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

1 The objective of this study was to determine the concentration-dependent effects of nisoldipine, a dihydropyridine Ca2+ channel blocker, on K+ currents in guinea-pig ventricular myocytes. 2 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 muM 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 Ca2+ current (I-Ca,I-L). 3 Nisoldipine inhibited I-Kr with an IC50 of 23 muM, and I-Ks with an IC50 of 40 muM. The drug also had weak inhibitory effects on inward- and outward-directed I-K1; the IC50 determined for outward-directed current was 80 muM. 4 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 greater than or equal to + 30 mV than at + 10 mV. 5 We estimate that nisoldipine is about 30 times less selective for delayed-rectifier K+ channels than for L-type Ca2+ channels in fully polarised guinea-pig ventricular myocytes, and several orders less selective in partially depolarised myocytes.