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-/-) (15±2% increase in dP/dt-EDV; P-/- (≈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-/-) 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

Fingerprint

Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type III
Sarcoplasmic Reticulum
Nitric Oxide
Calcium
Nitric Oxide Synthase
Sarcomeres
Excitation Contraction Coupling
Calcium-Transporting ATPases
Caffeine
Cardiac Myocytes
Muscle Cells
Protein Isoforms

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Nitric oxide regulation of myocardial contractility and calcium cycling : Independent impact of neuronal and endothelial nitric oxide synthases. / Khan, Shakil A.; Skaf, Michel W.; Harrison, Robert W.; Lee, Kwangho; Minhas, Khalid M.; Kumar, Anil; Fradley, Mike; Shoukas, Artin A; Berkowitz, Dan E; Hare, Joshua M.

In: Circulation Research, Vol. 92, No. 12, 27.06.2003, p. 1322-1329.

Research output: Contribution to journalArticle

Khan, Shakil A. ; Skaf, Michel W. ; Harrison, Robert W. ; Lee, Kwangho ; Minhas, Khalid M. ; Kumar, Anil ; Fradley, Mike ; Shoukas, Artin A ; Berkowitz, Dan E ; Hare, Joshua M. / Nitric oxide regulation of myocardial contractility and calcium cycling : Independent impact of neuronal and endothelial nitric oxide synthases. In: Circulation Research. 2003 ; Vol. 92, No. 12. pp. 1322-1329.
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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-/-) (15±2{\%} increase in dP/dt-EDV; P-/- (≈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-/-) 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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AU - Lee, Kwangho

AU - Minhas, Khalid M.

AU - Kumar, Anil

AU - Fradley, Mike

AU - Shoukas, Artin A

AU - Berkowitz, Dan E

AU - Hare, Joshua M.

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