Regional variation of the inwardly rectifying potassium current in the canine heart and the contributions to differences in action potential repolarization

Abstract

Background The inward rectifier potassium current, IK1, contributes to the terminal phase of repolarization of the action potential (AP), as well as the value and stability of the resting membrane potential. Regional variation in IK1 has been noted in the canine heart, but the biophysical properties have not been directly compared. We examined the properties and functional contribution of IK1 in isolated myocytes from ventricular, atrial and Purkinje tissue. Methods and Results APs were recorded from canine left ventricular midmyocardium, left atrial and Purkinje tissue. The terminal rate of repolarization of the AP in ventricle, but not in Purkinje, depended on changes in external K+ ([K+]o). Isolated ventricular myocytes had the greatest density of IK1 while atrial myocytes had the lowest. Furthermore, the outward component of IK1 in ventricular cells exhibited a prominent outward component and steep negative slope conductance, which was also enhanced in 10 mM [K+]o. In contrast, both Purkinje and atrial cells exhibited little outward IK1, even in the presence of 10 mM [K+]o, and both cell types showed more persistent current at positive potentials. Expression of Kir2.1 in the ventricle was 76.9-fold higher than that of atria and 5.8-fold higher than that of Purkinje, whereas the expression of Kir2.2 and Kir2.3 subunits was more evenly distributed in Purkinje and atria. Finally, AP clamp data showed distinct contributions of IK1 for each cell type. Conclusions IK1 and Kir2 subunit expression vary dramatically in regions of the canine heart and these regional differences in Kir2 expression likely underlie regional distinctions in IK1 characteristics, contributing to variations in repolarization in response to in [K+]o changes.

The inward rectifier current inhibitor PA‐6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models

“…In a direct comparison, ventricular I K1 density in canine ventricular cells is twofold to threefold higher than in human ventricular cardiomyocytes (Jost et al, ) which may increase the sensitivity of the human ventricle for I K1 inhibition compared to dog. Furthermore, I K1 densities found in the atrium are 10‐fold (Cordeiro et al, ) or fivefold (Wang et al, ) lower than in the ventricle of dogs and humans respectively, which may provide a safety margin for anti‐arrhythmic I K1 inhibition in the atrium and pro‐arrhythmic activity in the ventricle. Finally, we provided evidence that also human atrial I K1 is a target for PA‐6.…”

“…I channels are composed of four K ir 2.x subunits, either in a homo‐ or heteromeric configuration. In ventricles, K ir 2.1 subunits are the major constituents, whereas in atria, K ir 2.1, K ir 2.2 and K ir 2.3 subunits are more equally contributing to functional channels (De Boer et al, ; Cordeiro et al, ). Atrial cardiomyocytes have a 6‐ to 10‐fold lower I K1 density than ventricular cardiomyocytes (Wang et al, ; Cordeiro et al, ).…”

Transmural gradients in ion channel and auxiliary subunit expression

“…The Kir2.2 and Kir2.3 genes may, however, also make a significant contribution to I k1 (Liu et al, 2001) although their relative importance is species- and region dependent (Cordeiro et al, 2015; Dhamoon et al, 2004). To further complicate the molecular identity of I k1 , the different subunits can combine to form heteromultimeric channels (Dhamoon et al, 2004; Zobel et al, 2003).…”

The Beneficial Effects of Electro-acupuncture at PC6 (Neiguan-point) of Gene and Protein Expressions of Classical Inward-rectifier Potassium Channels in Myocardial Ischemic Rats

“…Normal heart rhythm depends on heart diastole and systole which is caused by the currents from the openness and closeness of ion channels on myocardial cell membrane [5]. Generally, I k1 current is regarded as a quite important role in maintaining cell rest potential [7,11]. Potassium channels are involved in cardiac repolarization [7], and classical inward-rectifier potassium channels (Kir), an important class of potassium ion channels, can regulate the excitability of cardiomyocytes and maintenance of resting potential of myocardial cells [8,9].…”

“…The normal condition of the ion channels are disordered during MI and hypoxia, and these variations play an important role in interference normal heart rhythm [6]. When the cells start to polarize, the permeability of I k1 current channel on K + reduces as the membrane potential rising and the outflow of K + reduces; I k1 current channel shuts down in further depolarization, which can prevent the excessive outflow of K + ; when cells enter the last phase of fast repolarization, I k1 current channel is activated due to the membrane potential reduction and the outflow of K + increase then accelerate repolarization [11]. (Fig.…”