Evidence for altered ETB receptor characteristics during development and progression of ventricular cardiomyocyte hypertrophy.
The hypothesis that endothelin (ET) receptor mechanisms are altered during development and progression of left ventricular hypertrophy (LVH) in vivo was tested using spontaneously hypertensive rats (SHRs). Ventricular cardiomyocytes were isolated from SHRs before onset (8 and 12 wk) and during progression (16, 20, and 24 wk) of LVH and compared with age-matched normotensive Wistar-Kyoto (WKY) rats. PreproET-1 mRNA expression was elevated in SHR (P < 0.05) relative to WKY cardiomyocytes at 20-24 wk. ET binding-site density was twofold greater in SHR than WKY cells at 12 wk (P < 0.05) but normalized at 20 wk. ET(B) receptors were detected on SHR cardiomyocytes as early as 8 wk and their affinity increased progressively with age (P < 0.05), whereas ET(B) receptors were not detected on WKY cells until 20 wk. ET-1 stimulated protein synthesis with similar maximum responses between strains (21-30%), in contrast with sarafotoxin 6c, which stimulated protein synthesis in SHR (13-20%) but not WKY cells at 12-20 wk. In SHR but not WKY cells, the ET(B) receptor-selective ligand A-192621 increased protein synthesis progressively with the development of LVH (15% maximum effect). In conclusion, the presence of ET(B) receptors (8-12 wk) coupled with functional responsiveness of SHR cells but not WKY cells to sarafotoxin 6c at 12 wk supports the involvement of ET(B) receptors before the onset of cardiomyocyte hypertrophy, whereas altered ET(B) receptor characteristics during active hypertrophy (16-24 wk) indicate that ET(B) receptor mechanisms may also contribute to disease progression.
Lee
Graham R
GR
Department of Therapeutics and Pharmacology, Centre for Cardiovascular and Genetics Research, School of Medicine, Queen's University of Belfast, Whitla Medical Bldg., 97 Lisburn Rd., Belfast BT9 7BL, Northern Ireland, UK.
Bell
David
D
Kelso
Elizabeth J
EJ
Argent
Cymone C H
CC
McDermott
Barbara J
BJ
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D018450:Disease Progression; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology; D019334:Endothelin-3 / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044023:Receptor, Endothelin B / Q000378:metabolism*; D014757:Viper Venoms / Q000494:pharmacology
D019332:Endothelin-1; D019334:Endothelin-3; D009124:Muscle Proteins; D044023:Receptor, Endothelin B; D014757:Viper Venoms; C057354:sarafotoxins s6