Nitric oxide regulation of myocardial contractility and calcium cycling: Independent impact of neuronal and endothelial nitric oxide synthases

Shakil A. Khan, Michel W. Skaf, Robert W. Harrison, Kwangho Lee, Khalid M. Minhas, Anil Kumar, Mike Fradley, Artin A. Shoukas, Dan E. Berkowitz, Joshua M. Hare

Research output: Contribution to journalArticle

Abstract

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 C57B1/6 mice (WT) stimulated both contractility (dP/dtmax normalized to end-diastolic volume; dP/dt-EDV) by 51±5% (P<0.001) and lusitropy (tau; τ) 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 τ; 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.

Original languageEnglish (US)
Pages (from-to)1322-1329
Number of pages8
JournalCirculation research
Volume92
Issue number12
DOIs
StatePublished - Jun 27 2003

Keywords

  • Excitation-contraction coupling
  • Force-frequency response
  • Nitric oxide
  • SERCA2a
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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