Potentiation by Bay-K-8644 of the Adrenal Catecholamine Secretory Response to Ca Re-Introduction and Ouabain: Possible Activation of Ca Influx Linked with Na Efflux

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Catecholamine (CA) secretion induced by Ca re-introduction or ouabain in the presence of Ca is markedly potentiated by Bay-K-8644 in the perfused cat adrenal. The mechanism of potentiation by this Ca agonist was investigated using perfused cat adrenal and isolated bovine chromaffin cells. The stimulatory effect of Bay-K-8644 on the response to Ca was very slight when cat adrenal was perfused with a Ca-deficient medium, in which 1mM Mg was added or the concentration of Na was lowered. The inhibitory effect of Mg was reversed by inhibition of the Na pump with K deprivation, ouabain, or KCN. The secretion induced by ouabain during maintained depolarization at a lowered concentration (0.25mM) of Ca, which is supposed to be due to Ca influx in exchange for Na efflux, was larger in the Bay-K-8644 treated adrenal than that in the untreated adrenal. The increase in secretion by the delayed addition of Bay-K-8644 during perfusion with a high K medium containing ouabain was larger when the concentration of Na in a high K medium was higher. When isolated chromaffin cells were stimulated with a Na-free (Tris) medium containing 0.5mM Ca, CA secretion from and ⁴⁵Ca uptake into the cells preincubated with a divalent cation-free medium were potentiated by Bay-K-8644. The stimulatory effect of Bay-K-8644 was not seen when a Ca-free treatment medium contained Mg or lacked Na, but the inhibitory effect of Mg was reversed by the addition of ouabain or KCN to the pretreatment medium. When isolated cells preloaded with ⁴⁵Ca were superfused with a Ca-free medium, Ca re-introduction increased the rate of Ca efflux only under conditions in which significant increases in CA secretion and ⁴⁵Ca uptake were previously observed under the static incubation system. Bay-K-8644 further increased this Ca efflux rate under these conditions. These results support the view that Ca influx linked with Na efflux is through a pathway with properties similar to those of voltage-dependent Ca channels, and suggest that this Ca pathway is activated by Bay-K-8644, which is an activator of voltage-dependent Ca channels.