. Evidence for altered ET B receptor characteristics during development and progression of ventricular cardiomyocyte hypertrophy. Am J Physiol Heart Circ Physiol 287: H425-H432, 2004. First published February 26, 2004 10.1152/ ajpheart.00461.2003The 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 Ͻ 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 Ͻ 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 Ͻ 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 CONCENTRIC LEFT VENTRICULAR hypertrophy (LVH) occurs after pressure overload and is associated with thickening of the ventricular wall to normalize wall stress but ultimately leads to mechanical dysfunction and failure (24). Increased cardiac mass is attributed to increased mass of individual cardiomyocytes, proliferation of nonmyocytes, and synthesis of extracellular matrix (36,40). Epidemiological studies indicate that regression of LVH with antihypertensive agents improves prognosis (27). Such treatments, however, only partially regress LVH; involvement of nonhemodynamic factors has also been postulated (9).Endothelin (ET)-1 is a potent vasoconstrictor peptide; ET-2 and ET-3 differ from ET-1 by 2 and 6 amino acids, respectively (44). Increased plasma levels of ET-1 occur during hypertension and heart failure and correlate with severity of LVH (15). ET receptor antagonists attenuate LVH in some experimental models in vivo (17,20). It is unclear whether this occurs as a direct result of ET receptor blockade on cardiomyocytes or represents an indirect effect that is due to reduction in systolic pressure; elevated ET-like immunoreactivit...
