Attenuation of cAMP accumulation in adult rat cardiac fibroblasts by IL-1 and NO: role of cGMP-stimulated PDE2

Gustafsson, Åsa B., and Laurence L. Brunton. Attenuation of cAMP accumulation in adult rat cardiac fibroblasts by IL-1 and NO: role of cGMP-stimulated PDE2. Am J Physiol Cell Physiol 283: C463–C471, 2002; 10.1152/ajpcell. 00299.2001.—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 nitroprussidetreated 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.