Calcitonin gene-related peptide (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 study was conducted in a canine model in which regional myocardial ischemia was reproducibly evoked by serial periods of atrial pacing (80 beats per min 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 (before versus after treatment: DeltaEG, 1.92 +/- 0.23 versus 0.54 +/- 0.24 mV; p < 0.05) and tended to increase LAD flow (7.7 +/- 0.7 versus 9.4 +/- 1.4 ml/min; p = 0.10), whereas the coronary constrictor serotonin increased ischemia severity (before versus after treatment: DeltaEG, 2.11 +/- 0.44 versus 4.90 +/- 1.46 mV; p < 0.05) concomitant with a reduction in LAD flow (9.1 +/- 1.1 versus 5.4 +/- 1.5 ml/min; p < 0.05). A 30 microg/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 to 0.3 microg/kg CGRP. This dose of CGRP((8-37)), administered either intravenously or intra-atrially, 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 microg/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.