Published online before print January 6, 2005, doi: 10.1161/01.RES.0000155331.09458.A7
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on June 15, 2004
Revised on December 8, 2004
Accepted on December 28, 2004
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
Shintaro Kinugawa ;
From the Department of Physiology, New York Medical College, Valhalla, NY.
* To whom correspondence should be addressed. E-mail: Thomas_Hintze{at}nymc.edu.
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.
Key words: endothelial nitric oxide synthase • neuronal nitric oxide synthase • superoxide anion • p38 • oxygen consumption
This article has been cited by other articles:
 |
|
 |
|
  D. R. Gonzalez, A. V. Treuer, and R. A. Dulce Neuronal nitric oxide synthase in heart mitochondria: a matter of life or death J. Physiol., June 15, 2009; 587(12): 2719 - 2720. [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Balligand, O. Feron, and C. Dessy eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues Physiol Rev, April 1, 2009; 89(2): 481 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, M. J. Kohr, C. J. Traynham, D. G. Wheeler, P. M. L. Janssen, and M. T. Ziolo Neuronal nitric oxide synthase signaling within cardiac myocytes targets phospholamban Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1566 - C1575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. H. Zhang, M. H. Zhang, C. E. Sears, K. Emanuel, C. Redwood, A. El-Armouche, E. G. Kranias, and B. Casadei Reduced Phospholamban Phosphorylation Is Associated With Impaired Relaxation in Left Ventricular Myocytes From Neuronal NO Synthase-Deficient Mice Circ. Res., February 1, 2008; 102(2): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Gonzalez, F. Beigi, A. V. Treuer, and J. M. Hare Deficient ryanodine receptor S-nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes PNAS, December 18, 2007; 104(51): 20612 - 20617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Wadley, J. Choate, and G. K. McConell NOS isoform-specific regulation of basal but not exercise-induced mitochondrial biogenesis in mouse skeletal muscle J. Physiol., November 15, 2007; 585(1): 253 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Yang and L. A. Barouch Leptin Signaling and Obesity: Cardiovascular Consequences Circ. Res., September 14, 2007; 101(6): 545 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Seddon, A. M. Shah, and B. Casadei Cardiomyocytes as effectors of nitric oxide signalling Cardiovasc Res, July 15, 2007; 75(2): 315 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Casadei The emerging role of neuronal nitric oxide synthase in the regulation of myocardial function Exp Physiol, November 1, 2006; 91(6): 943 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, A. Nivorozhkin, and C. Szabo Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol. Rev., March 1, 2006; 58(1): 87 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Balligand "La Donna e Mobile...": Is Cardiac Neuronal Nitric Oxide Synthase Such a Disconcerting Enzyme? Circulation, December 13, 2005; 112(24): 3668 - 3671. [Full Text] [PDF]
|
|
|
|
|
|
D. Dawson, C. A. Lygate, M.-H. Zhang, K. Hulbert, S. Neubauer, and B. Casadei nNOS Gene Deletion Exacerbates Pathological Left Ventricular Remodeling and Functional Deterioration After Myocardial Infarction Circulation, December 13, 2005; 112(24): 3729 - 3737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Saraiva, K. M. Minhas, S. V.Y. Raju, L. A. Barouch, E. Pitz, K. H. Schuleri, K. Vandegaer, D. Li, and J. M. Hare Deficiency of Neuronal Nitric Oxide Synthase Increases Mortality and Cardiac Remodeling After Myocardial Infarction: Role of Nitroso-Redox Equilibrium Circulation, November 29, 2005; 112(22): 3415 - 3422. [Abstract] [Full Text] [PDF]
|
|