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Melatonin inhibits NO‐induced cGMP accumulation by increasing PDE5 phosphorylation in coronary arteries
Author(s) -
Shukla Praveen,
GrazulBilska Anna,
O'Rourke Stephen T
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.957.3
Subject(s) - melatonin , zaprinast , coronary arteries , sodium nitroprusside , cgmp specific phosphodiesterase type 5 , medicine , endocrinology , chemistry , receptor , biology , nitric oxide , artery , guanylate cyclase , erectile dysfunction
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 −7 M) 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 −5 M) or the MT 2 ‐receptor antagonist, 4P‐PDOT (10 −7 M). Melatonin (10 −7 M) 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 −5 M) or 4P‐PDOT (10 −7 M). Immunohistochemical analysis confirmed localization of MT 2 ‐receptors in the vascular smooth muscle cell layer. Immunoblot analysis demonstrated PDE5 expression in coronary arteries. Incubation of the tissues with melatonin (10 −7 M) 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 MT 2 ‐receptors in coronary arteries, resulting in decreased cGMP accumulation in response to NO and impaired NO‐induced vasorelaxation. (Supported by NIH HL77204)