Potentiation of the effects of sodium nitroprusside and of isoproterenol by selective phosphodiesterase inhibitors

Abstract

This study identified a series of alkylated xanthines and a papaverine analogue with a range of potencies and selectivities as inhibitors of phosphodiesterases isolated from bovine coronary arteries. The abilities of these inhibitors to potentiate the relaxant effects of sodium nitroprusside (SNP) and isoproterenol were predictable from the potencies to inhibit the calmodulin-sensitive and the cyclic AMP-specific forms of phosphodiesterase, respectively. Although the xanthines potentiated the SNP- and isoproterenol-induced increases in cyclic GMP and cyclic AMP, respectively, in manners that were consistent with the involvement of the respective cyclic nucleotides in the relaxation process, the papaverine analogue did not potentiate isoproterenol-induced increases in cyclic AMP levels. These data are consistent with the hypothesis that increases in cyclic GMP levels are responsible for the relaxation of coronary artery strips by SNP. In addition, the data indicate that the calmodulin-sensitive phosphodiesterase activity does not contribute significantly to the hydrolysis of cyclic AMP in the intact bovine coronary artery smooth muscle cells.