Circulation Research. 2003
Published online before print May 22, 2003, doi: 10.1161/01.RES.0000078171.52542.9E
Published online before print May 22, 2003, doi: 10.1161/01.RES.0000078171.52542.9E
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Submitted on June 10, 2002
Revised on May 9, 2003
Accepted on May 9, 2003
Nitric Oxide Regulation of Myocardial Contractility and Calcium Cycling. Independent Impact of Neuronal and Endothelial Nitric Oxide Synthases
Shakil A. Khan ;
From the Departments of Medicine-Cardiology Division (S.A.K., M.W.S., R.W.H., K.M.M., A.K., M.F., J.M.H.), Biomedical Engineering (K.L., A.A.S., D.E.B.), and Anesthesiology and Critical Care Medicine (D.E.B.), The Johns Hopkins Medical Institution, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: jhare{at}mail.jhmi.edu.
The mechanisms by which nitric oxide (NO) influences myocardial Ca2+ cycling remain controversial. Because NO synthases (NOS) have specific spatial localization in cardiac myocytes, we hypothesized that neuronal NOS (NOS1) found in cardiac sarcoplasmic reticulum (SR) preferentially regulates SR Ca2+ release and reuptake resulting in potentiation of the cardiac force-frequency response (FFR). Transesophageal pacing (660 to 840 bpm) in intact C57Bl/6 mice (WT) stimulated both contractility (dP/dtmax normalized to end-diastolic volume; dP/dt-EDV) by 51±5% (P<0.001) and lusitropy (tau; 
) by 20.3±2.0% (P<0.05). These responses were markedly attenuated in mice lacking NOS1 (NOS1-/-) (15±2% increase in dP/dt-EDV; P<0.001 versus WT; and no change in ; P<0.01 versus WT). Isolated myocytes from NOS1-/- (
2 months of age) also exhibited suppressed frequency-dependent sarcomere shortening and Ca2+ transients ([Ca2+]i) compared with WT. SR Ca2+ stores, a primary determinant of the FFR, increased at higher frequencies in WT (caffeine-induced [Ca2+]i at 4 Hz increased 107±23% above 1 Hz response) but not in NOS1-/- (13±26%; P<0.01 versus WT). In contrast, mice lacking NOS3 (NOS3-/-) had preserved FFR in vivo, as well as in isolated myocytes with parallel increases in sarcomere shortening, [Ca2+]i, and SR Ca2+ stores. NOS1-/- had increased SR Ca2+ ATPase and decreased phospholamban protein abundance, suggesting compensatory increases in SR reuptake mechanisms. Together these data demonstrate that NOS1 selectively regulates the cardiac FFR via influences over SR Ca2+ cycling. Thus, there is NOS isoform-specific regulation of different facets of rate-dependent excitation-contraction coupling; inactivation of NOS1 has the potential to contribute to the pathophysiology of states characterized by diminished frequency-dependent inotropic responses.
Key words: nitric oxide • force-frequency response • phospholamban • SERCA2a • sarcoplasmic reticulum • excitation-contraction coupling
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