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A pharmacodynamic study of SR 47436, a selective AT 1 receptor antagonist, on blood pressure in conscious cynomolgus monkeys
Author(s) -
Roccon Alain,
Marchionni David,
Donat François,
Segondy Danielle,
Cazaubon Catherine,
Nisato Dino
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14036.x
Subject(s) - medicine , endocrinology , angiotensin ii , blood pressure , renin–angiotensin system , plasma renin activity , antagonist , angiotensin ii receptor type 1 , chemistry , blood sampling , receptor
1 Conscious normotensive cynomolgus monkeys were chronically instrumented for the measurement of arterial blood pressure and heart rate to investigate the relationships between the plasma concentration, suppression of the pressor response to angiotensin II (AII), compensatory increase in plasma AII, and hypotensive effect obtained after a single oral dose of SR 47436, a potent and specific nonpeptide AT 1 receptor antagonist. As blood sampling could influence the hypotensive effect of SR 47436 through activation of the renin angiotensin system (RAS), drug effects were studied in groups of animals with or without blood samplings. 2 SR 47436 at 10 mg kg −1 induced a hypotensive effect which was not greater following a second dose of 30 mg kg −1 , indicating that a maximal hypotensive effect had already been obtained. 3 A single oral dose of SR 47436 (10 mg kg −1 ) caused a sustained hypotension and a marked inhibition of the AII‐induced pressor response, lasting for up to 28 h. These effects of SR 47436 are consistent with good oral bioavailability and a slow elimination of the drug ( t 1/2 ≅ 20 h), and were accompanied by a sustained increase in plasma AII concentration. Taken together, both the hypotensive response and the compensatory increase in AII indicated that vascular and juxtaglomerular AII receptors were blocked. 4 Although a fair correlation between individual plasma drug concentrations and inhibition of AII‐induced pressor response was observed, neither the hypotensive effect nor the compensatory increase in AII correlated with the plasma drug levels. 5 Basal arterial pressure and AII‐induced pressor response were not affected by blood samplings. 6 These results suggest that SR 47436 is an effective and long lasting AT 1 receptor antagonist with a potent hypotensive action in normotensive cynomolgus monkeys. It may be an efficacious blocker of the RAS in man and suitable for once‐a‐day dosing.