Expression of inducible nitric oxide synthase depresses β-adrenergic-stimulated calcium release from the sarcoplasmic reticulum in intact ventricular myocytes

Mark T. Ziolo, Hideki Katoh, Donald M Bers

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)2961-2966
Number of pages6
JournalCirculation
Volume104
Issue number24
StatePublished - Dec 11 2001
Externally publishedYes

Keywords

  • Calcium
  • Heart failure
  • Nitric oxide
  • Receptors, adrenergic, beta
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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