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Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice
Published on: September 17, 2015
Induction of nitric oxide synthase activity by cytokines in ventricular myocytes is necessary but not sufficient to
D Ungureanu-Longrois1, J L Balligand, W W Simmons
1Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Circulation Research
|September 1, 1995
Summary
Inflammatory cytokines like IL-1 beta and IFN-gamma induce inducible nitric oxide synthase (iNOS) in heart cells, impairing their function. Insulin is crucial for nitric oxide production in these cells.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Increased inducible nitric oxide synthase (iNOS) activity in adult rat ventricular myocytes is linked to reduced contractile responsiveness.
- The specific inflammatory cytokines driving iNOS induction and subsequent contractile dysfunction in myocytes were not fully understood.
Purpose of the Study:
- To identify the specific inflammatory cytokines responsible for iNOS induction in myocytes.
- To determine if iNOS induction inevitably leads to impaired cardiac myocyte contractile function.
- To investigate the role of insulin in nitric oxide production and iNOS activity in myocytes.
Main Methods:
- Exposure of adult rat ventricular myocytes to conditioned medium from lipopolysaccharide-activated macrophages.
- Utilized IL-1 receptor antagonist and anti-rat TNF-alpha antiserum to block specific cytokines.
- Administered recombinant cytokines (IL-1 beta, TNF-alpha, IFN-gamma) and insulin to myocyte cultures.
- Assessed iNOS activity, iNOS mRNA levels, enzyme activity, nitrite release, and contractile responsiveness to isoproterenol.
Main Results:
- Interleukin-1 beta (IL-1 beta), in combination with Interferon-gamma (IFN-gamma), reproducibly caused contractile dysfunction in cardiac myocytes.
- IL-1 beta was identified as a key cytokine driving iNOS induction and contractile decline, while TNF-alpha played a lesser role.
- Insulin was essential for nitric oxide (NO) production via nitrite release in cytokine-treated myocytes, but did not affect iNOS mRNA or enzyme activity.
Conclusions:
- IL-1 beta and IFN-gamma are critical inducers of iNOS activity and subsequent contractile dysfunction in cardiac myocytes.
- Insulin is a necessary cofactor for NO production in cytokine-stimulated myocytes, independent of iNOS induction levels.
- These findings elucidate specific inflammatory pathways affecting cardiac myocyte function and highlight the role of insulin in NO signaling.
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