin ATI 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 GR117289 at angiotensin AT(1) receptors was determined in conscious renal hypertensive rats and conscious normotensive rats, dogs and marmosets. 2 Intra-arterial and oral administration of GR117289 (0.3-3mg kg(-1), i.a.; 1-10mg kg(-1), p.o.) to 6-day left renal artery ligated hypertensive (RALH) rats (DBP>140mmHg) produced significant, dose-related reductions in DBP with little apparent effect on heart rate (<15%). The antihypertensive effect of GR117289 developed progressively over several hours and with some doses persisted for 24-48 h after administration. 3 Administration of GR117289 (1 mg kg(-1), i.a.) on 5 consecutive days to RALH rats reduced DBP on each day. The antihypertensive effect of GR117289 was not cumulative as DBP had almost returned to base-line values, 24 h after administration of each dose. 4 A dose of GR117289 (3mg kg(-1), 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 (AII), DOCA-salt administration or genetic inbreeding. GR117289 reduced DBP in rats in which the renin-angiotensin system was activated by renal artery clipping or AII infusion but had little effect in normotensive rats, DOCA-salt rats and SHR. 5 Systemic administration of AII to RALH rats and to normotensive rats, dogs and marmosets elicited reproducible presser responses in all species. Systemic or oral administration of GR117289 (3 mg kg(-1)) inhibited the presser responses produced by AII, resulting in parallel, rightward displacements of AII. dose-response curves. 6 Maximal displacements of AII dose-response curves occurred 1 h and 1-7 h after systemic and oral administration, respectively. GR117289 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 GR117289 lasted for up to 24 h in rats and marmosets and for up to 24h after oral administration in all species. The antagonist activity appeared specific for angiotensin receptors as GR117289 did not inhibit presser responses to phenylephrine or vasopressin. 7 These experiments demonstrate that GR117289 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.