Tolbutamide in vitro diminishes spontaneous and oxytocin-induced contractions of uterine smooth muscle from diestrous rats.

The in vitro spontaneous isometric-developed tension (IDT) of uterine horns obtained from diestrous rats exhibited, after 60 min of post-isolation activity, a clear decrease in magnitude, averaging 18.2 +/- 5.2%. In presence of tolbutamide, a concentration-dependent decrease of IDT, significantly greater than the spontaneous reduction (75.1 +/- 5.4%, with tolbutamide at 10(-4) M), was observed. Incubation with propranolol (10(-6) M) or with sotalol (10(-4) M) failed to alter the negative inotropism evoked by tolbutamide. On the other hand, the sulfonylurea (10(-4) M) shifted most points of the dose-response curve to the right for the contractile stimulation elicited by oxytocin, an influence not altered by the simultaneous presence of propranolol or sotalol. Tolbutamide failed to influence the negative inotropic dose-response curve for isoproterenol and did not modify the decrease in contractions evoked by theophylline (10(-4) M). It was also found that tolbutamide was devoid of action on the basal release of prostaglandin E2 from uterine strips and on the positive inotropic dose-response curve for added PGE2 or PGF2 alpha, constructed in presence of indomethacin (5 X 10(-6) M). The present findings do not permit a simple explanation regarding possible factors underlying the negative uterine inotropic influence of tolbutamide in the rat uterus. However, it appears that alterations in the integrity of tissue excitability and contractile apparatus, adrenergic implications, changes in uterine cAMP levels, inhibition of cyclo-oxygenase or low PEG2 synthesis and release, are not plausible mechanisms to explain the negative inotropism of tolbutamide. Therefore, it is suggested that the contractile depression evoked by tolbutamide and its action on the contractile effect of oxytocin might be linked to the impaired synthesis of other prostanoids, namely PGF2 alpha, PGI2 or PGD2, although the participation of not yet determined factor(s), namely changes in Ca2+ ion movements, cannot be discarded.