Review Article
Nitric oxide and excitation–contraction coupling

https://doi.org/10.1016/S0022-2828(03)00143-3Get rights and content

Abstract

Excitation–contraction (EC) coupling is driven by an ion-channel-mediated calcium cycle that produces myofilament contraction and relaxation. Even though nitric oxide synthases (NOS) were definitively described within the heart a decade ago, the role that nitric oxide (NO) plays in cardiac regulation remains highly controversial. There is a growing consensus, however, that NO modulates the activity of several key calcium channels involved in EC coupling as well as mitochondrial respiratory complexes. To accomplish this regulation, different NOS isoforms are spatially confined in distinct cellular microdomains involved in EC coupling. Specifically, NOS1 localizes to the sarcoplasmic reticulum (SR) in proximity to the ryanodine receptor (RYR) and the SR Ca2+ ATPase (SERCA2a), and NOS3 is found in sarcolemmal caveolae compartmentalized with cell-surface receptors and the L-type Ca2+ channel. NO also participates in mitochondrial respiration, the process that fuels EC coupling, and either NOS1 or 3 resides within cardiac mitochondria. Here, we review the biochemical and cellular mechanisms whereby NO influences EC coupling. There is accumulating evidence that NO participates in all aspects of EC coupling, including receptor signal transduction, L-type Ca2+-channel activity, SR calcium release through the RYR, and mitochondrial respiration.

Section snippets

Introduction: ion channels involved in cardiac calcium cycling

Cardiac myocyte contraction is initiated by membrane depolarization, which leads to trans-sarcolemmal Ca2+ entry through the L-type Ca2+ channel [1]. This Ca2+ entry stimulates a larger Ca2+ release from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RYR), which activates myofilament contraction (systole), a process termed Ca2+-induced Ca2+ release [1], [2]. Myocyte relaxation (diastole) requires Ca2+ removal from the cytoplasm, which is mediated by the SR Ca2+ ATPase (SERCA2a)

NO signaling: biochemical mechanisms

Three NOS enzymes are described in mammalian systems, all of which oxidize the terminal guanidino nitrogen of L-arginine to form NO and the amino acid L-citrulline [6]. These isoforms—neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3)—play modulatory roles in essentially all organ systems; including (but not limited to) the nervous, immune, respiratory, urologic, gastrointestinal, and cardiovascular systems. NOS1 and 3 are activated by calcium and

Basal myocardial contractility

NO appears to have a weak effect on basal myocardial contractility. NO donors infused into isolated perfused rat hearts increase peak +dP/dt by 10–15% [26], [44]. Similar results are reported in isolated cardiac myoyctes [25]. Further consistent with NO supporting resting myocardial contraction, infusion of NOS inhibitors to animals [32] or humans [69] depresses peak +dP/dt. NO support of resting contractility appears to be cGMP independent, and likely involves nitrosylation of one or more ion

Induction of NOS2

NO has been implicated as contributing to myocardial dysfunction in the failing heart [31], [98]. A leading theory is that inflammation [99], [100] and/or cytokine activation [101], [102], [103] cause induction of NOS2, a high-output isoform [104]. NOS2, not normally present in myocardium, has been detected by immunohistochemistry, western blotting, polymerase chain reaction [105], and arginine-to-citrulline conversion assays [8], [106] in myocardium from patients with HF due to

Conclusion

It has been extremely difficult and controversial to dissect the specific effects of NO on the heart. Many dilemmas about NO cardiac signaling may be clarified through the viewpoint that NO signals in tightly controlled cellular microdomains, a contention supported by the presence of NOSs in appropriate organelles and demonstration that various NOSs uniquely influences cardiac EC coupling. Although, the multidirectional effects of NO on cardiac function initially obscured elucidation of NO

Acknowledgements

This work was supported by NIH grants RO1 HL-65455 and a Paul Beeson Physician Faculty Scholars in Aging Research Award.

References (116)

  • A.M. Shah et al.

    Effects of 8-bromo-cyclic GMP on contraction and on inotropic response of ferret cardiac muscle

    J Mol Cell Cardiol

    (1991)
  • J.E. Brenman et al.

    Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains

    Cell

    (1996)
  • F. Silvagno et al.

    Neuronal nitric-oxide synthase-μ, an alternatively spliced isoform expressed in differentiated skeletal muscle

    J Biol Chem

    (1996)
  • P.-F. Mery et al.

    Nitric oxide regulates cardiac Ca2+ current. Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activity

    J Biol Chem

    (1993)
  • O. Feron et al.

    Modulation of endothelial nitric-oxide synthase–caveolin interaction in cardiac myocytes

    J Biol Chem

    (1998)
  • T.E. Bates et al.

