Angiotensin II receptor blockade with single doses of valsartan in healthy, normotensive subjects.
Valsartan (CGP 48933), a specific blocker of the angiotensin II (Ang II) receptor subtype 1 (AT1 receptor) was administered in single, oral doses of 40 mg and 80 mg to six healthy, normotensive male volunteers in a double-blind, placebo-controlled, randomized crossover trial. The aims of the study were a) to assess the extent, time course and dose-dependency of inhibition of the pressor effect of exogenous Ang II; and b) to attempt to correlate AT1 receptor blockade with the drug levels in plasma and with other markers of biological activity of the trial drug such as plasma renin activity (PRA). Using the Finapres device and i.v. bolus injections of exogenous Ang II, AT1 receptor blockade 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 administration of placebo and of the two doses of valsartan. PRA was measured with a conventional radioimmunoassay method. Data evaluation included a) descriptive analysis of the changes of the Ang II dose-response curves after valsartan, as compared to the curve on placebo; b) calculation of the pressor dose D30 of Ang II at each time-point, using linear regression; c) assessment of the effect of 4 micrograms Ang II on systolic BP and HR and the calculation of the percentage inhibition of these effects after valsartan; d) description of the relationship between drug levels in plasma and the measures of AT1 blockade, including pharmacokinetic-pharmacodynamic modeling with an Emax model for the percentage inhibition of systolic BP and HR.(ABSTRACT TRUNCATED AT 400 WORDS)
Müller
P
P
Pharma Division, Ciba-Giegy Limited, Basel, Switzerland.
Cohen
T
T
de Gasparo
M
M
Sioufi
A
A
Racine-Poon
A
A
Howald
H
H
D000328:Adult; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D010919:Placebos; D012083:Renin / Q000097:blood; D015203:Reproducibility of Results; D013599:Systole / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D010919:Placebos; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D012083:Renin; D014633:Valine