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We have documented the effects of long-term endothelin receptor antagonism on intracellular Ca 2π regulation and Ca 2π regulatory protein expression in rat hearts with right ventricular hypertrophy without signs of heart failure. Rats were given either a single injection of monocrotaline (50 mg/kg, nΩ9) resulting in pulmonary hypertension-induced myocardial hypertrophy, or monocrotaline followed by daily administration of the endothelin subtype-A receptor antagonist 2-benzo(1,3)dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)-4-oxobut-2-enoate-Na (PD 155080, 50 mg/kg) over 9 weeks (nΩ8). Hearts from saline-injected rats served as controls (nΩ9). Monocrotaline-treated animals developed marked rightsided hypertrophy without fibrosis as evident from hydroxyproline measurements, systolic contractility was increased, fully compensating for the increased afterload, but diastolic function was impaired as evident from protracted relaxation and slowed diastolic intracellular Ca 2π handling (measured by aequorin bioluminescence). In hypertrophic hearts, quantitative immunoblotting analyses showed increased levels both of sarco(endo)plasmic reticulum Ca 2π -ATPase (SERCA) and phosphorylated phospholamban, along with decreased levels of total phospholamban, which is in line with strengthened right ventricular systolic function. PD 155080 reversed abnormalities in Ca 2π handling, although SERCA and phospholamban protein levels were not altered (PΩnot significant versus monocrotaline group). Thus, endothelin-A receptor antagonism attenuates right ventricular remodeling and improves myocardial Ca 2π handling, but has no discernable effect on elevated expression of SERCA and phospholamban observed in hypertrophic hearts. These data indicate that the hypotensive action of PD 155080 is independent of its effects, if any, on SERCA and its regulation.