Characterization of inward-rectifier K+ channel inhibition by antiarrhythmic piperazine

Strong inward-rectifier K(+) (Kir) channels play a significant role in shaping the cardiac action potential: they help produce its long plateau and accelerate its rate of repolarization. Consequently, genetic deletion of the gene encoding the strongly rectifying K(+) channel IRK1 (Kir2.1) prolongs the cardiac action potential in mice. In principle, broadening the action potential lengthens the refractory period, which may in turn be antiarrhythmogenic. Interestingly, previous studies showed that piperazine, an inexpensive and safe anthelmintic, both inhibits IRK1 channels and is antiarrhythmic in some animal preparations. This potential pharmacological benefit motivated us to further characterize the energetic, kinetic, and molecular properties of IRK1 inhibition by piperazine. We show how its blocking characteristics, in particular, its shallow voltage dependence, allow piperazine to be effective even in the presence of high-affinity polyamine blockers. We also examine the channel selectivity of piperazine and its molecular determinants.