Potentiation by indomethacin of receptor-mediated catecholamine secretion in rat adrenal medulla

Effects of indomethacin on catecholamine secretion evoked by receptor agonists, muscarine, bradykinin or histamine, in rat adrenal chromaffin cells were studied. Indomethacin at 200 mu M increased a sustained component of secretion during stimulation with muscarine, bradykinin and histamine by a factor of 2.3, 2.1 and 2.9, respectively, whereas it did not significantly alter basal, high-K+- and nicotine-evoked secretions. Although indomethacin at above 400 mu M dose-dependently increased basal secretion, the amount of secretion induced by indomethacin alone was much smaller than that in muscarine-evoked secretion as compared at the same concentration of indomethacin applied. Bradykinin-evoked secretion and its potentiation by indomethacin were not inhibited by 20 mu M nifedipine but were suppressed by 0.5 mM Ni2+. The cyclooxygenase inhibitor, ibuprofen (200 mu M) did not mimic the effect of indomethacin; prostaglandin E(2) (20 mu M) and arachidonic acid (100 mu M) did not significantly alter either bradykinin-evoked secretion itself or its potentiation by indomethacin. Bradykinin increased the intracellular free Ca2+ concentration, [Ca2+](i), in cells loaded with indo-1, and this response was enhanced in the presence of indomethacin. These results suggest that indomethacin may promote Ca2+ entry to potentiate agonist-evoked catecholamine secretions through a novel action that is not directly related to the inhibition of cyclo-oxygenase activity with indomethacin.