Cross talk between NO and cyclic-nucleotide phosphodiesterases in the modulation of signal transduction in blood vessel

An increase in cAMP and/or cGMP induces vasodilation:which could be potenti ated by endothelium or NO-donors. Cyclic nucleotide phosphodiesterases (PDE ) are differently distributed in vascular tissues. cAMP hydrolyzing PDE iso zymes in endothelial cells are represented by PDE2 (cGMP stimulated-PDE) an d PDE4 (cGMP insensitive-PDE), whereas in smooth muscle cells PDE3 (cGMP in hibited-PDE) and PDE4 are present. To investigate the role of NO in vasodil ation induced by PDE inhibitors, we studied the effects of PDE3- or PDE4-in hibitor alone and their combination on cyclic nucleotide levels, on relaxat ion of precontracted aorta and on protein kinase implication. Furthermore, the direct effect of dinitrosyl iron complex (DNIC) was studied on purified recombinant PDE4B. The results show that: 1) in endothelial cells PDE4 inh ibition may up-regulate basal production of NO, this effect being potentiat ed by PDE2 inhibition; 2) in smooth muscle cGMP produced by NO inhibits PDE 3 and increases cAMP level allowing PDE4 to participate in vascular contrac tion; 3) protein kinase G mediates the relaxing effects of PDE3 or PDE4 inh ibition. 4) DNIC inhibits, non competitively PDE4B indicating a direct effe ct of NO on PDE4 which could explain an additive vasodilatory effect of NO. A direct and a cGMP related cross-talk between NO and cAMP-PDEs, may parti cipate into the vasomodulation mediated by cAMP activation of protein kinas e G.