The effect of 2,3-butanedione 2-monoxime (BDM) on ventricular trabeculae from the avian heart

Abstract

2,3-butanedione 2-monoxime (BDM, 3-30 mM) decreased twitch force of intact ventricular trabeculae isolated from 19-day embryonic chick hearts in a dose-dependent manner. The responses to BDM were rapid and reversible. In an attempt to determine the cellular basis for the inhibitory effect of BDM, experiments were carried out on skinned muscle fibres and isolated myocytes. In trabeculae skinned with Triton X-100, BDM depressed maximum calcium activated force (Fmax) with an IC50 of 14 mM. At 3 mM BDM, the proportional decrease in twitch force in intact tissue was similar to that of Fmax in skinned tissue. At higher BDM concentrations (10 and 30 mM), however, the proportional decrease in twitch force was greater than that of Fmax. BDM (up to 10 mM) had no effect on the normalized force-pCa relationship. In saponin-skinned preparations, BDM (3 and 30 mM) released calcium from the fully loaded sarcoplasmic reticulum to a slightly greater extent in the absence of calcium (pCa 8.5) than in the presence of a fixed level of free calcium (pCa 5.5). Whole cell patch clamping of freshly isolated chick myocytes demonstrated that BDM caused a dose-dependent decrease in the T- and L-type calcium current. Therefore, at low BDM concentrations (3 mM), the decrease in twitch force can be ascribed predominantly to depression of the contractile apparatus while, at higher concentrations of BDM, there is an additional inhibitory effect of BDM on excitation-contraction coupling.