1. The effect of
GR117289, an
angiotensin AT1 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 AT1 receptors was determined in conscious renal hypertensive rats and conscious normotensive rats, dogs and marmosets. 2. Intra-arterial and
oral administration of
GR117289 (0.3-3 mg kg-1, i.a.; 1-10 mg kg-1, 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
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 (3 mg 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 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-1)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 GRI17289 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 AT1 receptors in conscious rats, dogs and marmosets.