Two components of delayed rectifier current in canine atrium and ventricle - Does I-Ks play a role in the reverse rate dependence of class III agents?

Because the number and characteristics of delayed rectifier K+ current (I-K) components vary between species, the role of each component in the action potential and modulation by class III agents is uncertain. To address these issues, I-K was assessed in adult isolated canine ventricular and atrial myocytes by using whole-cell and perforated-patch techniques. I-K components were characterized by using two complementary approaches: a kinetic approach (based on biexponential fits to deactivating tail currents) and a pharmacological approach (using the methanesulfonanilide compound E-4031). In ventricular myocytes, two exponential tail current components were distinguished; these components differed in the voltage and time dependence of activation and the effect of lower [K+](o). Both kinetic components contributed equally to peak tail current amplitude (measured at -35 mV) after a single 300-ms pulse to 5 mV, simulating an action potential. By use of E-4031, rapidly and slowly activating components of I-K (I-Kr and I-Ks respectively) that were analogous to tail components described kinetically were identified. The activation kinetics and rectification properties of canine I-Kr and I-Ks are qualitatively similar to those described previously for guinea pigs. In contrast, canine I-Kr and I-Ks deactivation kinetics differed markedly from those found in guinea pigs, with canine I-Kr deactivating slowly (time constant tau, 2 to 3 s near -35 mV) and I-Ks deactivating rapidly (tau, 150 ms near -35 mV and decreasing to 30 ms near -85 mV). E-4031 elicited reverse rate-dependent effects (greater drug-induced prolongation of the action potential at slower stimulation rates); this effect is inconsistent with the hypothesis attributing reverse rate dependence to incomplete I-Ks deactivation during rapid stimulation (due to rapid deactivation of canine I-Ks). Two I-K components with characteristics comparable to those found in ventricular myocytes were also observed in atrial myocytes. In conclusion, (1) I-Kr- and I-Ks-like components of I-K are present in canine atrial and ventricular myocytes, with deactivation kinetics strikingly different from those found in guinea pigs, and (2) the rapid deactivation kinetics of canine I-Ks do not support its role in reverse rate dependence with class III agents in this species.