This Article Full Text Full Text (PDF) All Versions of this Article: 92/12/1352    most recent 01.RES.0000079026.70629.E5v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wunderlich, C. Articles by Schrader, J. Search for Related Content PubMed PubMed Citation Articles by Wunderlich, C. Articles by Schrader, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE CARBON DIOXIDE CARBON MONOXIDE NITROGEN OXYGEN Related Collections Contractile function Biochemistry and metabolism Energy metabolism Genetically altered mice Heart failure - basic studies

(Circulation Research. 2003;92:1352.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Acute Inhibition of Myoglobin Impairs Contractility and Energy State of iNOS-Overexpressing Hearts

Carsten Wunderlich, Ulrich Flögel, Axel Gödecke, Jacqueline Heger, Jürgen Schrader

From the Institute for Cardiovascular Physiology, Heinrich-Heine-University, Düsseldorf, Germany.

Correspondence to Jürgen Schrader, MD, Institut für Herz-und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany. E-mail schrader{at}uni-duesseldorf.de

Elevated cardiac levels of nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) have been implicated in the development of heart failure. The surprisingly benign phenotype of recently generated mice with cardiac-specific iNOS overexpression (TGiNOS) provided the rationale to investigate whether NO scavenging by oxymyoglobin (MbO₂) yielding nitrate and metmyoglobin (metMb) is involved in preservation of myocardial function in TGiNOS mice. ¹H nuclear magnetic resonance (NMR) spectroscopy was used to monitor changes of cardiac myoglobin (Mb) metabolism in isolated hearts of wild-type (WT) and TGiNOS mice. NO formation by iNOS resulted in a significant decrease of the MbO₂ signal and a concomitantly emerging metMb signal in spectra of TGiNOS hearts only (MbO₂: -46.3±38.4 µmol/kg, metMb: +41.4±17.6 µmol/kg, n=6; P<0.05) leaving contractility and energetics unaffected. Inhibition of the Mb-mediated NO degradation by carbon monoxide (20%) led to a deterioration of myocardial contractility in TGiNOS hearts (left ventricular developed pressure: 78.2±8.2% versus 96.7±4.6% of baseline, n=6; P<0.005), which was associated with a profound pertubation of cardiac energy state as assessed by ³¹P NMR spectroscopy (eg, phosphocreatine: 13.3±1.3 mmol/L (TGiNOS) versus 15.9±0.7 mmol/L (WT), n=6; P<0.005). These alterations could be fully antagonized by the NOS inhibitor S-ethylisothiourea. Our findings demonstrate that myoglobin serves as an important cytoplasmic buffer of iNOS-derived NO, which determines the functional consequences of iNOS overexpression.

Key Words: inducible nitric oxide synthase • myoglobin • cardiac contractility and energetics • magnetic resonance spectroscopy

This article has been cited by other articles:

				G. C. Brown and V. Borutaite Nitric oxide and mitochondrial respiration in the heart Cardiovasc Res, July 15, 2007; 75(2): 283 - 290. [Abstract] [Full Text] [PDF]

				J. W. Elrod, J. J.M. Greer, N. S. Bryan, W. Langston, J. F. Szot, H. Gebregzlabher, S. Janssens, M. Feelisch, and D. J. Lefer Cardiomyocyte-Specific Overexpression of NO Synthase-3 Protects Against Myocardial Ischemia-Reperfusion Injury Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1517 - 1523. [Abstract] [Full Text] [PDF]

				J. Fraser, L. Vieira de Mello, D. Ward, H. H. Rees, D. R. Williams, Y. Fang, A. Brass, A. Y. Gracey, and A. R. Cossins From The Cover: Hypoxia-inducible myoglobin expression in nonmuscle tissues PNAS, February 21, 2006; 103(8): 2977 - 2981. [Abstract] [Full Text] [PDF]

				A. Godecke On the impact of NO-globin interactions in the cardiovascular system Cardiovasc Res, February 1, 2006; 69(2): 309 - 317. [Abstract] [Full Text] [PDF]

				H. Kitagawa, T. Yamazaki, T. Akiyama, M. Sugimachi, K. Sunagawa, and H. Mori Microdialysis separately monitors myocardial interstitial myoglobin during ischemia and reperfusion Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H924 - H930. [Abstract] [Full Text] [PDF]

				G. W. Booz Putting the Brakes on Cardiac Hypertrophy: Exploiting the NO-cGMP Counter-Regulatory System Hypertension, March 1, 2005; 45(3): 341 - 346. [Abstract] [Full Text] [PDF]

				S. P. Jones, J. J. M. Greer, P. D. Ware, J. Yang, K. Walsh, and D. J. Lefer Deficiency of iNOS does not attenuate severe congestive heart failure in mice Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H365 - H370. [Abstract] [Full Text] [PDF]

				A. Godecke and J. Schrader The Janus Faces of NO? Circ. Res., April 2, 2004; 94(6): e55 - e55. [Full Text] [PDF]

				E. Tiravanti, A. Samouilov, and J. L. Zweier Nitrosyl-Heme Complexes Are Formed in the Ischemic Heart: EVIDENCE OF NITRITE-DERIVED NITRIC OXIDE FORMATION, STORAGE, AND SIGNALING IN POST-ISCHEMIC TISSUES J. Biol. Chem., March 19, 2004; 279(12): 11065 - 11073. [Abstract] [Full Text] [PDF]

				W. Li, T. Jue, J. Edwards, X. Wang, and T. H. Hintze Changes in NO bioavailabilty regulate cardiac O2 consumption: control by intramitochondrial SOD2 and intracellular myoglobin Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H47 - H54. [Abstract] [Full Text] [PDF]

				I. N. Mungrue, D. J. Stewart, and M. Husain The Janus Faces of iNOS Circ. Res., October 3, 2003; 93 (7): e74 - e74. [Full Text] [PDF]

				P.B. Massion, O. Feron, C. Dessy, and J.-L. Balligand Nitric Oxide and Cardiac Function: Ten Years After, and Continuing Circ. Res., September 5, 2003; 93(5): 388 - 398. [Abstract] [Full Text] [PDF]