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Vol. 58, Issue 6, 1470-1478, December 2000
-Adrenergic Stimulation of Rat Cardiac Fibroblasts Enhances
Induction of Nitric-Oxide Synthase by Interleukin-1 via Message
Stabilization
Biomedical Sciences Graduate Program (Å.B.G.), Departments of
Pharmacology and Medicine (L.L.B.), University of California at San
Diego, La Jolla, California
We have investigated factors modulating expression of inducible NO
synthase (iNOS) in isolated adult rat cardiac fibroblasts. Treatment of
cardiac fibroblasts with interleukin-1
(IL-1) promotes induction
of iNOS mRNA and protein and production of NO. Simultaneous incubation
of cells with isoproterenol enhances the response to IL-1, even
though isoproterenol alone is without effect.
NG-nitro-L-arginine methyl ester
inhibits the effect of isoproterenol + IL-1 on NO production.
2-Adrenergic receptors appear to mediate this effect of
isoproterenol. Reverse transcriptase-polymerase chain reaction
analyses show that 2-receptor mRNA is the predominant -receptor message; in pharmacologic studies, ICI-118,551
significantly antagonizes isoproterenol-stimulated cyclic AMP
production whereas CGP20712A does not. Dibutyryl-cyclic AMP and
forskolin mimic the synergistic effect of isoproterenol on
IL-1-induced NO production; H-89, a cyclic AMP-dependent protein
kinase (PKA) inhibitor, antagonizes the enhancing effect of
isoproterenol. Nuclear run-off experiments indicate that enhancement of
iNOS by isoproterenol does not occur at the level of transcription.
Message stability studies demonstrate that isoproterenol increases the
half-life of iNOS mRNA from 1.0 to 1.9 h; this change is
sufficient to account for the observed augmentation of iNOS mRNA and
protein. Thus, cardiac fibroblasts produce significant amounts of NO in
response to IL-1 via induction of iNOS; -adrenergic stimulation
enhances the IL-1 effect by stabilizing the iNOS message. These data
suggest that cardiac fibroblasts could participate in a paracrine
mechanism whereby the direct positive inotropic effect of
1-adrenergic stimulation of myocytes is opposed by
2-adrenergic enhancement of NO production, a negative
inotropic event, in neighboring fibroblasts.
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