The effect of isoenzyme-selective PDE inhibitors on methacholine-induced contraction of guinea-pig and rat ileum

1 We have examined the effects of the isoenzyme-selective phosphodiesterase (PDE) inhibitors, vinpocetine (type 1), siguazodan (type 3), rolipram (type 4) and zaprinast (type 5) and the non-selective PDE inhibitor enprofylline on methacholine (MCh) contractile concentration-response curves on guinea-pig and rat isolated ileum. 2 In guinea-pig ileum, vinpocetine (10-300 mu M), zaprinast (1-300 mu M) and enprofylline (100-1000 mu M) produced a concentration-dependent depression of the maximum response (E(max)) to MCh only without effect on the MCh EC(50) values (rank order of potency: zaprinast > vinpocetine > enprofylline). In contrast, siguazodan (10-300 mu M) and rolipram (10-300 mu M) produced a rightward displacement of the MCh concentration-response curve (increase in EC(50): rank order: rolipram > siguazodan), with effects on the MCh maximum seen only at higher concentrations. 3 In the rat ileum, vinpocetine (10-300 mu M), zaprinast (0.1-300 mu M) and enprofylline (100-1000 mu M) caused depression of the MCh maximum contraction (rank order: zaprinast > vinpocetine > enprofylline). Low concentrations of rolipram and siguazodan had no significant effect on the MCh maximum. In the presence of higher concentrations (>100 mu M) of rolipram and siguazodan, a maximum response was not achieved at the highest concentration of MCh tested. As in the guinea-pig ileum, only rolipram (10-300 mu M) and siguazodan (10-300 mu M) produced a significant, concentration-dependent, rightward displacement of the MCh concentration-response curve (increase in EC(50): rank order: rolipram >siguazodan). 4 In the guinea-pig ileum, isoprenaline (0.1 mu M) produced a rightward displacement (similar to 3 fold) of the MCh concentration-response curve, accompanied by a significant depression of the maximum response. Increasing the isoprenaline concentration (1 mu M) had no further effect on either parameter. Sodium nitroprusside (SNP, greater than or equal to 10 mu M) produced a concentration-dependent depression of the MCh maximum without an effect on the EC(50).