Regulation of the myocardial endothelin system by angiotensin-II and losartan.
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- (ET(A)) and endothelin-B- (ET(B)) 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 ET(A)- and ET(B)-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, ET(A)- or ET(B)-receptor expression. Combined treatment resulted in an increase in PPET-1 mRNA (p < 0.001) and ET(B)-receptor mRNA expression (p < 0.01), while ET(A)-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.
McEwan
P E
PE
Department of Biomedical Sciences, University of Edinburgh, Scotland, UK.
Sherry
L
L
Kenyon
C J
CJ
Webb
D J
DJ
Gray
G A
GA
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics* / Q000502:physiology
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D000804:Angiotensin II; D000450:Aldosterone; D019808:Losartan