title: A defect of neuronal nitric oxide synthase increases xanthine oxidase-derived superoxide anion and attenuates the control of myocardial oxygen consumption by nitric oxide derived from endothelial nitric oxide synthase.
abstract: Endothelial nitric oxide synthase (eNOS) plays an important role in the control of myocardial oxygen consumption (MVO2) by nitric oxide (NO). A NOS isoform is present in cardiac mitochondria and it is derived from neuronal NOS (nNOS). However, the role of nNOS in the control of MVO2 remains unknown. MVO2 in left ventricular tissues from nNOS-/- mice was measured in vitro. Stimulation of NO production by bradykinin or carbachol induced a significant reduction in MVO2 in wild-type (WT) mice. In contrast to WT, bradykinin- or carbachol-induced reduction in MVO2 was attenuated in nNOS-/-. S-methyl-L-thiocitrulline, a potent isoform selective inhibitor of nNOS, had no effect on bradykinin-induced reduction in MVO2 in WT. Bradykinin-induced reduction in MVO2 in eNOS-/- mice, in which nNOS still exists, was also attenuated. The attenuated bradykinin-induced reduction in MVO2 in nNOS-/- was restored by preincubation with Tiron, ascorbic acid, Tempol, oxypurinol, or SB203850, an inhibitor of p38 kinase, but not apocynin. There was an increase in lucigenin-detectable superoxide anion (O2-) in cardiac tissues from nNOS-/- compared with WT. Tempol, oxypurinol, or SB203850 decreased O2- in all groups to levels that were not different from each other. There was an increase in phosphorylated p38 kinase normalized by total p38 kinase protein level in nNOS-/- compared with WT mice. These results indicate that a defect of nNOS increases O2- through the activation of xanthine oxidase, which is mediated by the activation of p38 kinase, and attenuates the control of MVO2 by NO derived from eNOS.
authors.affiliation: Department of Physiology New York Medical College Valhalla, NY 10595, USA.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kinugawa
authors.forename: Harer
authors.initials: H
authors.lastname: Huang
authors.forename: Ziping
authors.initials: Z
authors.lastname: Wang
authors.forename: Pawel M
authors.initials: PM
authors.lastname: Kaminski
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D015151:Immunoblotting; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D010117:Oxypurinol / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
chemical_list: D000098:Acetophenones; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; C110881:S-nitro-N-acetylpenicillamine; D013481:Superoxides; D009569:Nitric Oxide; D002217:Carbachol; C056165:acetovanillone; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D014969:Xanthine Oxidase; D048051:p38 Mitogen-Activated Protein Kinases; D010117:Oxypurinol; D010396:Penicillamine; D001920:Bradykinin