Inhibition of transient outward K+ current by DHP Ca2+ antagonists and agonists in rabbit cardiac myocytes

Abstract

The 1,4-dihydropyridine (DHP) Ca2+ antagonists and agonists can inhibit a time- and voltage-dependent, but intracellular Ca(2+)-independent transient outward K+ current (It), in myocytes from rabbit atrium. In the presence of 0.3 mM CdCl2, DHPs decreased the peak It slightly and markedly accelerated its apparent rate of inactivation. When the inhibition of It was measured from integrated It records, the 50% inhibitory concentrations (IC50) of nicardipine and BAY K 8644 were 630 nM and 7 microM, respectively, and the IC50 of nicardipine for inhibition of the Ca2+ current (ICa) was only approximately fourfold lower (160 nM). The inhibition of It by nicardipine was not affected by changing holding potential from -55 to -100 mV; in contrast, the inhibitory effect on ICa was significantly reduced by this hyperpolarization. We conclude that the DHP Ca2+ antagonist nicardipine blocks It at similar doses to those that block ICa and that nicardipine blocks this K+ current by mechanism different from that for ICa inhibition. This inhibitory effect on It is shared by other DHP compounds; the rank order for potency of It inhibition is nicardipine greater than benidipine greater than nisoldipine greater than BAY K 8644 greater than nitrendipine greater than nifedipine.