474 Hypoglycemic Agents Sulfonylureas Constrict the Fetal Ductus Arteriosus in the Rat

Abstract

Background: Sulfonylureas (tolbutamide = Rastinon, glibenclamide = glyburide, glimepiride = Amaryl) inhibit KATP channels and induce release of insulin. In in-vitro studies, glibenclamide constricts the ductus arteriosus. Placental transport of sulfonylureas is variable; high with tolbutamide, and low with glibenclamide, respectively.Purpose: To clarify the in-vivo ductus constrictive effects of various sulfonylureas.Methods: Sulfonylureas were administered orogastrically to pregnant near-term (21FD) or preterm (19FD) Wistar rats. Fetal ductus arteriosus was studied 2, 4, 8 and 24 hours later, with a rapid whole-body freezing method and measurement of the inner diameter of the ductus.Results: Tolbutamide constricted the fetal ductus dose-dependently. With clinical dose (10 and 30 mg/kg), the near-term fetal ductus constricted moderately, and the ductal diameter decreased to 0.8 and 0.5 compared to the control four hours later. With a large dose (100 mg/kg), the fetal ductus constricted severely, and the diameter decreased to 0.2 compared to the control four hours later. Tolbutamide constricted the pre-term ductus comparatively less. Glimepiride with a large dose of 10 mg/kg constricted the near-term fetal ductus only mildly. With a large dose of glibenclamide (10 mg/kg), it did not constrict the near-term or the preterm ductus arteriosus, reflecting poor placental transport.Conclusion: Clinical doses of tolbutamide constrict the fetal ductus moderately. With a 10 times larger dose, the ductus closes completely. Experimental comparison suggests tolbutamide is more potent constrictor of the fetal ductus than indomethacin, and can be used to close a premature PDA in the rat model.FD = Fetal Days.