Calcitonin gene-related peptide8-37 antagonizes capsaicin-induced vasodilation in the skin: evaluation of a human in vivo pharmacodynamic model.
The purpose of this study was to identify the mediators involved in capsaicin-induced vasodilation in the human skin and to evaluate a pharmacodynamic model for the early clinical evaluation of calcitonin gene-related peptide (CGRP) receptor antagonists. Dermal blood flow (DBF) response of the forearm skin to topically applied capsaicin was measured using laser Doppler perfusion imaging in 22 subjects. The effect of intra-arterially administered CGRP(8-37) (1200 ng . min(-1) . dl(-1) forearm), indomethacin (5 mug . min(-1) . dl(-1) forearm), and N(G)-monomethyl-l-arginine (l-NMMA; 0.2 mg . min(-1) dl(-1) forearm), and orally administered aprepitant (375 mg) on capsaicin-induced dermal vasodilation was assessed. Furthermore, the diurnal variation of the DBF response to capsaicin was studied. CGRP(8-37) inhibited the capsaicin-induced DBF increase: 217(145, 290)% in infused versus 370 (254, 486)% in the noninfused arm [mean (95% CI); p = 0.004]. In contrast, indomethacin, l-NMMA, aprepitant, and the time of assessment did not affect the DBF response to capsaicin. Thus, capsaicin-induced vasodilation in the human forearm skin is largely mediated by CGRP, but not by vasodilating prostaglandins, nitric oxide, or substance P. The response to capsaicin does not display a circadian rhythm. A pharmacodynamic model is proposed to evaluate CGRP receptor antagonists in humans in vivo.
Van der Schueren
B J
BJ
Center for Clinical Pharmacology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. bart.vanderschueren@uz.kuleuven.be
Rogiers
A
A
Vanmolkot
F H
FH
Van Hecken
A
A
Depré
M
M
Kane
S A
SA
De Lepeleire
I
I
Sinclair
S R
SR
de Hoon
J N
JN
D000293:Adolescent; D000328:Adult; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology*; D018592:Cross-Over Studies; D004336:Drug Antagonism; D005542:Forearm; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology*; D010599:Pharmacokinetics; D018015:Receptors, Calcitonin Gene-Related Peptide; D012039:Regional Blood Flow; D016037:Single-Blind Method; D012867:Skin / Q000098:blood supply*; D014664:Vasodilation / Q000187:drug effects*
D010446:Peptide Fragments; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin