Short- and long-term effects of melatonin on myocardial post-ischemic recovery

Melatonin, the chief secretory product of the pineal gland, has been shown to protect the heart against ischemia-reperfusion injury. This was attributed to its free radical scavenging and broad-spectrum antioxidant properties. The possibility that melatonin may act via its receptor and intracellular signaling, has not yet been addressed in this regard. In all previous studies, only the acute effects of melatonin on the heart, were evaluated. The aims of the present study were to: (i) compare the acute and long-term effects of melatonin on infarct size and functional recovery of the ischemic heart, and (ii) evaluate the role of the melatonin receptor in cardioprotection. For evaluation of the short-term effects of melatonin on contractile recovery and infarct size, the isolated perfused working rat heart was subjected to 20 min global ischemia or 35 min regional ischemia respectively, and melatonin (25-50 mu m) administered either before and during reperfusion, or before ischemia or during reperfusion after ischemia. The melatonin receptor was manipulated using luzindole and N-acetyltryptamine. The long-term effects of melatonin were evaluated 24 hr after melatonin administration (2.5 or 5.0 mg/kg, i.p.) or after oral administration for 7 days (20 or 40 mu g/mL). Infarct size and mechanical recovery during reperfusion of the working heart were used as endpoints. Melatonin (50 mu m), when administered either before and during reperfusion after ischemia or during reperfusion only, significantly improved cardiac output and work performance and reduced infarct size compared with untreated controls. Luzindole (5 mu m), a melatonin receptor antagonist, abolished these cardioprotective effects. Long-term administration of melatonin (i.p. or orally for 7 days) caused a significant reduction in infarct size of hearts subjected to 35 min regional ischemia. The cardioprotection persisted for 2-4 days after discontinuation of treatment. In summary, the results obtained suggest that melatonin induces short- as well as long-term protection and that the melatonin receptor is also involved in its cardioprotective actions.