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Calcitonin gene–related peptide: Exploring its vasodilating mechanism of action in humans
Author(s) -
Hoon Jan N.,
Pickkers Peter,
Smits Paul,
StruijkerBoudier Harry A.J.,
Van Bortel Luc M.A.B.
Publication year - 2003
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(03)00007-9
Subject(s) - calcitonin gene related peptide , vasodilation , tetraethylammonium chloride , endocrinology , medicine , chemistry , calcitonin , glibenclamide , omega n methylarginine , nitric oxide , nitric oxide synthase , pharmacology , potassium , neuropeptide , receptor , organic chemistry , diabetes mellitus
Objective In vitro studies suggest that the vasodilator mechanism of action of calcitonin gene–related peptide (CGRP) involves various endothelium‐dependent and endothelium‐independent mechanisms. An in vivo analysis of the contribution of nitric oxide, prostaglandins, calcium‐sensitive potassium channels (K + Ca channels), and adenosine triphosphate (ATP)–sensitive potassium channels (K + ATP channels) to CGRP‐induced vasodilation in humans was performed. Methods CGRP (3, 10, and 30 ng · min −1 · dL −1 forearm) was infused into the brachial artery of 40 healthy subjects. Forearm vascular responses were measured by venous occlusion plethysmography. First, dose‐response curves were constructed during coinfusion of CGRP with placebo (sodium chloride, 0.9%). After washout, in 5 subgroups (n = 8 each), the infusions of CGRP were repeated with placebo (time‐control experiments), N G ‐monomethyl‐ L ‐arginine ( L ‐NMMA, a nitric oxide–synthase inhibitor), indomethacin (a cyclooxygenase inhibitor), tetraethylammonium chloride (TEAC) (a K + Ca ‐channel blocker), and glyburide (INN, glibenclamide) (a K + ATP ‐channelblocker), respectively. Results CGRP induced a dose‐dependent and reproducible decrease in forearm vascular resistance ( P < .001). Compared with placebo, L ‐NMMA reduced the decrease in forearm vascular resistance induced by CGRP ( P < .001) (3 and 10 ng · min −1 · dL −1 forearm). The absence of an inhibitory effect of L ‐NMMA on CGRP‐induced vasodilation at the highest dose of CGRP suggests that still other mechanisms are involved. The vasodilator response to CGRP was not affected by coinfusion of indomethacin, tetraethylammonium chloride, or glyburide. Conclusions The intrabrachial infusion of CGRP results in a dose‐dependent and reproducible forearm vasodilator response. CGRP‐induced vasodilation is dependent at least in part on the release of nitric oxide anddoes not involve the release of prostaglandins or the activation of K + Ca channels or K + ATP channels in humans. Clinical Pharmacology & Therapeutics (2003) 73 , 312–321; doi: 10.1016/S0009‐9236(03)00007‐9