Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist.
1. The effect of icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) a potent B2-kinin receptor antagonist, was studied on bradykinin-induced vasodilation in the human forearm. 2. Eight healthy normotensive men were studied in a rising dose random-placebo controlled study. Placebo and icatibant (20, 50 and 100 micrograms kg-1 i.v.) were administered double-blind. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of bradykinin (10-3,000 ng min-1) 60-90 min after placebo or icatibant. 3. Plasma concentrations of icatibant fell exponentially following each of three doses, up to the final measurement. Elimination half-lives calculated from linear regression of the mean data were 25, 27 and 29 min after 20, 50 and 100 micrograms kg-1 doses respectively. 4. Icatibant inhibited the effect of bradykinin (P < 0.001 at each dose of icatibant) in a dose-dependent manner. Bradykinin (100 ng min-1) increased mean blood flow in the infused arm by 238 +/- 31% when infused following placebo, by 112 +/- 21% after icatibant 20 micrograms kg-1, by 71 +/- 14% after icatibant 50 micrograms kg-1 and by 48 +/- 9% after icatibant 100 micrograms kg-1. 5. These results demonstrate that icatibant antagonises B2-receptor 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 inhibitors and in circulatory disease.
Department of Clinical Pharmacology, United Medical School, Guy's Hospital, London.
J R
JR
Cockcroft
P J
PJ
Chowienczyk
S E
SE
Brett
N
N
Bender
J M
JM
Ritter
D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000704:Analysis of Variance; D001794:Blood Pressure / Q000187:drug effects; D001916:Brachial Artery / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005542:Forearm / Q000098:blood supply; D006207:Half-Life; D006801:Humans; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D011863:Radioimmunoassay; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D065168:Bradykinin Receptor Antagonists; C053748:B 4162; C065679:icatibant; D001920:Bradykinin