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 prior to onset (8 and 12 weeks), and during progression (16, 20, 24 weeks) of LVH, and compared to 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 weeks. ET binding site density was 2 fold greater in SHR than WKY cells at 12 weeks (P<0.05) but normalised at 20 weeks. ET_B receptors were detected on SHR cardiomyocytes as early as 8 weeks and their affinity increased progressively with age (P<0.05), whereas ET_B receptors were not detected on WKY cells until 20 weeks. ET-1 stimulated protein synthesis with similar maximum responses between strains (21-30%), in contrast to sarafotoxin 6c which stimulated protein synthesis in SHR (13-20%) but not WKY cells at 12-20 weeks. 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 weeks), coupled with functional responsiveness of SHR cells, but not of WKY cells, to sarafotoxin 6c at 12 weeks supports the involvement of ET_B receptors prior to the onset of cardiomyocyte hypertrophy, while altered ET_B receptor characteristics during active hypertrophy (16-24 weeks) indicate that ET_B receptor-mechanisms may also contribute to disease progression.