Ca²⁺ Overload Evokes a Transient Outward Current in Guinea-Pig Ventricular Myocytes

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There are 2 types of transient outward currents (I_to) in the hearts of various mammals: a 4-aminopyridine (4-AP) sensitive K⁺ current and a 4-AP resistant Ca²⁺ activated current, carried by Cl^-, (referred to as I_to1 and I_to2, respectively). However, the I_to has been considered to be absent in guinea-pig ventricular myocytes and so this study tested the hypothesis that I_to1 is generally absent in guinea-pig ventricular myocytes, but I_to2 appears under the condition of Ca²⁺ overload. Membrane currents were recorded by the whole-cell patch-clamp technique and Ca²⁺ overload was achieved by adding internal, and eliminating external, Na⁺ with subsequent enhancement of Ca²⁺ influx via the Na⁺-Ca²⁺ exchange. Under physiological conditions, I_to could not be elicited by 300 ms-test pulse from -70 mV to 0 mV (n=32). However, under Ca²⁺ overload, a biphasic current resulting from the overlap of the L-type Ca²⁺ channel current and I_to was elicited (n=38). This I_to was resistant to 4-AP (3 mmol/L, n=30) but sensitive to both anthrancene-9-carboxylic acid (9-AC, 3 mmol/L, n=8) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (100 μmol/L, n=3). Replacing K⁺ with Cs⁺ on both sides of the membrane failed to abolish I_to (n=38). I_to disappeared by lowering the external Cl- (n=3). The amplitude of I_to was dependent on that of the L-type Ca²⁺ channel current (n=4). Because Ca²⁺ release from the sarcoplasmic reticulum was prevented by caffeine (5 mmol/L), I_to was negligible (n=6). These results suggest that I_to1 is absent, but Ca²⁺ overload evokes I_to2 in guinea-pig ventricular myocytes. (Circ J 2002; 66: 87 - 92)