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

Abstract

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. ETB receptors were detected on SHR cardiomyocytes as early as 8 wk and their affinity increased progressively with age ( P < 0.05), whereas ETB 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 ETB receptor-selective ligand A-192621 increased protein synthesis progressively with the development of LVH (15% maximum effect). In conclusion, the presence of ETB 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 ETB receptors before the onset of cardiomyocyte hypertrophy, whereas altered ETB receptor characteristics during active hypertrophy (16–24 wk) indicate that ETB receptor mechanisms may also contribute to disease progression.