ANGIOTENSIN-II RECEPTOR BLOCKADE WITH SINGLE DOSES OF VALSARTAN IN HEALTHY, NORMOTENSIVE SUBJECTS

Valsartan (CGP 48933), a specific blocker of the angiotensin II (Ang I I) receptor subtype I (AT(1) receptor) was administered in single, ora l doses of 40 mg and 80 mg to six healthy, normotensive male volunteer s in a double-blind, placebo-controlled, randomized crossover trial. T he aims of the study were a) to assess the extent, time course and dos e-dependency of inhibition of the presser effect of exogenous Ang II; and b) to attempt to correlate AT(1) receptor blockade with the drug l evels in plasma and with other markers of biological activity of the t rial drug such as plasma renin activity (PRA). Using the Finapres devi ce and i.v. bolus injections of exogenous Ang II, AT(1) receptor block ade was assessed by measuring blood pressure (BP) and heart rate (HR) on a beat-by-beat basis. A dose-response curve for Ang II was obtained for each subject before and at 2, 4, 6, 8 and 24 h after administrati on of placebo and of the two doses of valsartan. PRA was measured with a conventional radioimmunoassay method. Data evaluation included a) d escriptive analysis of the changes of the Ang II dose-response curves after valsartan, as compared to the curve on placebo; b) calculation o f the presser dose D-30 of Ang II at each time-point, using linear reg ression; c) assessment of the effect of 4 mu g Ang II on systolic BP a nd HR and the calculation of the percentage inhibition of these effect s after valsartan; d) description of the relationship between drug lev els in plasma and the measures of AT(1) blockade, including pharmacoki netic-pharmaco dynamic modeling with an E(max) model for the percentag e inhibition of systolic BP and HR.It is concluded that (a) the method ology used is suitable to evaluate AT(1) receptor blockade in man; (b) instead of using a full dose-response curve for Ang II at each timepo int, an abbreviated approach with only one pre-determined Ang II dose may be adopted without substantial loss of information; (c) valsartan is an inhibitor of the AT, receptor in man, with a mean E(max) of 74% and a mean IC50 of 0.53 mu mol.l(-1) for the blood pressure response t o exogenous Ang II; (d) receptor blockade after single oral doses of 4 0 mg and 80 mg valsartan reaches its maximum at 2 h and is detectable up to 24 h after administration; (e) despite a doubling of systemic ex posure, the relationship between dose and receptor blockade appears to be rather flat in the dose range 40 to 80 mg; and (f) valsartan is we ll tolerated by healthy subjects in the dose range tested.