SYSTEMIC HYPERTENSION INDUCED BY HEPATIC OVEREXPRESSION OF HUMAN PREPROENDOTHELIN-1 IN RATS

Endothelin-1 (ET-1) has been implicated in the regulation of vascular tone in various pathological conditions, To examine the effect of in v ivo overexpression of the peptide in rats, we prepared recombinant ade novirus stocks encoding the human preproET-1 cDNA (Ad.ET-1) or Escheri chia coli lacZ (Ad.beta Gal), each driven by cytomegalovirus early pro moter, Ad.ET-1 or Ad.beta Gal was injected into the caudal vein of rat s and the animals were studied under anesthesia 96 h later, Hepatic ov erexpression of the virus-derived human ET-1 mRNA was accompanied by a 13-fold elevation of liver ET-1 content in the Ad.ET-1 group. Circula ting plasma ET-1 levels in the Ad.ET-1 group were sixfold higher than those in the Ad.beta Gal group. Mean arterial blood pressure was incre ased by 28 mmHg in the Ad.ET-1 group as compared with the Ad.beta Gal group. In the Ad.ET-1 group, intravenous infusion of the ET(A) recepto r antagonist FR 139317 reduced the blood pressure to levels seen in th e Ad.beta Gal group, whereas the same antagonist did not significantly alter the blood pressure in the Ad.beta Gal group. Intravenous infusi on of the ET(B) receptor antagonist BQ-788 caused a small but signific ant increase in blood pressure in both groups, These findings demonstr ate that endogenous overexpression of preproET-1, accompanied by an el evation of plasma ET-1 concentrations to the levels seen in pathophysi ological states, can cause systemic hypertension through the activatio n of the ET(A) receptor.