Adenovirus gene transfer of endothelin-1 (ET-1) in rats causes a transient elevation of plasma ET-1 levels, leading to systemic hypertension. Our aim was to evaluate modulation of both ET receptor subtypes in this experimental model. Recombinant adenovirus encoding either the human preproendothelin-1 (Ad.CMV.ET-1) or β-galactosidase (Ad.CMV.β-gal) as control was injected systemically into rats. Elevated plasma ET-1 levels and systemic blood pressure were confirmed 96 h after viral administration. Competition binding studies were carried out using tissues from liver, heart, kidney and brain to measure affinities and receptor densities. In the liver, both ET receptor densities were significantly reduced in the Ad.CMV.ET-1 group. In the heart, only the endothelin-A-(ETA) receptor density was significantly reduced. In the kidney and brain, the density of the ET receptors did not differ from the control group. In all tissues studied, there was no change in affinities between the two groups. The tissue-specific modulation of ET receptors and the fine regulation of ETA-receptors in the heart support the suggested role of the ET system in the development of cardiovascular diseases.
*Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K., and †Department of Molecular Genetics, Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, Texas, U.S.A.
Address correspondence and reprint requests to Dr Anthony P. Davenport, Clinical Pharmacology Unit, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, U.K.
© 2000 Lippincott Williams & Wilkins, Inc.