Extracellular K+ dependence of inward rectification kinetics in human left ventricular cardiomyocytes

Abstract

Background: In human ventricular cells, the inwardly rectifying K+ current (IK1) is very similar to that of other mammalian species, but detailed knowledge about the K+-dependent distribution of open and blocked states during rectification and about the K+-dependent modulation of inactivation on hyperpolarization is currently lacking.

Methods and results: We used the whole-cell patch-clamp technique to record IK1 in myocytes isolated from subendocardial layers of left ventricular septum from patients with nonfailing hearts with aortic stenosis and cardiac hypertrophy who were undergoing open-heart surgery. Outward currents were very small at voltages positive to the reversal potential but increased at high external [K+]. Chord conductance measurements and kinetic analyses allowed us to estimate the proportion of channels in the open state and of those showing either slow unblock or instantaneous unblock (the so-called slow or instantaneous "activation") on hyperpolarization: the distribution in the individual states was dependent on external [K+]. The proportion of channels unblocking slowly was greater than that of channels unblocking instantaneously on hyperpolarization from the plateau voltage range. Hence, because of the previously reported link between the presence of highly protonated blocking molecules and slow unblock kinetics, it is suggested that high cellular concentrations of spermine may account for the low outward current density recorded in these cells. The current decrease observed on extended hyperpolarization was significantly relieved by an increase in external [K+].

Conclusions: The pattern of IK1 current alterations observed in the present model of human ventricular hypertrophy might favor enhanced excitability and underlie ventricular arrhythmias, possibly via increased intracellular polyamine levels.