Transgenic rats expressing the human ET-2 gene: a model for the study of endothelin actions in vivo

Previous studies have characterized the endothelin peptides (ET-1, ET-2, ET -3) as strong vasoconstrictors which are possibly involved in the pathogene sis of cardiovascular disease. Whereas ET-1 and ET-3 have been characterize d using a number of approaches, little is known about the function of ET-2. The aim of this study was to define the role of ET-2 in physiology and pat hophysiology using a transgenic approach. Transgenic rats expressing a geno mic construct of the human ET-2 gene were generated by microinjection of fe rtilized oocytes from Sprague-Dawley rats. Two transgenic lines were genera ted, and one line was further characterized in detail. Studies on mRNA expr ession demonstrated that the transgene is expressed predominantly in kidney , gastrointestinal tract, adrenal gland, lung, and brain. Plasma endothelin levels were elevated 2-fold, and big-endothelin levels were elevated 2.5-f old. Despite these-alterations blood pressure in transgenic rats remained n ormal. Further analysis of transgenic animals revealed that endothelin rece ptors were not downregulated, and that infusion of exogenous human ET-2 res ults in an enhanced blood pressure response. These observations suggest the presence of counterregulatory mechanisms influencing the effects of endoth elin on blood pressure. One of these mechanisms may involve the nitric oxid e system since infusion of an inhibitor of nitric oxide synthase resulted i n a greater blood pressure response than in nontransgenic littermates. Desp ite unchanged blood pressure, alterations were observed in organ developmen t and function, namely of hearts and kidneys, indicating an interference be tween transgene expression and growth processes. Male rats seem to be more susceptible to endothelin actions. These data show that the elevation in en dothelin-2 expression in this transgenic model does not induce hypertension but leads to changes at the end-organ level. Normotension is most likely d ue to compensatory mechanisms such as increased nitric oxide formation.