Block of cardiac delayed‐rectifier and inward‐rectifier K + currents by nisoldipine

The objective of this study was to determine the concentration‐dependent effects of nisoldipine, a dihydropyridine Ca 2+ channel blocker, on K + currents in guinea‐pig ventricular myocytes. Myocytes in the conventional whole‐cell configuration were bathed in normal Tyrode's solution or K + ‐free Tyrode's solution for the measurement of the effects of 0.01–100 μ M nisoldipine on rapidly activating delayed‐rectifier K + current ( I Kr ), slowly activating delayed‐rectifier K + current ( I Ks ), inwardly rectifying K + current ( I K1 ), and reference L‐type Ca 2+ current ( I Ca,L ). Nisoldipine inhibited I Kr with an IC 50 of 23 μ M , and I Ks with an IC 50 of 40 μ M . The drug also had weak inhibitory effects on inward‐ and outward‐directed I K1 ; the IC 50 determined for outward‐directed current was 80 μ M . Investigation of nisoldipine action on I Ks showed that inhibition occurred in the absence of previous pulsing, and with little change in the time courses of activation and deactivation. However, the drug‐induced inhibition was significantly weaker at +30 mV than at +10 mV. We estimate that nisoldipine is about 30 times less selective for delayed‐rectifier K + channels than for L‐type Ca 2+ channels in fully polarised guinea‐pig ventricular myocytes, and several orders less selective in partially depolarised myocytes.British Journal of Pharmacology (2003) 140 , 863–870. doi: 10.1038/sj.bjp.0705518