Mechanism of smooth muscle relaxation by tiropramide

Experiments on rabbit isolated colon show that a carbachol-induced contraction is accompanied by a decrease in cAMP content of the smooth muscle. (+/-)-alpha-(Benzoylamino)-4-[2-(diethylamino)-ethoxy]-NN-di-propylbenzen-propanamid (tiropramide, CR 605), a new tyrosine derivative with antispastic properties, increases cAMP concentrations within the same dose range that produces smooth muscle relaxation with or without carbachol (0.1 microM). These effects are potentiated by 1 mM theophylline, a phosphodiesterase inhibitor. In a purified microsomal preparation from rabbit colon smooth muscle, corresponding to sarcoplasmic reticulum, tiropramide induced a dose-dependent increase Ca2+ binding in the presence of ATP and Mg2+. Tiropramide inhibited phosphodiesterase activity in rabbit colon homogenates in a range of doses about ten times that producing relaxation, cAMP content enhancement and increase Ca2+ binding to sarcoplasmic reticulum. The effects of tiropramide on the carbachol-stimulated rabbit colon in the presence of theophylline, indomethacin of PGE1 are more in agreement with an action of tiropramide as inhibitor of cAMP catabolism than as a result of a prostaglandin-mediated effect. These observations suggest that the smooth muscle relaxant activity of tiropramide arises from drug-induced increase of cAMP concentrations possibly because of inhibition of cAMP catabolism. This effect is accompanied by the binding to the sarcoplasmic reticulum of Ca2+, preventing its interaction with the contractile proteins of the smooth muscle. A direct effect of tiropramide-enhanced cAMP content on contractile proteins in the smooth muscle cannot be excluded.