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.