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.
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 degrees 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.
D000313:Adrenal Medulla / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002838:Chromaffin System / Q000378:metabolism; D004558:Electric Stimulation; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010042:Ouabain / Q000378:metabolism*
D002316:Cardiotonic Agents; D007093:Imidazoles; D010042:Ouabain; C029758:sulmazole; D002118:Calcium; D009638:Norepinephrine