Melatonin receptor-mediated protection against myocardial ischaemia/reperfusion injury: role of its anti-adrenergic actions.

Abstract

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.

• Authors: Sonia Genade, Amanda Genis, Kirsti Ytrehus, Barbara Huisamen, Amanda Lochner
• Journal: Journal of pineal research (J Pineal Res) Vol. 45 Issue 4 Pg. 449-58 (Nov 2008) ISSN: 1600-079X [Electronic] England
• PMID: 18691357 (Publication Type: Journal Article)

Chemical References

• 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
• Adrenergic Antagonists
• Indoles
• Maleimides
• Oxadiazoles
• Quinoxalines
• Receptors, Melatonin
• Tryptamines
• luzindole
• Colforsin
• Nitric Oxide
• Propranolol
• Cyclic AMP
• Protein Kinase C
• p38 Mitogen-Activated Protein Kinases
• Guanylate Cyclase
• Melatonin
• Isoproterenol
• bisindolylmaleimide
• NG-Nitroarginine Methyl Ester

Topics

• Adrenergic Antagonists (pharmacology)
• Animals
• Colforsin (pharmacology)
• Cyclic AMP (metabolism)
• Guanylate Cyclase (metabolism)
• Heart (drug effects, physiology)
• Indoles (pharmacology)
• Isoproterenol (pharmacology)
• Male
• Maleimides (pharmacology)
• Melatonin (agonists, pharmacology)
• Myocardial Infarction (pathology)
• Myocardial Reperfusion Injury (prevention & control)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitric Oxide (physiology)
• Oxadiazoles (pharmacology)
• Propranolol (pharmacology)
• Protein Kinase C (metabolism)
• Quinoxalines (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Melatonin (metabolism)
• Tryptamines (physiology)
• p38 Mitogen-Activated Protein Kinases (metabolism)