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

Academic Article


  • 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.
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    Author List

  • Khan SA; Skaf MW; Harrison RW; Lee K; Minhas KM; Kumar A; Fradley M; Shoukas AA; Berkowitz DE; Hare JM
  • Start Page

  • 1322
  • End Page

  • 1329
  • Volume

  • 92
  • Issue

  • 12