Melatonin inhibits NO‐induced cGMP accumulation by increasing PDE5 phosphorylation in coronary arteries

Abstract

Melatonin impairs NO‐induced relaxation by inhibiting the NO‐induced increase in cGMP in coronary arteries. We tested the hypothesis that the inhibitory effect of melatonin on NO‐signaling is due to increased phosphodiesterase type‐5 (PDE5) activation. Melatonin (10−7M) inhibited sodium nitroprusside (SNP) induced relaxation of isolated coronary arteries but had no effect on relaxation induced by 8‐Br‐cGMP. The inhibitory effect of melatonin on SNP‐induced relaxation was abolished in the presence of either the PDE inhibitor, zaprinast (10−5M) or the MT2‐receptor antagonist, 4P‐PDOT (10−7 M). Melatonin (10−7M) markedly reduced the SNP‐induced increase in cGMP levels in coronary arteries, and this effect of melatonin was significantly attenuated in the presence of either zaprinast (10−5M) or 4P‐PDOT (10−7 M). Immunohistochemical analysis confirmed localization of MT2‐receptors in the vascular smooth muscle cell layer. Immunoblot analysis demonstrated PDE5 expression in coronary arteries. Incubation of the tissues with melatonin (10−7M) caused a significant increase in PDE5 phosphorylation, which was abolished in the presence of 4P‐PDOT (10−7 M). The data indicate that melatonin increases the catalytic activity of PDE5 by activating MT2‐receptors in coronary arteries, resulting in decreased cGMP accumulation in response to NO and impaired NO‐induced vasorelaxation. (Supported by NIH HL77204)