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February 1, 1995Journal of Clinical InvestigationOpen Access

The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta.

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Key result

Cytokine-induced nitric oxide production caused significant cardiac myocyte death, which was completely prevented by the nitric oxide synthase inhibitor L-NMMA or transforming growth factor-beta.

Why the study?

Does NO synthase antagonism or TGF-beta prevent cytokine-induced NO-mediated cytotoxicity in adult rat cardiac myocytes?

Population

Adult rat cardiac myocytes exposed to either cytokines alone or to activated J774 macrophages in coculture

Comparison

Competitive NO synthase inhibitor L-NMMA or… vs Cytokine treatment or activated macrophages…

Design

Preclinical

Authors

DPDavid J. PinskyScripps Research InstituteBCBolin CaiSouth China Agricultural UniversityXYXiaochun YangNortheastern University

Discussion

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Implication

Rat myocyte findings do not support clinical use; leaves open whether NO synthase inhibition or TGF-beta benefits human cardiomyopathies.

Key Points

  • To evaluate the impact of inducible nitric oxide synthase on cardiac myocyte cytotoxicity induced by cytokines.
  • Exposed adult rat cardiac myocytes to cytokines and cocultured with activated J774 macrophages.
  • Assessed iNOS expression, NO synthesis, and myocyte death through nitrite production and CPK release.
  • Examined the effects of TGF-beta on iNOS expression and NO-mediated cytotoxicity.
  • Cytokine treatment increased myocyte death, indicated by elevated CPK levels and loss of membrane integrity.
  • L-NMMA treatment significantly reduced nitrite production and cytotoxicity in treated cultures.
  • TGF-beta treatment decreased iNOS expression and NO-mediated cytotoxicity in cardiac myocytes.

Structured PICO

Does NO synthase antagonism or TGF-beta prevent cytokine-induced NO-mediated cytotoxicity in adult rat cardiac myocytes?

P
Population
Adult rat cardiac myocytes exposed to either cytokines alone (TNF-alpha, IL-1 beta, and IFN gamma) or to activated J774 macrophages in coculture
I
Intervention
Competitive NO synthase inhibitor L-NMMA or transforming growth-factor beta (TGF-beta)
C
Comparator
Cytokine treatment or activated macrophages alone without inhibitors
O
Outcome
Cardiac myocyte cytotoxicity (measured by CPK release and trypan blue staining) and NO synthesis (nitrite production)surrogate

Main Result

Absolute Event Rate: 59% vs 38%

p-value: p=<0.05

Cytokine-induced nitric oxide production causes cardiac myocyte cytotoxicity, which can be blocked by NO synthase antagonism or TGF-beta, suggesting a potential therapeutic target for cardiomyopathies.

Limitations

  • In vitro experimental model using isolated rat myocytes and murine macrophages, which may not fully replicate in vivo human pathophysiology
  • The exact physiological role and multiple potential mechanisms of iNOS toxicity within cardiac myocytes remain to be fully identified

Cite This Study

Pinsky et al. (1995) studied Cytokine-induced nitric oxide toxicity in cardiac myocytes. L-NMMA or Transforming Growth Factor-beta (TGF-β) vs. Cytokines alone (IFN-γ, TNF-α, IL-1β) or unstimulated controls was evaluated on Myocyte death at 24 hours (percentage of dead cells) (p=<0.05). Cytokine-induced nitric oxide production caused significant cardiac myocyte death, which was completely prevented by the nitric oxide synthase inhibitor L-NMMA or transforming growth factor-beta.

synapsesocial.com/papers/6a0f8e792badbc352afe5682https://doi.org/10.1172/jci117713
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Also Consider

Synapse has enriched 4 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Cytokine gene transcription in vascularised organ grafts: analysis using semiquantitative polymerase chain reaction.1991 · 264 citations
  2. 2Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells.1989 · 1,760 citations
  3. 3Cellular Components of Allograft Rejection: Identity, Specificity, and Cytotoxic Function of Cells Infiltrating Acutely Rejecting Allografts1977 · 109 citations
  4. 4Role of basal release of nitric oxide on coronary flow and mechanical performance of the isolated rat heart.1992 · 77 citations