Received for publication August 4, 2008.
Revised November 6, 2008.
Accepted for publication November 6, 2008.

CGRP Receptor Antagonism Does Not Affect the Severity of Myocardial Ischemia during Atrial Pacing in Dogs with Coronary Artery Stenosis

Abstract

CGRP is a sensory neuropeptide that also has potent vasodilator activity. There are conflicting preclinical reports regarding the effect of CGRP receptor antagonism in the setting of myocardial ischemia. The present studies were conducted in a canine model in which regional myocardial ischemia was reproducibly evoked by serial periods of atrial pacing (80 bpm above baseline rate) in the presence of a 40% stenosis of the left anterior descending (LAD) coronary artery. Ischemia severity was quantitated by changes in unipolar epicardial electrograms (EG) recorded in the area of ischemia. In validation studies, the calcium entry blocker diltiazem reduced ischemia severity (pre vs post-treatment: EG: 1.92±0.23 vs 0.54±0.24 mV, p<0.05) and tended to increase LAD flow (7.7±0.7 vs 9.4±1.4 ml/min, p=0.10), whereas the coronary constrictor serotonin increased ischemia severity (pre vs post-treatment: EG: 2.11±0.44 vs 4.90±1.46 mV, p<0.05) concomitant with a reduction in LAD flow (9.1±1.1 vs 5.4±1.5 ml/min, p<0.05). A 30 µg/kg/min i.v. infusion test dose of the CGRP receptor antagonist CGRP(_8-37) was validated by demonstrating complete block of the depressor effects of exogenous i.v. 0.03-0.3 µg/kg CGRP. This dose of CGRP(_8-37), administered either i.v. or i.a., had no effect on ischemia severity or paced LAD flow, indicating no intrinsic effect of CGRP receptor antagonism on the severity of acute myocardial ischemia. Likewise, the administration of a hemodynamically active dosing regimen of CGRP (0.03 µg/kg/min i.v.) had no effect on paced coronary flow or ischemia severity, suggesting no major role of CGRP in regulating ischemic blood flow.

Key words: CGRP, CGRP receptor antagonist, coronary flow, diltiazem, myocardial ischemia, serotonin