CHARACTERIZATION OF THE ANGIOTENSIN-II RECEPTOR ANTAGONIST TCN-116 INHEALTHY-VOLUNTEERS

The purpose of this study was to assess the inhibitory effect of TCV-1 16, an orally active angiotensin II (Ang II) antagonist, on the presse r action of exogenous Ang II and to determine the compensatory rise in plasma renin activity and Ang II levels. Twenty-three male volunteers were treated for 8 days in a double-blind fashion with either placebo or TCV-116 (1, 2, or 4 mg PO daily) and challenged on the first, four th, and eighth days with repeated bolus injections of Ang II. An addit ional 4 subjects received 8 mg PO daily in a single-blind fashion. The inhibitory effect on the systolic blood pressure response to Ang II w as long lasting and clearly dose related. Six hours after 4 mg TCV-116 , the systolic blood pressure response to a given dose of Ang II was r educed to 40+/-4% and 35+/-8% of baseline value on days 1 and 8, respe ctively. TCV-116 induced a dose-related increase in plasma renin activ ity and Ang II levels that was more pronounced on the eighth than on t he first day of drug administration. Despite this compensatory mechani sm, the relation between the time-integrated systolic blood pressure r esponse to Ang II and the time-integrated CV-11974 levels, the active metabolite of TCV-116, was not different between days 1 and 8. In conc lusion, TCV-116 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of Ang II in men.