Key result
In cultured adult rat cardiac fibroblasts, IL-1beta and NO production decrease cAMP accumulation largely through cGMP-mediated activation of PDE2, attenuating the response to isoproterenol by ~50%.
This study demonstrates that in cardiac fibroblasts, NO decreases cAMP accumulation primarily via cGMP-mediated activation of PDE2, rather than direct inhibition of adenylyl cyclase.
PDE2 may attenuate beta-adrenergic responses in inflamed cardiac fibroblasts; leaves open translational relevance to human remodeling.
Treatment of cultured adult rat cardiac fibroblasts with interleukin-1beta (IL-1beta) 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 N(G)-monomethyl-L-arginine, an NOS inhibitor. Effects of NO are not restricted to the beta-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-1beta 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-1beta-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.
No takes yet. Share an insight, caveat, or question.
Gustafsson et al. (2002) studied this question. IL-1beta and NO donors was evaluated on cAMP accumulation. In cultured adult rat cardiac fibroblasts, IL-1beta and NO production decrease cAMP accumulation largely through cGMP-mediated activation of PDE2, attenuating the response to isoproterenol by ~50%.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: