PHARMACOLOGICAL EFFECTS OF GR138950, A NOVEL ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST

The antagonist activity of GR138950 -4-cyclopropyl-2-ethyl-1H-imidazol e-5-carboxamide) was investigated at angiotensin AT(1) receptors and A T(2) receptors in vitro and on blood pressure in conscious rats. GR138 950 suppressed and displaced angiotensin II (AII) concentration-effect curves in the rabbit isolated aorta (pK(b) similar to 9.0-9.7) but ha d no effect against phenylephrine or serotonin induced-contractions. G R138950 competed with [H-3]-AII for angiotensin AT(1) receptors in rat liver membranes (pK(i) = 9.09). GR138950 had no apparent affinity for angiotensin AT(2) receptors (bovine cerebellum; pK(i) < 6.0). GR13895 0 (1 mg/kg i.a. and p.o.) inhibited presser responses to AII, but not phenylephrine, in conscious normotensive rats. Parallel displacements in AII dose-response curves occurred without any reduction in the maxi mum response to AII. The antagonist activity of GR138950 lasted for up to 24 h. GR138950 (> 0.03 mg/kg i.a., > 0.3 mg/kg p.o.) significantly reduced diastolic blood pressure (DBP) in renal artery ligated hypert ensive rats. DBP was reduced maximally, 5 to 7 h after administration and the antihypertensive effect of GR138950 lasted for up to 48 h. Dai ly administration (5 days) of GR138950 to renal artery ligated hyperte nsive rats produced a sustained reduction in DBP. Acute administration of GR138950 (1 mg/kg i.a.) also significantly reduced DBP in spontane ously hypertensive rats but not in normotensive rats. Heart rate was l ittle changed in renal artery ligated hypertensive rats, normotensive rats and spontaneously hypertensive rats. These experiments demonstrat e that GR138950 is a potent, selective and specific angiotensin AT(1) receptor antagonist that is orally active and reduces DBP in conscious hypertensive rats. This profile of activity suggests that the compoun d should be clinically effective in the treatment of hypertension and heart failure.