BUTANEDIONE MONOXIME PROMOTES VOLTAGE-DEPENDENT INACTIVATION OF L-TYPE CALCIUM CHANNELS IN HEART - EFFECTS ON GATING CURRENTS

The effect of 20 mM extracellularly applied 2,3-Butanedione monoxime ( BDM) on L-type Ca2+ channel charge movement current was studied in who le-cell voltage-clamped guinea-pig ventricular myocytes. Intramembrane ous charge movement in response to depolarizing pulses (charge 1), was reduced after the application of BDM. The effect was more pronounced at the OFF of the charge transient (41%) than at the ON (7%). The stea dy-state availability curve of charge 1 was shifted to the left; the m agnitude of the voltage shift was similar to the shift in Ca2+ current availability. Charge movement recorded in the negative voltage range (charge 2) after conditioning depolarizing pulses of different duratio n, was increased by BDM. For a 300-ms conditioning pulse, charge 2 mea sured during a negative test pulse increased 40% (in Ba2+ external sol ution) or 35% (In Ca2+ external solution). These results show that BDM promotes voltage-dependent inactivation of L-type Ca2+ channels in pa rallel with charge interconversion between intramembranous charges 1 a nd 2. Mechanistically they are consistent either with dephosphorylatio n or a dihydropyridine-like action, but argue against open channel blo ck as the mechanism of the effect of the drug. (C) 1997 Academic Press Limited.