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Aim: To examine the role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning induced by prostaglandins in isolated guinea pig hearts., Methods: The isolated guinea pig hearts were perfused in a Langendorff model. The heart rate, coronary flow, left ventricular pressure, and its first derivatives (+/-dp/dt(max)) were recorded and the calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) and 6-keto-PGF(1 alpha) were measured., Results: Endothelin-1 (200 pmol in 1 mL K-H buffer) reduced the left ventricular developed pressure and its first derivatives (+/-dp/dt(max)), heart rate, and coronary flow. Preconditioning with two cycles of 5-min global ischemia and 5-min reperfusion attenuated endothelin-1 induced myocardial injury, and concentrations of both CGRP and 6-keto-PGF(1alpha) in the coronary effluent were markedly raised in the preconditioning periods. Pretreatment with capsaicin, which depletes endogenous CGRP, abolished the elevated level of CGRP concomitantly with loss of the cardioprotection induced by ischemic preconditioning. CGRP(8-37) (100 nmol/L), a selective CGRP1 receptor antagonist, also abolished the protective effects of ischemic preconditioning. After pretreatment with indometacin (10 micromol/L), an inhibitor of cyclooxygenase, the protective effects of ischemic preconditioning were abolished and the release of 6-keto-PGF1alpha was no longer elevated. Pretreatment with indometacin abolished the elevated level of CGRP in the coronary effluent., Conclusion: Endogenous prostaglandins are involved in the protective effects of ischemic preconditioning, and the beneficial effects of prostaglandins are mediated by CGRP in the guinea pig heart.

Preconditioning of the heart induced by a brief ischemia or hyperthermia is exerted in two phases, early and delayed protection. The cardioprotection of ischemic preconditioning is related to the release of endogenous mediators. Calcitonin gene-related peptide (CGRP), a principal transmitter of capsaicin-sensitive sensory nerves, is involved in the mediation of ischemic preconditioning, and CGRP-mediated ischemic preconditioning has been shown to protect the endothelial cells. The cardioprotection mediated by endogenous CGRP is also found in heat stress reaction. Drug-induced preconditioning, such as by nitroglycerin, may be related to stimulated release of CGRP. These findings suggest that CGRP may be an endogenous myocardial protective substance and plays an important role in the mediation of preconditioning.