INHIBITION OF BRADYKININ-INDUCED VASODILATION IN HUMAN FOREARM VASCULATURE BY ICATIBANT, A POTENT B-2-RECEPTOR ANTAGONIST

1 The effect of icatibant (D-Arg-[Hyp(3), Thi(5), D-Tic(7), Oic(8)] br adykinin) a potent B-2-kinin receptor antagonist, was studied on brady kinin-induced vasodilation in the human forearm. 2 Eight healthy normo tensive men were studied in a rising dose random-placebo controlled st udy. Placebo and icatibant (20, 50 and 100 pg kg(-1) i.v.) were admini stered double-blind. Forearm blood flow was measured by venous occlusi on plethysmography during rising dose brachial artery infusions of bra dykinin (10-3,000 ng min(-1)) 60-90 min after placebo or icatibant. 3 Plasma concentrations of icatibant fell exponentially following each o f three doses, up to the final measurement. Elimination half-lives cal culated from linear regression of the mean data were 25, 27 and 29 min after 20, 50 and 100 mu g kg(-1) doses respectively. 4 Icatibant inhi bited the effect of bradykinin (P < 0.001 at each dose of icatibant) i n a dose-dependent: manner. Bradykinin (100 ng min(-1)) increased mean blood flow in the infused arm by 238 +/- 31% when infused following p lacebo, by 112 +/- 21% after icatibant 20 mu g kg(-1), by 71 +/- 14% a fter icatibant 50 mu g kg(-1) and by 48 +/- 9% after icatibant 100 mu g kg(-1). 5 These results demonstrate that icatibant antagonises B-2-r eceptor mediated vasodilation in human forearm resistance vessels. The findings provide a quantitative basis for future studies of the role of bradykinin in the response to angiotensin converting enzyme inhibit ors and in circulatory disease.