Embryopathic effects of diazoxide and the reduction of sulfonylurea-induced dysmorphogenesis in vitro

Abstract

Diazoxide is a benzothiadiazine used in oral and intravenous preparations to treat hypertension and hypoglycaemia, but its effect on embryonic development has not been well studied. Previous in vivo work has suggested placental transfer and teratogenicity of diazoxide in humans and laboratory animals, but this study represents the first in vitro investigation of the effect of diazoxide on the embryo. The in vitro method of whole-embryo culture was used to expose mouse embryos to specific levels of diazoxide (0–200 μg/ml) during organogenesis at well-defined (4–6 and 20–25 somite) stages of development. In addition, the combined effect of diazoxide [ATP-sensitive K + (K ATP) channel opener] and the sulfonylurea oral hypoglycaemic agent chlorpropamide (K ATP channel blocker), was evaluated in vitro in embryos with 4–6 somites. Diazoxide produced malformations and growth retardation in mouse embryos exposed to 100 μg/ml or more for 24 hr in vitro at both stages of organogenesis. In addition, a subteratogenic concentration of diazoxide (25 μg/ml) reduced the embryopathic effects of chlorpropamide (130 μg/ml) in embryos with 4–6 somites. A potential mechanism for these effects involves K ATP channels.