Conclusions And Potential Clinical Relevance

With the limited data at hand, it is still difficult to discern the overall role of melatonin in vascular regulation. From the few studies which address tissue distribution, it appears that melatonin may target only certain vascular beds. This strategy may allow for local adjustment in the face of global circadian changes in the cardiovascular system. The functional effects of melatonin observed so far in vitro differ among the various vascular preparations examined, however. These findings may reflect different melatonin receptor subtypes, receptor heterogeneity and/or multiple cellular targets, different receptor coupling and/or signal transduction mechanisms, variations in the resting tone of the vessel and/or interactions with endothelial factors or other vasoactive agents. The various possibilities are areas for future investigation.

Using rat cerebral and tail arteries, our laboratory has obtained evidence for two receptor-mediated contractile responses to melatonin. Constriction is produced via mt1-like melatonin receptors located in arterial smooth muscle that appear to signal through Gi/o proteins to inhibit cyclic AMP and modulate calcium-dependent potassium channels. Constrictor effects of melatonin appear to be sensitive to membrane potential, arterial pressure and perfusion shear stress. Melatonin also can produce relaxation. The latter response appears to be mediated by the MT2 melatonin receptor subtype because it is blocked by the selective antagonists, 4-P-ADOT and 4-P-PDOT. Consistent with these data, rat and human arteries express mRNA for both the mt1 and MT2 receptor subtypes. Interestingly, MT2 receptor-mediated dilation in vascular smooth muscle is enhanced by estrogen, suggesting that the relative proportion of dilator MT2 and constrictor mt1-like receptors may be modulated under different physiological conditions to optimize vascular responses to melatonin.

Given the current use of melatonin as a popular over-the-counter jet lag and sleeping aid, it is important to understand the potential for cardiovascular effects in people self-administering melatonin. Possible interactions with estrogen are additional considerations for women taking melatonin during puberty, childbearing years and hormone replacement therapy after menopause. In addition, defining the role of mela-tonin in vascular regulation may lead to novel approaches for treating migraine, stroke and cardiovascular disease.

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