Endothelins, their receptors, and retinal vascular dysfunction in galactose-fed rats

Purpose: Endothelins are potent vasoactive factors that have been implicate d in the pathogenesis of several vascular disorders. This study was conduct ed to determine the role that endothelins play in the development of retina l microangiopathy under hyperhexosemic conditions induced by galactose feed ing. Methods: Retinal blood flow was determined using Doppler sonography in galactose fed rats with or without an endothelin receptor antagonist (Bose ntan) treatment and were compared to control rats after 1 and 6 months of f ollow-up. Levels of endothelin-l. endothelin-3, (ET-1, ET3) and receptors e ndothelin A, endothelin B, (ETA, ETB) mRNA expression were determined by se miquantitative RT-PCR. Immunohistochemical distribution of ET-I and ET-3, l igand binding, and autoradiography to determine ET receptor distribution we re carried out. Results: Retinal vasoconstriction measured by an increase i n resistivity index (RI) was present in 1 month galactose feeding compared to controls, which was prevented by Bosentan treatment. After 6 months of f ollow up all animal groups exhibited higher RI compared to their 1 month co unterpart, although they were not different from each other. Compared to th e controls, after 1 month levels of mRNA for ET-1, ET-3, and ET, were incre ased in galactose-fed rats, whereas ET, mRNA production remained similar to controls. After 6 months, all four genes exhibited increased levels compar ed to the controls, and no effect of Bosentan treatment on gene expression was evident. Increased immunoreactivity of ET-1 and ET-3 was determined, as well as increased ET receptor concentration was further present in the ret ina of galactose-fed animals. Conclusion: The data suggests that endothelin production is increased under hyperhexosemic conditions and that the endot helins play an important role in regulating the hemodynamics of retinal blo od flow. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.