Four different components contribute to outward current in rat ventricular myocytes

In rat ventricle, two Ca2+-insensitive components of K+ current have been distinguished kinetically and pharmacologically, the transient, 4-aminopyridine (4-AP)-sensitive I-to and the sustained, tetraethylammonium (TEA)-sensitive I-K. However, a much greater diversity of depolarization-activated K+ channels has been reported on the level of mRNA and protein. In the search for electrophysiological evidence of further current components, the whole cell voltage-clamp technique was used to analyze steady-state inactivation of outward currents by conditioning potentials in a wide voltage range. Peak (I-peak) and late (I-late) currents during the test pulse were analyzed by Boltzmann curve fitting, producing three fractions each. Fractions a and b had different potentials of half-maximum inactivation (V-0.5); the third residual fraction, r, did not inactivate. Fractions a for I-peak and I-late had similar relative amplitudes and V-0.5 values, whereas size and V-0.5 of fractions b differed significantly between I-peak and I-late. Only b of I-peak was transient, suggesting a relation with I-to, whereas a, b, and r of I-late appeared to be three different sustained currents. Therefore, four individual outward current components were distinguished: I-to (b of I-peak), I-K (a), the steady-state current I-ss (r), and the novel current I-Kx (b of I-late). This was further supported by differential sensitivity to TEA, 4-AP, clofilium, quinidine, dendrotoxin, heteropodatoxin, and hanatoxin. With the exception of I-to, none of the currents exhibited a marked transmural gradient. Availability of I-K was low at resting potential; nevertheless, I-K contributed to action potential shortening in hyperpolarized subendocardial myocytes. In conclusion, on the basis of electrophysiological and pharmacological evidence, at least four components contribute to outward current in rat ventricular myocytes.