Mechanism of relaxant action of papaverine IV. Roles of sodium ion and cyclic AMP.

It has been suggested that papaverine relaxes the smooth muscle through inhibition of cyclic AMP phosphodiesterase (PDE) and subsequent accumulation of cellular cyclic AMP (1-4). On the other hand, our previous study indicated that the relaxant effect of papaverine on the smooth muscle is partially due to a mechanism which is only activated in the presence of external sodium ion (5). Therefore, it is important to investigate possible interactions between external sodium ion and some smooth muscle relaxants whose relaxant activities are related to the cyclic AMP system. In the present study, the influence of manipulating external sodium ion concentration on the relaxant effects of papaverine, dibutyryl cyclic AMP and deoxycholate, which exhibits its action through partial involvement of the cyclic AMP system (6), were compared in guinea-pig taenia coli. Strips of taenia coli were dissected from male guinea pigs weighing 300 to 450 g. The strip was mounted in a 10 ml organ bath filled with Locke-Ringer solution (normal solution) which had the following com-The bathing solution was kept at 32 • Ž and continuously bubbled with air. The mechanical response of the muscle was isotonically recorded by means of a lever loaded with 1 g. After 30 min equilibration in the normal solution, the taenia was repeatedly applied with hypertonic 20 mM KCI at intervals of 15 min until the contractile response became constant. Thereafter, the muscle preparation was immersed in either the normal solution or Na-free or Na-deficient (10 mM sodium ion containing) Locke-Ringer solution for 20 min. The Na-free or Na-deficient solution was prepared by replacing NaCI and NaHCO3 in the normal solution by isosmolar amounts of sucrose and KHCO3, respectively. The potassium ion concentration was adjusted to the normal level by omitting KCI from the solution. Following the immersion of the taenia, dose-relaxation curves of papaverine (Sigma), dibutyryl cyclic AMP (Sigma) and deoxycholate (Tokyo Tanabe) were obtained on the muscle depolarized by 20 mM KCI in each solution. When papaverine was cummulatively applied to the taenia, a dose-dependent relaxation took place in either normal, Na-free or 10 mM sodium ion containing solution (Fig. 1A). In the Na-free solution, the dose-relaxation curve was significantly shifted to the right as compared with that in the normal solution. This indicates that the relaxant activity of papaverine is greatly reduced in the absence of external sodium ion. The reduced relaxant activity was partially restored in the presence of a …