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Endothelin-1 (ET-1) induces cardiac hypertrophy. Because Ca2+is a major second messenger of ET-1, the role of Ca2+in ET-1-induced hypertrophic responses in cultured cardiac myocytes of neonatal rats was examined. ET-1 activated the promoter of the β-type myosin heavy chain gene (β-MHC) (−354 to +34 base pairs) by about 4-fold. This activation was inhibited by chelation of Ca2+and the blocking of protein kinase C activity. Similarly, the β-MHCpromoter was activated by Ca2+ionophores and a protein kinase C activator. β-MHCpromoter activation induced by ET-1 was suppressed by pretreatment with the calmodulin inhibitor, W7, the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor, KN62, and the calcineurin inhibitor, cyclosporin A. β-MHCpromoter activation by ET-1 was also attenuated by overexpression of dominant-negative mutants of CaMKII and calcineurin. ET-1 increased the activity of CaMKII and calcineurin in cardiac myocytes. Pretreatment with KN62 and cyclosporin A strongly suppressed ET-1-induced increases in [3H]phenylalanine uptake and in cell size. These results suggest that Ca2+plays a critical role in ET-1-induced cardiomyocyte hypertrophy by activating CaMKII- and calcineurin-dependent pathways.