Nitric oxide cAMP interactions in the control of rat renal vascular resistance

This study aimed to characterize the interaction between nitric oxide (NO)- and cAMP-related pathways in the control of renal blood flow. Using the is olated perfused rat kidney model, we determined the effects of inhibition o f NO formation by N-omega-nitro-L-arginine methyl ester (L-NAME; 1 mmol/L) and of NO administration by sodium nitroprusside (SNP, 10 mu mol/L) on rena l vascular resistance under conditions of elevated vascular cAMP levels. cA MP levels were increased either by adenylate cyclase activation via isoprot erenol or by inhibition of cAMP phosphodiesterases (PDEs) 1, 3, and 4. We f ound that L-NAME markedly increased vascular resistance and that this effec t was completely reversed by SNP. Both isoproterenol and inhibitors of the cAMP PDEs lowered basal vascular resistance. In the presence of isoproteren ol (3 nmol/L) and inhibitors of PDE-1 [8-methoxymethyl-1-methyl-3-(2-methyl propyl)-xanthine; 8-MMIBMX, 20 mu moyL] and PDE-4 (rolipram, 20 mu mol/L), L-NAME again substantially increased vascular resistance, and this effect o f L-NAME was completely reversed by SNP. In the presence of the PDE-3 inhib itors milrinone (20 mu mol/L) and trequinsin (200 nmol/L), however, both L- NAME and SNP failed to exert any additional effects. Because PDE-3 is a cGM P-inhibited cAMP PDE and because the vasodilatory effect of SNP was abrogat ed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxali n-1-one (ODQ) (20 mu mol/L), our findings an compatible with the idea that an action of NO on PDE-3 could account for the vasodilatory properties of N O on the renal vasculature. Moreover, our findings suggest that PDE-3 activ ity is an important determinant of renal vascular resistance.