Calcitonin gene-related peptide-induced vasodilation in the human forearm is antagonized by CGRP8-37: evaluation of a human in vivo pharmacodynamic model.
OBJECTIVE
The aims of this study were to assess the potential of CGRP8-37, the C-terminal fragment of calcitonin gene-related peptide (CGRP), to inhibit CGRP-induced vasodilation in the human forearm and to evaluate a pharmacodynamic model to aid the clinical development of novel CGRP-receptor antagonists.


METHODS
Forearm blood flow (FBF) responses to intra-arterial CGRP infusions were measured via venous occlusion plethysmography in 21 healthy subjects. Dose response to CGRP was assessed during graded infusion of CGRP (1, 3, and 10 ng.min(-1).dL(-1) forearm; n = 6). After a 90-minute washout period, CGRP infusions were repeated during coinfusion of CGRP8-37 (333 ng.min(-1).dL(-1) forearm) to assess inhibition by CGRP8-37. To determine the antagonistic potency of CGRP8-37, a 4-period, placebo-controlled crossover study was conducted in 6 subjects, in which CGRP (10 ng.min(-1).dL(-1) forearm) was infused for 20 minutes together with placebo or CGRP8-37 (300, 600, or 1200 ng.min(-1).dL(-1) forearm). In addition, the effect of each dose of CGRP8-37 on resting FBF was evaluated.


RESULTS
CGRP8-37 significantly inhibited the CGRP-induced increase in FBF compared with placebo (from 3.2 +/- 1.1 mL.min(-1).dL(-1) forearm at baseline to 4.8 +/- 1.0, 7.7 +/- 1.9, and 12.3 +/- 3.8 mL.min(-1).dL(-1) forearm versus 3.1 +/- 0.7 mL.min(-1).dL(-1) forearm to 3.8 +/- 0.6, 5.2 +/- 1.5, and 8.5 +/- 3.0 mL.min(-1).dL(-1) forearm for placebo and CGRP8-37, respectively; P < .001). The FBF response during the 20-minute infusion of CGRP was dose-dependently inhibited by CGRP8-37 (area under the curve, 200 +/- 51 mL.dL(-1) forearm for placebo versus 181 +/- 23, 160 +/- 40, and 132 +/- 56 mL.dL(-1) forearm for CGRP8-37, 300, 600, and 1200 ng.min(-1).dL(-1) forearm, respectively; P < .001). CGRP8-37 did not affect resting FBF.


CONCLUSIONS
CGRP8-37 inhibits CGRP-induced vasodilation in the human forearm without affecting resting FBF. Venous occlusion plethysmography combined with brachial artery administration of CGRP provides a suitable pharmacodynamic model to aid the clinical development of CGRP-receptor antagonists.
Vanmolkot
Floris H M
FH
Center for Clinical Pharmacology, University Hospital Gasthuisberg (Katholieke Universiteit Leuven), Leuven, Belgium. floris.vanmolkot@med.kuleuven.be
Van der Schueren
Bart J E P
BJ
de Hoon
Jan N J M
JN
D000328:Adult; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D015203:Reproducibility of Results; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D010446:Peptide Fragments; D014665:Vasodilator Agents; C058636:calcitonin gene-related peptide (8-37); D009599:Nitroprusside; D014700:Verapamil; D015740:Calcitonin Gene-Related Peptide