ROLE OF PHOSPHODIESTERASE-III AND PHOSPHODIESTERASE-IV IN THE MODULATION OF VASCULAR CYCLIC-AMP CONTENT BY THE NO CYCLIC-GMP PATHWAY

1 The effect on cyclic nucleotide contents of selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) isoforms III and IV (respect ively SK&F 94120 and rolipram) and their interactions with endothelium and NO have been studied in rat aorta in the presence of indomethacin (10 mu M). The participation of NO was assessed by using either N-G-n itro-L-arginine methyl ester (L-NAME) (NO synthase inhibitor: 30 mu M) or 3-morpholinosydnonimine (SIN-1, NO donor: 10 mu M with SOD 100 uni ts ml(-1)). 2 The presence of endothelium significantly increased both adenosine 3':5'-cyclic monophosphate (cyclic AMP, 1.7 fold) and guano sine 3':5'-cyclic monophosphate (cyclic GMP, 2.2 fold) contents. Cycli c GMP was largely affected by L-NAME or SIN-1 treatment, this was riot the case for cyclic AMP suggesting that the presence of endothelium m odified cyclic AMP content in aorta independently of the NO production . 3 In the presence or absence of endothelium, neither SK&F 94120 nor rolipram, alone or combined, significantly modified cyclic GMP content . 4 The PDE III inhibitor significantly affected cyclic AMP content on ly in non treated aorta without endothelium. In contrast, the PDE IV i nhibitor increased cyclic AMP in all conditions. These increases were generally about 2 fold but markedly higher in aorta treated with SIN-1 and superoxide dismutase (SOD, 6 fold). Association of a low concentr ation of the PDE III inhibitor (5 mu M) with the PDE IV inhibitor (30 mu M) potentiated the effect of the PDE IV inhibitor on cyclic AMP con tent, except for aorta without endothelium treated with SIN-1 plus SOD . 5 These data indicate that the presence of the endothelium could inc rease cyclic AMP content independently of NO and prostacyclin (PGI(2)) production. Furthermore, an increase in cyclic GMP content (modulated by NO production) could enhance the cyclic AMP accumulation induced b y the PDE IV inhibitor. This result supports the hypothesis that PDE I II inhibition by endogenous cyclic GMP may potentiate the effect of PD E IV inhibition on cyclic AMP content. Taken together with our previou s studies on relaxation, these results suggest that the NO/cyclic GMP pathway could induce PDE IV-dependent regulation of cyclic AMP via PDE III inhibition.