Influence of papaverine derivatives on phosphodiesterase activity, cyclic 3',5'-AMP levels and relaxing effect on rabbit ileum.

The correlations between the relaxing effect of papaverine derivatives, inhibition of low Km-phosphodiesterase (cAMP-PDE = EC 3.1.4.17) activity and cyclic 3',5'-AMP (cAMP) levels in isolated rabbit ileum were investigated. There was a strong correlation between the relaxing effect, inhibition of PDE activity and cAMP content for eupaverine, ethylpapaverine and papaverine. Eupaverine was the most effective relaxing agent (I50 = 7.5 muM) and the most potent inhibitor of PDE activity (Ki = 0.6 muM), followed by ethylpapaverine (I50 = 10 muM;Ki 0.8 muM) and papaverine (I50 = 20 muM;Ki = 2 muM). In contrast, there was a strong relaxing effect (I50 = 6 muM) but only slight inhibition of PDE activity (Ki = 350 muM) by tetrahydropapaveroline (THP). The adenylate cyclase stimulating effect of THP which was shown by others is most likely the reason for comparatively higher cAMP levels, which were found to be elevated about seven times over basal levels of 0.35 nmoles/g wet weight, and effective relaxation. Relaxation could be induced by exogenously added cAMP (I50 = 45 muM) and dibutyryl-cAMP (I50 = 450 muM). Our results support the assumption that smooth muscle relaxation in rabbit ileum is mediated by cAMP. Some of these observations have been published in abstract form (Schulz and Berndt, 1972).