Effects of the cardiotonic drug ARL-115 on the release of noradrenaline from the cat atrium, the binding of ³H-ouabain to plasma membranes and the movements of calcium in mitochondria

Summary

The cardiotonic pyridine derivative ARL-115 increased the spontaneous and electrically-evoked release of ³H-noradrenaline from the cat right atrium superfused with oxygenated Krebs-bicarbonate solution at 37°C. On the contrary, ouabain inhibited the evoked release while it also enhanced the spontaneous release of the transmitter. Vanadate did not affect either spontaneous or evoked release. Tetraethylammonium chloride (TEA) and 4-aminopyridine (4-AP) greatly potentiated ³H-noradrenaline release induced by electrical stimulation; when applied in addition to each agent, ARL-115 failed to further increase the secretory response. ³H-ouabain specific binding to partially purified bovine adrenal medulla plasma membranes was very efficiently antagonized by cold ouabain, but not by vanadate or ARL-115, even at concentrations as high as 10⁻³ mol/l. ⁴⁵Ca uptake into isolated bovine adrenal medulla mitochondria was prevented by dinitrophenol (DNP) but unchanged in the presence of ARL-115. ⁴⁵Ca release from preloaded mitochondria was, again, markedly increased by DNP, but not affected by ARL-115. The results suggest that ARL-115 enhances the release of noradrenaline from cardiac sympathetic nerves by a TEA- and 4-AP-like action. In this manner, ARL-115 would inactivate the K⁺ current in the nerve terminals, thereby prolonging the duration of the action potential, allowing the Ca²⁺ channels to remain open longer and more Ca²⁺ to enter the terminal. ARL-115 is not acting like digitalis.