Effect of an antihypertensive hydrazine derivative on Ca2+ current of single frog cardiac cells

The effects of MP 518, an acylated 2-chlorobenzylidene hydrazidone derivative with antihypertensive properties were investigated on the CA current, ICa, recorded under whole-cell patch-clamp in single frog ventricular cells. MP 518 (1-100 microM) had no effect on ICa under control conditions. However, at 10 microM it significantly increased the beta-adrenergic stimulated ICa, an effect similar to that of isobutylmethyl-xanthine (IBMX), a non-specific phosphodiesterase inhibitor. The effects of MP 518 and IBMX were not, however, additive. This positive effect was also observed with both compounds, MP 518 and IMBX, when a submaximal dose of cyclic AMP was intracellularly perfused. In the presence of IBMX or at a high concentration (100 microM), MP 518 had a negative effect on beta-adrenergic stimulated ICa. It was thus considered that the main effect of MP 518 is an antiphosphodiesterase activity, since the increase in ICa induced by low concentrations of MP 518 could be related to inhibition of cAMP degradation; however, at higher concentrations, MP 518 antagonizes beta-adrenergic stimulation, possibly at several levels. Such an antiphosphodiesterase activity can account for the vasorelaxant effects as well as the tachycardic effects of MP 518.