    Mitochondrial nitric oxide synthase: a ubiquitous regulator of oxidative phosphorylation?

    Biochem Biophys Res Comm

    (1996)
  • A. Wawrzynow et al.

    Chemical modification of the Ca(2+)-ATPase of rabbit skeletal muscle sarcoplasmic reticulum: identification of sites labeled with aryl isothiocyanates and thiol-directed conformational probes

    Biochim Biophys Acta

    (1993)
  • D.M. Bers

    Cardiac excitation-contraction coupling

    Nature

    (2002)
  • D.M. Bers

    Calcium and cardiac rhythms: physiological and pathophysiological

    Circ Res

    (2002)
  • I.A. Hobai et al.

    Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation–contraction coupling in canine heart failure

    Circulation

    (2001)
  • I.A. Hobai et al.

    Enhanced Ca(2+)-activated Na(+)–Ca(2+) exchange activity in canine pacing-induced heart failure

    Circ Res

    (2000)
  • K. Schuh et al.

    The plasmamembrane calmodulin-dependent calcium pump: a major regulator of nitric oxide synthase I

    J Cell Biol

    (2001)
  • T. Michel et al.

    Nitric oxide synthases: which, where, how and why?

    J Clin Invest

    (1997)
  • K.Y. Xu et al.

    NO synthase in cardiac sarcoplasmic reticulum

    Proc Natl Acad Sci USA

    (1999)
  • H. Senzaki et al.

    Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure

    FASEB J

    (2001)
  • J. Layland et al.

    Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes

    J Physiol

    (2002)
  • D.L. Campbell et al.

    Redox modulation of L-type calcium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols

    J Gen Physiol

    (1996)
  • J. Sun et al.

    Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO

    Proc Natl Acad Sci USA

    (2001)
  • J.S. Scharfstein et al.

    In vivo transfer of nitric oxide between a plasma protein-bound reservoir and low molecular weight thiols

    J Clin Invest

    (1994)
  • J.S. Stamler et al.

    Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin

    Proc Natl Acad Sci USA

    (1992)
  • D.I. Simon et al.

    Polynitrosylated proteins: characterization, bioactivity, and functional consequences

    Proc Natl Acad Sci USA

    (1996)
  • L. Xu et al.

    Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation

    Science

    (1998)
  • J. Sun et al.

    Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO

    Proc Natl Acad Sci USA

    (2001)
  • L. Liu et al.

    A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans

    Nature

    (2001)
  • J.M. Chesnais et al.

    Positive and negative inotropic effects of NO donors in atrial and ventricular fibres of the frog heart

    J Physiol

    (1999)
  • N. Paolocci et al.

    cGMP-independent inotropic effect of nitric oxide and peroxynitirite donors: potential role for S-nitrosylation

    Am J Physiol

    (2000)
  • G. Muller-Strahl et al.

    Inhibition of nitric oxide synthase augments the positive inotropic effect of nitric oxide donors in the rat heart

    J Physiol

    (2000)
  • B. Preckel et al.

    Inotropic effects of glyceryl trinitrate and spontaneous NO donors in the dog heart

    Circulation

    (1997)
  • J.M. Hare et al.

    NOS: modulator, not mediator of cardiac performance

    Nat M

    (1999)
  • J.M. Hare et al.

    Nitric oxide inhibits the contractile response to β-adrenergic stimulation in humans with left ventricular dysfunction

    Circulation

    (1995)
  • J.M. Hare et al.

    Contribution of caveolin protein abundance to augmented nitric oxide signaling in conscious dogs with pacing-induced heart failure

    Circ Res

    (2000)
  • A.M. Shah et al.

    8-Bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes

    Circ Res

    (1994)
  • S.J. Zieman et al.

    Upregulation of the nitric oxide-cGMP pathway in aged myocardium: physiological response to L-arginine

    Circ Res

    (2001)
  • F.A. Recchia et al.

    Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog

    Circ Res

    (1998)
  • W.F. Saavedra et al.

    Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart

    Circ Res

    (2002)
  • E. Clementi et al.

    Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione

    Proc Natl Acad Sci USA

    (1998)
  • P.L. Huang et al.

    Hypertension in mice lacking the gene for endothelial nitric oxide synthase

    Nature

    (1995)
  • R. Gyurko et al.

    Modulation of mouse cardiac function in vivo by eNOS and ANP

    Am J Physiol Heart Circ Physiol

    (2000)
  • P. Varghese et al.

    Beta(3)-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility

    J Clin Invest

    (2000)
  • J.F. Keaney et al.

    Inhibition of nitric oxide synthase potentiates the positive inotropic response to β-adrenergic stimulation in normal dogs

    Am J Physiol

    (1996)
  • Cited by (0)

    View full text