Comparative interactions of organic Ca++ channel antagonists with myocardial Ca++ and K+ channels

Dose-dependent inhibition by three organic calcium channel antagonists, D-600, nisoldipine and diltiazem, of the inward calcium current (iCa) and the delayed, outward potassium current (iK) in single frog atrial cells was examined using a voltage clamp technique. At holding potentials of -60 mV, low concentrations of these antagonists produced considerable inhibition of iCa without significant alterations in iK, suggesting that iK in single frog atrial cells is not a calcium-activated K+ conductance. Higher concentrations of each of these antagonists, however, inhibited iK. The estimated Kd values for inhibition of iCa and iK, respectively, were 3.7 X 10(-7) M and 8.2 X 10(-4) M for D-600, 1.6 X 10(-8) M and 1.6 X 10(-5) M for nisoldipine and 4.4 X 10(-6) M and 3.3 X 10(-4) M for diltiazem. Under these experimental conditions, D-600 and nisoldipine interact more selectively with myocardial Ca++ channels than K+ channels compared to diltiazem, which is less selective. In addition, the inhibition of iK by each of these antagonists was found to exhibit an apparent voltage dependence; block was enhanced at more negative membrane potentials and relieved at more positive membrane potentials. This voltage-dependent block of iK is, therefore, opposite to the voltage-dependent inhibition of iCa produced by these compounds, where block of iCa is accentuated at positive membrane potentials.