This study tested whether sarcoplasmic-endoplasmic reticulum Ca2+-ATPase regulates the ability of endothelin receptor antagonist to inhibit the endothelin-1 constriction. The endothelin A receptor antagonist BQ-123 (1 mu M) completely relaxed constriction to 10 nM endothelin-1 in endothelium-denuded rat aorta. Challenge with cyclopiazonic acid (10 mu M), a sarcoplasmic-endoplasmic reticulum Ca2+-ATPase inhibitor, during the plateau of endothelin-1 constriction enhanced the constriction by similar to 30%. BQ-123 relaxed the endothelin- 1 plus cyclopiazonic acid constriction by only similar to 10%. In contrast, prazosin (1 mu M), an alpha-adrenergic receptor antagonist, still completely relaxed the 0.3 mu M phenylephrine constriction in the presence of cyclopiazonic acid. Verapamil relaxed the endothelin-1 plus cyclopiazonic acid constriction by similar to 30%, whereas Ni2+ and 2-aminoethoxydiphenyl borate, nonselective cation channel and store-operated channel blockers, respectively, completely relaxed the constriction. These results suggest that lowered sarcoplasmic-endoplasmic reticulum Ca2+-ATPase activity selectively decreases the ability of endothelin receptor antagonist to inhibit the endothelin A receptor. The decreased antagonism may be related to the opening of store-operated channels and subsequent greater internalization of endothelin A receptor.