EICOSANOIDS RELEASED FOLLOWING INHIBITION OF THE ENDOPLASMIC-RETICULUM CA2-RAT-LIVER( PUMP STIMULATE CA2+ EFFLUX IN THE PERFUSED)

In the isolated perfused rat liver 2,5-di(tert-butyl)hydroquinone (tBu HQ), a selective inhibitor of the endoplasmic reticulum Ca2+ pump, ind uces a prolonged glucose output and stimulates Ca2+ efflux. The presen t study shows that tBuHQ depleted the hormone-sensitive Ca2+ pool in t he perfused liver, abolishing the vasopressin- or phenylephrine-induce d Ca2+ efflux. The effects of tBuHQ were reversible, since the respons e to these agonists gradually returned within 1 hr of perfusion, and p rotein synthesis was not required for this recovery. Since tBuHQ does not cause Ca2+ efflux from isolated hepatocytes, we examined the mecha nism responsible for the tBuHQ-induced Ca2+ efflux observed in the int act liver. The cyclooxygenase inhibitor indomethacin prevented the Ca2 + extrusion stimulated by tBuHQ, but not that induced by vasopressin. During infusion of tBuHQ there was a 9-fold increase in the concentrat ion of thromboxane B2 in the perfusate. The Ca2+ efflux response to tB uHQ was inhibited by the thromboxane/prostaglandin endoperoxide recept or antagonist, L-655,240 -[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol- 2-yl] 2,2-dimethylpropanoic acid} in the absence of any effect on thro mboxane B2 release. Thus, the inhibition of the endoplasmic reticulum Ca2+ pump by tBuHQ results in a rise in the cytosolic Ca2+ concentrati on in non-parenchymal cells, leading to the formation of cyclooxygenas e products. The released eicosanoids, in tum, stimulate Ca2+ efflux fr om hepatocytes.