A pharmacodynamic study of SR 47436, a selective AT₁ receptor antagonist, on blood pressure in conscious cynomolgus monkeys

Abstract

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. 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. 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 (t1/2 ≅ 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. 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. Basal arterial pressure and AII‐induced pressor response were not affected by blood samplings. 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.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…In conscious monkeys the degree of antagonism of the ANG blood pressure response by irbesartan was correlated to its plasma concentration (Roccon et al, 1994). Accordingly, in some studies the ED 50 for inhibiting the ANG-induced BP elevation was not expressed based on dose but rather based on the corresponding total and free plasma concentration, e.g., for EXP3174 in conscious rats (Wong et al, 1996).…”

“…injections of ANG in the absence and presence of one or more doses of an ARB. Such studies have mostly been performed in rats (see below), but some studies have also been performed in hamsters (Trippodo et al, 1995;Jin et al, 1997), dogs Kubo et al, 1993;Christ et al, 1994;Ito et al, 1995;Hashimoto et al, 1997;Hayashi et al, 1997), cats (Champion and Kadowitz, 1997), or monkeys Criscione et al, 1993;Roccon et al, 1994) (for human studies see below).…”

A Review of the New Angiotensin II‐Receptor Antagonist Irbesartan

“…Oral administration of irbesartan 10 m g k g to conscious, normotensive cynomolgus monkeys significantly lowered MAP by -20 mmHg. The administration of an additional dose of irbesartan 30 m g k g did not produce any further decreases in MAP, suggesting that maximal RAS blockade was obtained with the 10-mgkg dose (58). Oral administration of a single irbesartan 10-mgkg dose significantly inhibited the response to exogenous A11 (100 ngkg) by 5 6 4 to 70%, decreased MAP by approximately 20%, and elevated plasma A11 levels by over 200% (p < 0.05 vs controls) up to 28 h postdosing.…”

“…In hypertensive rats (33) and normotensive monkeys (34,58), irbesartan demonstrated dose-dependent decreases in BP. In spontaneously hypertensive rats, intravenous administration of irbesartan at doses of 10 m g k g and 30 m g k g significantly reduced mean arterial pressure (MAP) compared with controls by 1 I and 20 mmHg, respectively (33).…”

“…This phenomenon is theorized to result from the ability of the AT, receptor to exist in two interconvertible states (active and inactive), with insurmountable antagonists having a higher affinity for the inactive state. In normotensive conscious rats, dogs, and monkeys, irbesartan consistently inhibited the AII-induced pressor response after either intravenous or oral administration (9,34,58).…”