Activation of
melatonin receptors induces cardioprotection. Mitochondrial
potassium channels (mKCa and mKATP) are involved in the signaling cascade of preconditioning. The
melatonin receptor agonist
ramelteon is an approved oral medication for treatment of
insomnia, but nothing is known about possible cardioprotective properties. We investigated whether (1)
ramelteon induces cardioprotection mediated by the
melatonin receptor; (2) this effect is concentration-dependent; and (3) mKCa and/or mKATP channels are critically involved in
ramelteon-induced cardioprotection. Hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with
Krebs-Henseleit buffer at a constant pressure of 80 mm Hg. All hearts were subjected to 33 minutes of global
ischemia and 60 minutes of reperfusion. Before, ischemic hearts were perfused with different concentrations of
ramelteon (0.01-5 μM) for determination of a concentration-effect curve. In subsequent experiments, the lowest protective concentration of
ramelteon was administered together with
paxilline (mKCa channel inhibitor) and
5-hydroxydecanoate (mKATP channel inhibitor). To determine whether the reduction of
ischemia and
reperfusion injury by
ramelteon is mediated by
melatonin receptor, we combined
ramelteon with
luzindole, a
melatonin receptor antagonist.
Infarct size was determined by
triphenyltetrazolium chloride staining. In control animals,
infarct size was 58% ± 6%.
Ramelteon in a concentration of 0.03 µM reduced
infarct size to 28% ± 4% (P < 0.0001 vs. Con). A lower concentration of
ramelteon did not initiate cardioprotection, and higher concentrations did not further decrease
infarct size.
Paxilline,
5-hydroxydecanoate, and
luzindole completely blocked the
ramelteon-induced cardioprotection. This study shows for the first time that (1)
ramelteon induces cardioprotection through
melatonin receptor; (2) the effect is not concentration-dependent; and (3) activation of mKCa and mKATP channels is involved.