Melatonin has potent cardioprotective properties. These actions have been attributed to its free radical scavenging and anti-oxidant actions, but may also be receptor mediated. Melatonin also exerts powerful anti-adrenergic actions based on its effects on contractility of isolated papillary muscles. The aims of this study were to determine whether melatonin also has anti-adrenergic effects on the isolated perfused rat heart, to determine the mechanism thereof and to establish whether these actions contribute to protection of the heart during ischaemia/reperfusion. The results showed that melatonin (50 microM) caused a significant reduction in both isoproterenol (10(-7) M) and forskolin (10(-6) M) induced cAMP production and that both these responses were melatonin receptor dependent, since the blocker, luzindole (5 x 10(-6) M) abolished this effect. Nitric oxide (NO), as well as guanylyl cyclase are involved, as L-NAME (50 microM), an NO synthase inhibitor and ODQ (20 microM), a guanylyl cyclase inhibitor, significantly counteracted the effects of melatonin. Protein kinase C (PKC), as indicated by the use of the inhibitor bisindolylmaleimide (50 microM), also play a role in melatonin's anti-adrenergic actions. These actions of melatonin are involved in its cardioprotection: simultaneous administration of L-NAME or ODQ with melatonin, before and after 35 min regional ischaemia, completely abolished its cardioprotection. PKC, on the other hand, had no effect on the melatonin-induced reduction in infarct size. Cardioprotection by melatonin was associated with a significant activation of PKB/Akt and attenuated activation of the pro-apoptotic kinase, p38MAPK during early reperfusion. In summary, the results show that melatonin-induced cardioprotection may be receptor dependent, and that its anti-adrenergic actions, mediated by NOS and guanylyl cyclase activation, are important contributors.

中文翻译：

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褪黑素受体介导的抗心肌缺血/再灌注损伤的保护作用：其抗肾上腺素的作用。

褪黑激素具有强大的心脏保护作用。这些作用归因于其自由基清除和抗氧化作用，但也可能是受体介导的。褪黑素还对孤立的乳头肌收缩产生影响，因此具有强大的抗肾上腺素作用。这项研究的目的是确定褪黑激素是否也对离体的灌流大鼠心脏具有抗肾上腺素的作用，确定其机制，并确定这些作用在缺血/再灌注期间是否有助于保护心脏。结果表明，褪黑激素（50 microM）引起异丙肾上腺素（10（-7）M）和福司可林（10（-6）M）诱导的cAMP产生均显着降低，并且这两种反应均是褪黑激素受体依赖性的，因为其具有阻断剂，luzindole（5 x 10（-6）M）取消了这种效果。一氧化氮（NO）和鸟苷酸环化酶都参与其中，其中一氧化氮合酶抑制剂L-NAME（50 microM）和鸟苷酸环化酶抑制剂ODQ（20 microM）显着抵消了褪黑激素的作用。如使用抑制剂bisindolylmaleimide（50 microM）所表明的，蛋白激酶C（PKC）在褪黑激素的抗肾上腺素作用中也起作用。褪黑激素的这些作用涉及其心脏保护作用：在局部缺血35分钟之前和之后与褪黑激素同时施用L-NAME或ODQ，完全取消了其心脏保护作用。另一方面，PKC对褪黑激素诱导的梗塞面积缩小没有影响。褪黑素的心脏保护作用与早期再灌注期间PKB / Akt的显着激活和促凋亡激酶p38MAPK的激活减弱有关。总之，结果表明褪黑激素诱导的心脏保护作用可能是受体依赖性的，其由NOS和鸟苷酸环化酶激活介导的抗肾上腺素作用是重要的贡献者。