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

1 The effect of GR117289, an angiotensin ATI receptor antagonist, on d iastolic blood pressure (DBP) was determined in angiotensin-dependent and angiotensin-independent models of hypertension in rats. In additio n, the antagonist profile of GR117289 at angiotensin AT(1) receptors w as determined in conscious renal hypertensive rats and conscious normo tensive rats, dogs and marmosets. 2 Intra-arterial and oral administra tion 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) produ ced significant, dose-related reductions in DBP with little apparent e ffect on heart rate (<15%). The antihypertensive effect of GR117289 de veloped 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 d ay. 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 s ubstantial reduction in DBP (about 70 mmHg) in RALH rats, was administ ered to rats in which blood pressure was elevated either by unilateral renal artery clipping, sustained infusion of angiotensin II (AII), DO CA-salt administration or genetic inbreeding. GR117289 reduced DBP in rats in which the renin-angiotensin system was activated by renal arte ry clipping or AII infusion but had little effect in normotensive rats , DOCA-salt rats and SHR. 5 Systemic administration of AII to RALH rat s and to normotensive rats, dogs and marmosets elicited reproducible p resser responses in all species. Systemic or oral administration of GR 117289 (3 mg kg(-1)) inhibited the presser responses produced by AII, resulting in parallel, rightward displacements of AII. dose-response c urves. 6 Maximal displacements of AII dose-response curves occurred 1 h and 1-7 h after systemic and oral administration, respectively. GR11 7289 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 o f GR117289 lasted for up to 24 h in rats and marmosets and for up to 2 4h after oral administration in all species. The antagonist activity a ppeared specific for angiotensin receptors as GR117289 did not inhibit presser responses to phenylephrine or vasopressin. 7 These experiment s demonstrate that GR117289 reduces blood pressure in conscious hypert ensive rats after both systemic and oral administration, and is an eff ective antagonist at angiotensin AT, receptors in conscious rats, dogs and marmosets.