Calcitonin gene-related peptide: exploring its vasodilating mechanism of action in humans.
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 x min(-1) x 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)-channel blocker), 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 x min(-1) x 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 and does not involve the release of prostaglandins or the activation of K(+)(Ca) channels or K(+)(ATP) channels in humans.
de Hoon
Jan N
JN
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastrict University, The Netherlands. jan.dehoon@uz.kuleuven.ac.be
Pickkers
Peter
P
Smits
Paul
P
Struijker-Boudier
Harry A J
HA
Van Bortel
Luc M A B
LM
D000328:Adult; D001916:Brachial Artery; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin; D007261:Infusions, Intra-Arterial; D008297:Male; D010991:Plethysmography; D015221:Potassium Channels / Q000187:drug effects; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D015221:Potassium Channels; D019323:omega-N-Methylarginine; D019789:Tetraethylammonium; D015740:Calcitonin Gene-Related Peptide; D005905:Glyburide; D007213:Indomethacin