Unblock of the slow inward current induces the arrhythmogenic transient inward current in isolated guinea-pig myocytes

This study investigated whether abrupt changes in extracellular Ca²⁺ concentration or washout of the Ca²⁺ antagonists Mn²⁺ or verapamil, could induce transient inward current (I_TI) in enzymatically disaggregated guinea-pig myocytes. Single electrode voltage-clamp techniques were used. I_TI was elicited upon repolarization to various voltage steps from an activating step to +20 mV. The holding potential was -80 mV. Slow inward current (I_Ca) was induced by steps to -10 mV. Continuous exposure to either 2.5 or 6.0 mm Ca²⁺ did not induce I_TI; however, following exposure of cells to 0.5 mm Ca²⁺ for 20 min which decreased I_Ca, return to 2.5 or 6.0 mm Ca²⁺ induced I_TI. I_TI could be observed for 10 to 20 min following sudden elevations of Ca²⁺. Similar effects also were seen when Ca²⁺ was increased from 2.5 to 6.0 mm. Exposure to 2.0 mm Mn²⁺ or 2.0 μm verapamil blocked I_Ca. Washout of either blocker induced I_TI, particularly in 6.0 mm Ca²⁺. Peak I_TI occurred upon repolarization at c. -70 mV; a reversal potential could not be demonstrated. Thus, abrupt changes in Ca²⁺ influx, produced either by sudden changes in external Ca²⁺ or by washout of Ca²⁺ antagonists, induced I_TI with characteristics similar to those described for I_TI induced by toxic concentrations of cardiac glycosides.