A pharmacodynamic study of SR 47436, a selective AT1 receptor antagonist, on blood pressure in conscious cynomolgus monkeys.
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 AT1 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 approximately 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 AT1 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.
Cardiovascular Department, Sanofi Recherche, Montpellier, France.
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A
Roccon
D
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Marchionni
F
F
Donat
D
D
Segondy
C
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Cazaubon
D
D
Nisato
D000284:Administration, Oral; D000704:Analysis of Variance; D000804:Angiotensin II / Q000097:blood* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D007022:Hypotension / Q000139:chemically induced; D000077405:Irbesartan; D008252:Macaca fascicularis; D008297:Male; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan