Levels of endothelin-1 in embryos from control and neonatal streptozotocin-induced diabetic rats, and their relationship with nitric oxide generation.

Abstract

Endothelin-1 (ET-1), a potent vasoconstrictor peptide and modulator of vasoactive substances such as prostanoids and nitric oxide (NO), plays an important role during embryo and fetal development. In this work, ET-1, nitrate and nitrite, and prostaglandin E2 (PGE2) levels in embryos from control and neonatal streptozotocin-induced (n-stz) diabetic rats were assessed, and the modulatory pathways regulating the generation of these vasoactive agents investigated. Endothelin-1 concentrations were found to be increased in embryos from n-stz diabetic rats when compared with controls. Additions of spermine NONOate, a nitric oxide donor, enhanced ET-1 levels in embryos from both control and n-stz diabetic rats, whereas N(G)-monomethyl-L-arginine, a nitric oxide inhibitor, diminished embryonic ET-1 content. Thus, enhanced ET-1 levels in the embryos from n-stz diabetic rats may be related to the elevated NO levels found in those embryos. Additions of ET-1 or bosentan (an endothelin A and endothelin B receptor antagonist), did not alter PGE2 generation in embryos from either control or n-stz diabetic rats. Endothelin-1 additions diminished nitrate and nitrite levels in embryos from both control and n-stz diabetic rats, whereas bosentan stimulated nitrate and nitrite generation in those embryos. In the present work, it was found that ET-1 levels were enhanced in embryos from n-stz diabetic rats, probably as a result of NO overproduction, an alteration which may be related to embryonic abnormalities and growth delay. Endothelin-1 has been shown to be a negative modulator of embryonic NO levels, a mechanism likely to be important during development. Endothelin-1 may prevent damage induced by NO overproduction in embryos from n-stz diabetic rats.