© 1995 by European Society of Cardiology
Copyright © 1995, European Society of Cardiology
Nitric oxide synthesis in cardiac myocytes and fibroblasts by inflammatory cytokines
aDepartment of Cardiology Jichi Medical School, Minamikawachi, Tochigi 329-04, Japan
bDepartment of Internal Medicine, First Division, Kobe University School of Medicine, Kobe, Japan
* Correspondence to Dr Ikeda.
Objective: The aim was to investigate nitric oxide (NO) synthase activity in cultured neonatal rat cardiac myocytes and fibroblasts upon treatment with inflammatory cytokines interleukin 1β (IL-1β), tumour necrosis factor a (TNF-
), IL-2, IL-6, IL-8, transforming growth factor β (TGF-β) and gram negative bacterial lipopolysaccharide (LPS). Methods: NO and guanosine 3',5'-cyclic monophosphate (cGMP) synthesis was measured in cultured neonatal rat cardiac myocytes and fibroblasts, using Griess reagent and an enzyme immunoassay kit, respectively. The expression of inducible NO synthase (iNOS) mRNA and protein was assayed by northern and western blotting, respectively. Results: Incubation of cardiac myocytes for 24 h with IL-1β (10 ng·ml–1) or LPS (1 µg·ml–1) caused significant increases in NO and cGMP production. TNF-, IL-2, IL-6, IL-8, and TGF-β showed no significant effect on their production. IL-1β induced NO and cGMP production in a time and dose dependent manner. IL-β also increased iNOS mRNA and protein accumulation in cardiac myocytes. Simultaneous incubation of IL-1β with NG-monomethyl-L-arginine, genistein, calphostin C, cycloheximide, or actinomycin D completely inhibited the IL-1β induced NO production by cardiac myocytes. TGF-β, dexamethasone, or cyclosporin A also dose dependently inhibited the IL-1β induced NO production. Exposure to IL-1β for 12–24 h decreased the beating rate of cardiac myocytes, but addition of dexamethasone completely overcame this inhibition. In contrast to cardiac myocytes, incubation of cardiac fibroblasts for 24 h with IL-1β or LPS showed no significant effect on NO or cGMP production. Conclusions: These observations suggest that IL-1β/LPS responsive iNOS, which is an important regulator of contractile function of the heart, is present in cardiac myocytes but not in cardiac fibroblasts.
KEYWORDS interleukin 1; lipopolysaccharide; guanosine 3',5'-cyclic monophosphate; nitrite; transforming growth factor β
This study was supported by grants from the Ministry of Education, Culture and Science (No 5670632), and the Molecular Cardiology Study Group (Japan).
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