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 microm) 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 microg/mL).
Infarct size and mechanical recovery during reperfusion of the working heart were used as endpoints.
Melatonin (50 microm), 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 microm), 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.