A PHARMACODYNAMIC STUDY OF SR-47436, A SELECTIVE AT(1) RECEPTOR ANTAGONIST, ON BLOOD-PRESSURE IN CONSCIOUS CYNOMOLGUS MONKEYS

1 Conscious normotensive cynomolgus monkeys were chronically instrumen ted for the measurement of arterial blood pressure and heart rate to i nvestigate the relationships between the plasma concentration, suppres sion of the pressor response to angiotensin II (AII), compensatory inc rease in plasma AII, and hypotensive effect obtained after a single or al dose of SR 47436, a potent and specific nonpeptide AT(1) receptor a ntagonist. As blood sampling could influence the hypotensive effect of SR47436 through activation of the renin angiotensin system (RAS), dru g effects were studied in groups of animals with or without blood samp lings. 2 SR 47436 at 10 mg kg(-1) induced a hypotensive effect which w as not greater following a second dose of 30 mg kg(-1), indicating tha t a maximal hypotensive effect had already been obtained. 3 A single o ral dose of SR 47436 (10 mg kg(-1)) caused a sustained hypotension and a marked inhibition of the AII-induced presser response, lasting for up to 28 h. These effects of SR 47436 are consistent with good oral bi oavailability and a slow elimination of the drug (t1/2 approximate to 20 h), and were accompanied by a sustained increase in plasma AII conc entration. Taken together, both the hypotensive response and the compe nsatory increase in AII indicated that vascular and juxtaglomerular AI I receptors were blocked. 4 Although a fair correlation between indivi dual plasma drug concentrations and inhibition of AII-induced presser response was observed, neither the hypotensive effect nor the compensa tory increase in AII correlated with the plasma drug levels. 5 Basal a rterial pressure and AII-induced presser response were not affected by blood samplings. 6 These results suggest that SR 47436 is an effectiv e and long lasting AT(1) receptor antagonist with a potent hypotensive action in normotensive cynomolgus monkeys. It may be an efficacious b locker of the RAS in man and suitable for once-a-day dosing.