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(Circulation Research. 1999;85:870-871.)
© 1999 American Heart Association, Inc.

Editorials

Parsing the Effects of Nitric Oxide, S-Nitrosothiols, and Peroxynitrite on Inducible Nitric Oxide Synthase–Dependent Cardiac Myocyte Apoptosis

Joseph S. Beckman

From the Department of Anesthesiology, University of Alabama at Birmingham.

Correspondence to Joseph S. Beckman, PhD, Department of Anesthesiology, THT 958, University of Alabama at Birmingham, 1900 University Blvd, Birmingham, AL 35233. E-mail Joe.Beckman@ccc.uab.edu

Key Words: peroxynitrite • nitric oxide • nitrosothiol

	Introduction

 
The actions of nitric oxide (NO) mediating vasorelaxation through activating guanylate cyclase to produce cGMP are now well-established, as recognized by the award of the Nobel prize in 1998. However, the production of NO is also implicated in a much broader range of physiological and pathological actions that are independent of cGMP. Cytokines in particular are known to greatly stimulate NO production as part of the nonspecific immune system and may play a significant role in heart disease. Cytokines are known to induce expression of the inducible nitric oxide synthase (iNOS) in cardiac myocytes, which contributes in part to myocyte contractile dysfunction.

In this issue of Circulation Research, Arstall et al¹ demonstrate that iNOS upregulation by interleukin-1ß and interferon- increases apoptosis in cultured myocytes by a process that was independent of guanylate cyclase activation and cGMP. Cell death was blocked by both selective and general iNOS inhibitors, clearly implicating the production of NO in cell death. However, concentrations of an NO donor added in similar concentrations to the amount of endogenous nitrite produced by myocytes after cytokine treatment did not stimulate cell death, suggesting that NO itself was not cytotoxic.

The chemical reactivity and toxicity of NO can be greatly increased by its diffusion-limited reaction with superoxide (O₂^.-) to form peroxynitrite (ONOO^-). A role for ONOO^- was implicated in myocyte apoptosis by Arstall et al¹ by showing that the O₂^.-and ONOO^- scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP) protected myocytes from cytokine-induced apoptosis. Myocytes were also shown . . . [Full Text of this Article]

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