Effects of the prototype serotonin 5-HT(1B/1D) receptor agonist sumatriptan and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37) on myocardial reactive hyperemic response in conscious dogs.
The triptans, serotonin 5-HT(1B/1D) receptor agonists exemplified by sumatriptan, are a mainstay migraine therapy but have class labeling contraindicating their use in patients with coronary artery disease. Triptans constrict human coronary artery in vitro, and there are case reports of myocardial infarction in patients using sumatriptan. However, preclinical studies with sumatriptan in normal dogs have failed to demonstrate effects on resting coronary flow. Calcitonin gene-related peptide (CGRP) receptor antagonism, exemplified by the prototype CGRP receptor antagonist peptide CGRP(8-37), is a new antimigraine mechanism which also has been reported to have no effect on coronary flow in normal, non-stressed animals. The goal of the present studies was to compare the effects of sumatriptan (10microg/kg/min i.v.) and CGRP(8-37) (30microg/kg/min i.v.) on systemic and coronary hemodynamics in conscious dogs under resting conditions and during myocardial reactive hyperemia following a brief 15s of coronary artery occlusion. Neither CGRP(8-37) nor sumatriptan affected resting coronary flow. However, whereas CGRP(8-37) had no effect on myocardial reactive hyperemic response, sumatriptan reduced peak reactive hyperemic coronary artery blood flow (baseline vs treatment: 75.4+/-12.7 vs 60.0+/-10.3ml/min, P<0.05), reactive hyperemic flow (16.7+/-5.2 vs 11.6+/-3.3ml, P<0.05) and the repayment of coronary blood flow debt following coronary artery occlusion (484+/-76 vs 369+/-57%, P<0.05), indicating an impairment in coronary blood flow reserve. The positive control nitric oxide synthase inhibitor L-NNA (30mg/kg/30min i.v.) likewise significantly attenuated myocardial reactive hyperemic response. These findings provide evidence for a differentiation between CGRP receptor antagonism and triptan effects on coronary vascular function.
Lynch
Joseph J
JJ
WP46-300, Merck Research Laboratories, West Point PA, 19486, USA. joseph_lynch@merck.com
Shen
You-Tang
YT
Pittman
Tamara J
TJ
Anderson
Kenneth D
KD
Koblan
Kenneth S
KS
Gould
Robert J
RJ
Regan
Christopher P
CP
Kane
Stefanie A
SA
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002408:Catheters, Indwelling; D003243:Consciousness / Q000502:physiology; D003324:Coronary Artery Disease / Q000150:complications; D003326:Coronary Circulation / Q000187:drug effects*; D054059:Coronary Occlusion / Q000503:physiopathology; D018592:Cross-Over Studies; D004285:Dogs; D006439:Hemodynamics; D006940:Hyperemia / Q000188:drug therapy*; D007261:Infusions, Intra-Arterial; D008881:Migraine Disorders / Q000150:complications / Q000188:drug therapy; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D018170:Sumatriptan / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010446:Peptide Fragments; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; C058636:calcitonin gene-related peptide (8-37); D018170:Sumatriptan; D015740:Calcitonin Gene-Related Peptide