Review ArticleNitric oxide and excitation–contraction coupling
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)
- et al.
Nitric oxide synthase activities in human myocardium
Lancet
(1993) - et al.
Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes
J Biol Chem
(1995) - et al.
Cytokine-inducible nitric-oxide synthase (iNOS) expression in cardiac myocytes: characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro
J Biol Chem
(1994) - et al.
Nitrosylation. The prototypic redox-based signaling mechanism
Cell
(2001) - et al.
Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide
Free Rad Biol M
(1998) - et al.
Superoxide modulates the oxidation and nitrosation of thiols by nitric oxide-derived reactive intermediates
J Biol Chem
(1997) - et al.
The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions
Cell
(2000) - et al.
Role of nitric oxide in the regulation of myocardial function
Prog Cardiovasc Dis
(1995) - et al.
Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes
J Biol Chem
(1997) - et al.
The endothelial nitric-oxide synthase–caveolin regulatory cycle
J Biol Chem
(1998)