Effects of divalent cations on the E-4031-sensitive repolarization current, IKr, in rabbit ventricular myocytes

The effects of divalent cations on the E-4031-sensitive repolarization current (I-Kr) were studied in single ventricular myocytes isolated from rabbit hearts. One group of divalent cations (Cd2+, Ni2+, Co2+, and Mn2+) produced a rightward shift of the I-Kr activation curve along the voltage axis, increased the maximum I-Kr amplitude (i.e., relieved the apparent inward rectification of the channel), and accelerated I-Kr tail current kinetics. Another group (Ca2+, Mg2+ and Sr2+) had relatively little effect on I-Kr. The only divalent cation that blocked I-Kr was Zn2+ (0.1-1 mM). Under steady-state conditions, Ba2+ caused a substantial block of I-K1, as previously reported. However, block by Ba2+ was time dependent, which precluded a study of Ba2+ effects on I-Kr. We conclude that the various effects of the divalent cations can be attributed to interactions with distinct sites associated with the rectification and/or inactivation mechanism of the channel.