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

Abstract

Because the number and characteristics of delayed rectifier K+ current (IK) 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, IK was assessed in adult isolated canine ventricular and and atrial myocytes by using whole-cell and perforated-patch techniques. IK components were characterized by using two complementary approaches: a kinetic approach (based on biexponential fits to deactivating tail currents) and a pharmacological approach 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+). 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 described kinetically were identified. The activation kinetics and rectification properties of canine IKr and IKs are qualitatively similar to those described previously for guinea pigs. In contrast, canine IKr and IKs deactivation kinetics differed markedly from those found in guinea pigs, with canine IKr deactivating slowly (time constant tau, 2 to 3 s near -35 mV) and IKs 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 IKs deactivation during rapid stimulation (due to rapid deactivation of canine IKs). Two IK components with characteristics comparable to those found in ventricular myocytes were also observed in atrial myocytes. In conclusion, (1) IKr- and IKs-like components of IK 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 IKs do not support its role in reverse rate dependence with class III agents in this species.