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and NO: role of cGMP-stimulated PDE2
1 Biomedical Sciences Graduate Program, 2 Departments of Pharmacology and Medicine, University of California at San Diego, La Jolla, California 92093
Treatment of cultured adult rat cardiac
fibroblasts with interleukin-1
(IL-1) induces the inducible
nitric oxide synthase (iNOS) expression, increases nitric oxide (NO)
and cGMP production, and attenuates cAMP accumulation in response to
isoproterenol by ~50%. Reduced cAMP accumulation is due to NO
production: the effect is mimicked by NO donors and prevented by
NG-monomethyl-L-arginine, an NOS
inhibitor. Effects of NO are not restricted to the -adrenergic
response; the response to forskolin is similarly diminished. NO donors
only slightly (12%) decrease forskolin-stimulated adenylyl cyclase
(AC) activity in cardiac fibroblast plasma membranes, suggesting that
the main effect of NO is not a direct one on AC. An inhibitor of
soluble guanylyl cyclase inhibits the effects of IL-1 and NO donors;
inhibition of cGMP-dependent protein kinase is without effect.
3-Isobutyl-1-methylxanthine, a nonspecific phosphodiesterase (PDE)
inhibitor, and erythro-9-(2-hydroxy-3-nonyl)adenine, a specific
inhibitor of the cGMP-stimulated PDE (PDE2), completely restore cAMP
accumulation in sodium nitroprusside-treated fibroblasts and largely
reverse the attenuated response in IL-1-treated fibroblasts. Although NO reportedly acts by reducing AC activity in some cells, in
cardiac fibroblasts NO production decreases cAMP accumulation largely
by the cGMP-mediated activation of PDE2.
nitric oxide; interleukin-1; phosphodiesterase 2; guanosine
3',5'-cyclic monophosphate; soluble guanylyl cyclase
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