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This Article Full Text Full Text (PDF) All Versions of this Article: 287/1/H425    most recent 00461.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Lee, G. R. Articles by McDermott, B. J. Search for Related Content PubMed PubMed Citation Articles by Lee, G. R. Articles by McDermott, B. J.

Evidence for altered ET_B receptor characteristics during development and progression of ventricular cardiomyocyte hypertrophy

Department of Therapeutics and Pharmacology, Centre for Cardiovascular and Genetics Research, School of Medicine, Queen's University of Belfast, Belfast BT9 7BL, Northern Ireland, United Kingdom

Submitted 22 May 2003 ; accepted in final form 20 February 2004

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.

spontaneously hypertensive rats; pressure overload; endothelin receptor

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