Sarcoplasmic-endoplasmic reticulum Ca2+ -ATPase inhibition prevents endothelin A receptor antagonism in rat aorta.

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 µM) completely relaxed constriction to 10 nM endothelin- 1 in endothelium-denuded rat aorta. Challenge with cyclopiazonic acid (10 µM), a sarcoplasmic-endoplasmic reticulum Ca2+-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 µM), an α-adrenergic receptor antagonist, still completely relaxed the 0.3 µM phenylephrine constriction in the presence of cyclopiazonic acid. Verapamil relaxed the endothelin-1 plus cyclopiazonic acid constriction by ~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. [ABSTRACT FROM AUTHOR]