© 1995 American Heart Association, Inc.
Articles |
Induction of Nitric Oxide Synthase Activity by Cytokines in Ventricular Myocytes Is Necessary but Not Sufficient to Decrease Contractile Responsiveness to ß-Adrenergic Agonists
From the Cardiovascular Division, Department of Medicine, and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, and the Respiratory Physiology Program, Harvard School of Public Health (L.K.), Boston, Mass; the Department of Medicine, Johns Hopkins University, Baltimore, Md (C.J.L.); and the Department of Pathology, University of Michigan Medical School, Ann Arbor (S.L.K.).
Correspondence to Ralph A. Kelly, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
Abstract Recent evidence has documented that increased
activity of an inducible nitric oxide synthase (iNOS; type 2 NO
synthase) in primary isolates of adult rat ventricular
myocytes after exposure to soluble mediators in medium conditioned by
lipopolysaccharide-activated macrophages is
associated with a decrease in their contractile responsiveness to
ß-adrenergic agonists. It remained unclear which specific
inflammatory cytokines in this medium contribute to the
induction of iNOS activity in myocytes and whether induction of iNOS
would result in an obligatory decline in contractile function.
Interleukin (IL)-1ß and tumor necrosis factor-
(TNF-) were both
present in the lipopolysaccharide-activated
macrophage-conditioned medium. However, only IL-1 receptor
antagonist and not an anti–rat TNF- antiserum
diminished the extent of iNOS induction in myocytes exposed to this
medium and prevented a decline in contractile responsiveness to
isoproterenol. When recombinant cytokines were used, IL-1ß,
TNF-, and IFN-
each induced iNOS activity in cardiac myocytes at
24 hours. However, only the combination of IL-1ß and IFN-
reproducibly caused contractile dysfunction in cardiac myocytes. Among
the constituents of the defined medium routinely used for
maintenance of adult rat ventricular myocytes in
primary culture, it was noted that insulin (10-7 mol/L)
was required for NO production, as detected by nitrite release
in cytokine-pretreated myocytes, although insulin had no effect
on the extent of induction of iNOS mRNA or maximal enzyme activity in
myocyte cell lysates. Insulin was also required for the decrease in
contractile responsiveness to isoproterenol to be manifest. Thus,
induction of iNOS is necessary but not sufficient to cause inflammatory
cytokine-induced contractile dysfunction in cardiac
myocytes.
Key Words: interleukin-1 • interferon- • insulin • IL-1 receptor antagonist • tumor necrosis factor-
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