EFFECTS OF THE POTASSIUM CHANNEL OPENERS CROMAKALIM AND PINACIDIL ON CATECHOLAMINE SECRETION AND CALCIUM MOBILIZATION IN CULTURED BOVINE ADRENAL CHROMAFFIN CELLS

The effects of two K+ channel openers, cromakalim and pinacidil, on voltage-dependent and receptor-mediated catecholamine secretion and Ca2+ mobilization in bovine adrenal chromaffin cells were studied to determine the role of membrane K+ channels in the regulation of a Ca2+-dependent secretory process. Both cromakalim and pinacidil stimulated the efflux of Rb-86 (used to monitor K+ permeability) from preloaded cells. Cromakalim and pinacidil did not affect the catecholamine secretion induced by excessive depolarization with 56mM K+, but inhibited that induced by moderate depolarization with 31 mM K+ in a concentration-dependent manner (1 mu M-100 mu M). The 31 mM K+-induced induced Ca-45(2+) influx and increase in intracellular free Ca2+ concentration [Ca2+]i were also inhibited by these agents at similar concentrations to those for inhibition of catecholamine secretion. Cromakalim and pinacidil inhibited catecholamine secretion, Ca-45(2+) influx and increase in [Ca2+]i induced by stimulation of nicotinic acetylcholine (ACh) receptors with carbamylcholine. Furthermore, both cromakalim and pinacidil inhibited the increase in [Ca2+]i induced by carbamylcholine in the absence of extracellular Ca2+, which is thought to be mediated by muscarinic ACh receptors. On the other hand, they did not affect catecholamine secretion induced by Bay-K 8644, Ba2+, A23187, histamine or bradykinin. These results indicate that the K+ channel openers, cromakalim and pinacidil, selectively inhibit catecholamine secretion induced by moderate depolarization or by nicotinic ACh receptor stimulation by inhibiting Ca2+ influx and increase in [Ca2+]i. Furthermore, the results suggest that these K+ channel openers-sensitive membrane K+ channels are involved in the regulation of catecholamine secretion mainly indirectly through effects on the voltage-dependent membrane Ca2+ channels.