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(Circulation. 2001;104:2961.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Expression of Inducible Nitric Oxide Synthase Depresses ß-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes

Mark T. Ziolo, PhD; Hideki Katoh, MD; Donald M. Bers, PhD

From the Department of Physiology, Loyola University Medical Center, Maywood, Ill. Dr Katoh is now at Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Correspondence to Donald M. Bers, Department of Physiology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Background— ß-Adrenergic hyporesponsiveness in many cardiomyopathies is linked to expression of inducible nitric oxide synthase (iNOS) and increased production of NO. The purpose of this study was to examine whether iNOS expression alters the function of the sarcoplasmic reticulum (SR) Ca²⁺ release channel (ryanodine receptor, RyR) during ß-adrenergic stimulation.

Methods and Results— Expression of iNOS was induced by lipopolysaccharide (LPS) injection (10 mg/kg) 6 hours before rat myocyte isolation. Confocal microscopy (fluo-3) was used to measure Ca²⁺ spark frequency (CaSpF, reflecting resting RyR openings) and Ca²⁺ transients. CaSpF was greatly increased by the adenylate cyclase activator forskolin (100 nmol/L) in normal myocytes (iNOS not expressed), but this effect was suppressed (by 77%) in LPS myocytes (iNOS expressed). When NO production by iNOS was inhibited by aminoguanidine (1 mmol/L), there was a further increase in the forskolin-induced CaSpF in LPS myocytes (to levels similar to the forskolin-stimulated CaSpF in normal myocytes). This effect was also seen in myocytes isolated from a failing human heart. There was no effect of aminoguanidine on forskolin-stimulated CaSpF in normal myocytes. ODQ (10 µmol/L), an inhibitor of NO stimulation of guanylate cyclase, did not restore the forskolin-induced rise in CaSpF in LPS myocytes. Aminoguanidine also increased twitch Ca²⁺ transient amplitude in LPS myocytes after forskolin application (independent of changes in SR Ca²⁺ load).

Conclusions— iNOS/NO depresses ß-adrenergic–stimulated RyR function through a cGMP-independent pathway (eg, NO- and/or peroxynitrite-dependent redox modification). This mechanism limits ß-adrenergic responsiveness and may be an important signaling pathway in cardiomyopathies, including human heart failure.

Key Words: receptors, adrenergic, beta • nitric oxide • sarcoplasmic reticulum • calcium • heart failure

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