Influence of extracellular K+ concentrations on quinidine-induced K+ current inhibition in rat ventricular myocytes

Hypokalaemia is one of the important risk factors for development of torsad es de pointes. We recently reported that hypokalaemia increased the electro cardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigat ed the influence of extracellular potassium concentration ([K+](o)) on the inhibition of several types of cardiac potassium currents by quinidine. Suc h types of currents include the delayed rectifier potassium cut-rent (I-K), the transient outward current (I-to), and the inward rectifier potassium c urrent (I-K1), as measured in isolated rat ventricular cells using patch-cl amp techniques. Concentration-dependent effects of quinidine on I-K, I-to, and I-K1 were ev aluated under both normal ([K+](o) = 5.4 mM) and hypokalaemic ([K+](o) = 3. 5 mM) conditions. In contrast to both I-K and I-to, which were barely influ enced by changes in [K+](o), I-K1 was significantly inhibited by hypokalaem ia. Furthermore, while quinidine suppressed both I-K and I-to in a concentr ation-dependent manner, the inhibitory potency of quinidine on these curren ts was not influenced by changes in [K+](o). The respective normal and hypo kalaemic IC50 values for quinidine were 11.4 and 10.0 mu M (I-K), and 17.6 and 17.3 mu M (I-to). Although higher concentrations of quinidine were requ ired to inhibit I-K1, the inhibitory potency of quinidine was also found to be insensitive to changes in [K+](o). Thus, in rats, the inhibitory potenc y of quinidine for the K+ current-types I-K, I-to and I-K1 is barely influe nced by changes in [K+](o). These findings are consistent with our previous report showing that the QT- prolonging potency of quinidine was not altered under hypokalaemic conditio ns. However, whilst hypokalaemia does not affect I-K or I-to, it can inhibi t I-K1 and can result in QT prolongation in-vivo.