The pineal hormone, melatonin, plays a physiologic role in the regulation of circadian rhythms, and a host of synthetic melatonin agonists and antagonists are being developed for use in a wide range of disorders. Melatonin receptors are present in blood vessels but, at present, there is a decided lack of information regarding the mechanisms by which melatonin regulates vasomotor tone. In certain blood vessels, physiologically (and pharmacologically) relevant concentrations of melatonin can evoke either vasoconstrictor or vasodilator responses. In addition to these direct effects, studies in our laboratory indicate that melatonin exerts a powerful indirect effect on coronary arteries through the inhibition of nitric oxide (NO)-induced relaxations. Inasmuch as the NO pathway is a critical regulator of coronary vasomotor tone, inhibition of this pathway may contribute to the mechanisms by which melatonin influences coronary arterial function in health and disease. The primary objective of this proposal is to gain an increased understanding of the functional interactions occurring between melatonin and NO within coronary arteries. Experiments will be performed to test our overall hypothesis that melatonin acts via specific receptors to inhibit NO-induced activation of signaling events in coronary smooth muscle cells. Our initial aims are two-fold: 1) to characterize the specific melatonin receptor subtype(s) that mediates the inhibitory effect of melatonin on NO-induced relaxation of coronary arterial smooth muscle; and 2) to identify the NO-signaling pathway(s) that are inhibited by melatonin. Standard organ chamber methods, cyclic nucleotide assays, and patch-clamp recording techniques will be used to directly address the mechanisms by which melatonin regulates NO-signaling in isolated pig coronary arteries. The results from this multidimensional approach will provide new information regarding the cellular mechanisms by which melatonin regulates vascular smooth muscle function, and may identify novel mechanisms by which NO-signaling is regulated. ? ?
|Shukla, Praveen; Sun, Chengwen; O'Rourke, Stephen T (2012) Melatonin inhibits nitric oxide signaling by increasing PDE5 phosphorylation in coronary arteries. Am J Physiol Heart Circ Physiol 303:H1418-25|
|Tunstall, Radhika R; Shukla, Praveen; Grazul-Bilska, Anna et al. (2011) MT2 receptors mediate the inhibitory effects of melatonin on nitric oxide-induced relaxation of porcine isolated coronary arteries. J Pharmacol Exp Ther 336:127-33|