Evidence for interactions between the endothelin (ET) and renin-angiotensin systems is plentiful in vitro, but few studies have investigated these interactions in vivo. In the study reported here, we have investigated the influence of chronic angiotensin-II (A-II) infusion in vivo on expression of preproendothelin-1 (PPET-1) and endothelin-A-(ETA) and endothelin-B- (ETB) receptor mRNA in the heart. The role of the angiotensin type 1 (AT1)-receptor in mediating the actions of A-II was studied using losartan, the selective AT1-receptor antagonist. Male rats received an infusion of A-II (200 ng/kg/min) or vehicle for 14 days via mini-osmotic pumps; losartan (10 mg/kg/day) was administered in the drinking water. PPET-1 and ETA- and ETB-receptor mRNA were detected in heart sections using nonradioactive antisense in situ hybridization. Independent treatments with either A-II or losartan had no significant effect on PPET-1, ETA- or ETB-receptor expression. Combined treatment resulted in an increase in PPET-1 mRNA (p <0.001) and ETB-receptor mRNA expression (p <0.01), while ETA-receptor mRNA expression was decreased (p < 0.001). These results suggest that selective AT1-receptor blockade, in the presence of an elevated plasma A-II concentration, causes upregulation of ET-1 synthesis in the myocardium as well as modification of ET receptor expression. These effects may be mediated via angiotensin type 2 (AT2)-receptors.
Endothelial Cell Biology and Molecular Cardiology Section, Cardiovascular Interdisciplinary Group, Departments of Biomedical Sciences and *Medical Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.
Address correspondence and reprint requests to Dr Pauline E. McEwan, Department of Genetic Physiology, Harvard Medical School Cardiovascular Division, Thorn-13; Lab, Brigham and Womens Hospital, 75 Francis Street, Boston, MA, U.S.A.
© 2000 Lippincott Williams & Wilkins, Inc.