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This study tested whether sarcoplasmic-endoplasmic reticulum [Ca.sup.2+]-ATPase regulates the ability of endothelin receptor antagonist to inhibit the endothelin-1 constriction. The endothelin A receptor antagonist BQ-123 (1 [micro]M) completely relaxed constriction to 10 nM endothelin-1 in endothelium- denuded rat aorta. Challenge with cyclopiazonic acid (10 [micro]M), a sarcoplasmicendoplasmic reticulum [Ca.sup.2+]-ATPase inhibitor, during the plateau of endothelin-1 constriction enhanced the constriction by ~30%. BQ-123 relaxed the endothelin-1 plus cyclopiazonic acid constriction by only ~10%. In contrast, prazosin (1 [micro]M), an [alpha]-adrenergic receptor antagonist, still completely relaxed the 0.3 [micro]M phenylephrine constriction in the presence of cyclopiazonic acid. Verapamil relaxed the endothelin-1 plus cyclopiazonic acid constriction by ~30%, whereas [Ni.sup.2+] and 2-aminoethoxydiphenyl borate, nonselective cation channel and store-operated channel blockers, respectively, completely relaxed the constriction. These results suggest that lowered sarcoplasmicendoplasmic reticulum [Ca.sup.2+]-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. BQ-123; vascular smooth muscle; store-operated calcium; caveola