RT Journal Article SR Electronic T1 Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 248 OP 255 DO 10.1124/jpet.107.133868 VO 325 IS 1 A1 B. J. Van der Schueren A1 A. Rogiers A1 F. H. Vanmolkot A1 A. Van Hecken A1 M. Depré A1 S. A. Kane A1 I. De Lepeleire A1 S. R. Sinclair A1 J. N. de Hoon YR 2008 UL http://jpet.aspetjournals.org/content/325/1/248.abstract AB 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 CGRP8-37 (1200 ng · min–1 · dl–1 forearm), indomethacin (5 μg · min–1 · dl–1 forearm), and NG-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. CGRP8-37 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. The American Society for Pharmacology and Experimental Therapeutics