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.

Therapeutic benefit of melatonin in refractory central serous chorioretinopathy

“…In addition, melatonin might decrease norepinephrine plasmatic levels, as previously described, 52 or it may have antiadrenergic effects through the choroid-melatonin receptor. 53 One of the limitations of this study is the relatively small number of patients; however, the prevalence of CSCR has been estimated as low as 5.8 per 100 000 population, with chronic CSCR reported to be as infrequent as 5% of those cases, making very difficult to obtain larger recruitment groups. Another limitation of this study is the difficulty in obtaining reliable data about previous episodes of the patient's disease as most of them cannot recall the prior events with precision.…”

“…Five patients with chronic CSCR served as a control group. The mean age of control patients was 44 years old (range, [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53], with the woman/man ratio being 1 : 4. The number of right and left eyes studied was also similar (3 right eyes and 2 left eyes).…”

Non-Ultradian Cardiac Rhythms: Circadian Regulation of the Heart

“…In addition to its acute soporific, phase-shifting, and anti-hypertensive effects, melatonin has powerful cardioprotective benefits. This may be due in part to melatonin's properties as a potent anti-oxidant, but studies using a perfused rat heart system have demonstrated a possible receptor dependent protection against ischemia/reperfusion injury (Genade et al, 2008). Clinical trials are underway to test the effectiveness of melatonin in treating human patients with ischemic heart disease (Dominguez-Rodriguez, 2007;.…”

Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C

“…Male offspring rats at postnatal day 17 ± 1 weighing about 50 g were used. Obstructive jaundice was induced by opening a midline incision and ligating and dividing the common bile duct with double ligatures of the proximal duct as described previously (4).…”

“…Melatonin, an endogenously produced indoleamine secreted by the pineal gland, has the ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (3). The direct free radical scavenging effect of melatonin is independent of receptors; however, melatonin-mediated protective effect has been attributed to its receptor-dependent effect on the nitric oxide (NO) pathway (4). l-Arginine, a substrate for NO synthase to generate NO, is mainly derived from protein catabolism (85%) or from lcitrulline by argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL) (5).…”