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 vivo overexpression of the peptide in rats, we prepared recombinant adenovirus stocks encoding the human preproET-1 cDNA (Ad.ET-1) or Escherichia coli lacZ (Ad.βGal), each driven by cytomegalovirus early promoter. Ad.ET-1 or Ad.βGal was injected into the caudal vein of rats and the animals were studied under anesthesia 96 h later. Hepatic overexpression 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. Circulating plasma ET-1 levels in the Ad.ET-1 group were sixfold higher than those in the Ad.βGal group. Mean arterial blood pressure was increased by 28 mmHg in the Ad.ET-1 group as compared with the Ad.βGal group. In the Ad.ET-1 group, intravenous infusion of the ET(A) receptor antagonist FR 139317 reduced the blood pressure to levels seen in the Ad.βGal group, whereas the same antagonist did not significantly alter the blood pressure in the Ad.βGal group. Intravenous infusion of the ET(B) receptor antagonist BQ-788 caused a small but significant increase in blood pressure in both groups. These findings demonstrate that endogenous overexpression of preproET-1, accompanied by an elevation of plasma ET-1 concentrations to the levels seen in pathophysiological states, can cause systemic hypertension through the activation of the ET(A) receptor.