Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1‐receptor subtype

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Abstract
1 The pharmacological profile of valsartan, (S)-N-valeryl-N-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl}-valine, a potent, highly selective, and orally active antagonist at the angiotensin II (AII) AT1-receptor, was studied in vitro and in vivo. 2 Valsartan competed with [125I]-AII at its specific binding sites in rat aortic smooth muscle cell membranes (AT1-receptor subtype) with a Ki of 2.38 nm, but was about 30,000 times less active in human myometrial membranes (AT2-receptor subtype). 3 In rabbit aortic rings incubated for 5 min with valsartan, at concentrations of 2, 20 and 200 nm, the concentration-response curve of AII was displaced to the right and the maximum response was reduced by 33%, 36% and 40%, respectively. Prolongation of the incubation time with valsartan to 1 h or 3 h, further reduced the maximum response by 48% or 59% (after 20 nm) and by 59% or 60% (after 200 nm) respectively. After 3 h incubation an apparent pKB value of 9.26 was calculated. Contractions induced by noradrenaline, 5-hydroxytryptamine, or potassium chloride were not affected by valsartan. No agonistic effects were observed in the rabbit aorta at concentrations of valsartan up to 2 μm. 4 In bovine adrenal glomerulosa, valsartan inhibited All-stimulated aldosterone release without affecting the maximum response (pA2 8.4). 5 In the pithed rat, oral administration of valsartan (10 mg kg−1) shifted the All-induced pressor response curves to the right, without affecting responses induced by the electrical stimulation of the sympathetic outflow or by noradrenaline. Animals treated with valsartan 24 h before pithing also showed significant inhibition of the response to AII. 6 In conscious, two-kidney, one-clip renal hypertensive rats (2K1C), valsartan decreased blood pressure in a dose-dependent manner after single i.v. or oral administration. The respective ED30 values were 0.06 mg kg−1 (i.v.) and 1.4 mg kg−1 (p.o.). The antihypertensive effect lasted for at least 24 h after either route of administration. After repeated oral administration for 4 days (3 and 10 mg kg−1 daily), in 2K1C renal hypertensive rats, systolic blood pressure was consistently decreased, but heart rate was not significantly affected. 7 In conscious, normotensive, sodium-depleted marmosets, valsartan decreased mean arterial pressure, measured by telemetry, after oral doses of 1–30 mg kg−1. The hypotensive effect persisted up to 12 h after 3 and 10 mg kg−1 and up to 24 h after 30 mg kg−1. 8 In sodium-depleted marmosets, the hypotensive effect of valsartan lasted longer than that of losartan (DuP 753). In renal hypertensive rats, both agents had a similar duration (24 h), but a different onset of action (valsartan at 1 h, losartan between 2 h and 24 h). 9 These results demonstrate that valsartan is a potent, specific, highly selective antagonist of AII at the AT1-receptor subtype and does not possess agonistic activity. Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats and in conscious normotensive, sodium-depleted primates.

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