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

Purpose: Endothelins are potent vasoactive factors that have been implicated in the pathogenesis of several vascular disorders. This study was conducted to determine the role that endothelins play in the development of retinal microangiopathy under hyperhexosemic conditions induced by galactose feeding. Methods: Retinal blood flow was determined using Doppler sonography in galactose fed rats with or without an endothelin receptor antagonist (Bosentan) treatment and were compared to control rats after 1 and 6 months of follow-up. Levels of endothelin-l. endothelin-3, (ET-1, ET3) and receptors endothelin A, endothelin B, (ETA, ETB) mRNA expression were determined by semiquantitative RT-PCR. Immunohistochemical distribution of ET-I and ET-3, ligand binding, and autoradiography to determine ET receptor distribution were carried out. Results: Retinal vasoconstriction measured by an increase in resistivity index (RI) was present in 1 month galactose feeding compared to controls, which was prevented by Bosentan treatment. After 6 months of follow up all animal groups exhibited higher RI compared to their 1 month counterpart, although they were not different from each other. Compared to the controls, after 1 month levels of mRNA for ET-1, ET-3, and ET, were increased in galactose-fed rats, whereas ET, mRNA production remained similar to controls. After 6 months, all four genes exhibited increased levels compared 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 retina of galactose-fed animals. Conclusion: The data suggests that endothelin production is increased under hyperhexosemic conditions and that the endothelins play an important role in regulating the hemodynamics of retinal blood flow. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.