Properties of the delayed rectifier potassium current in porcine sino‐atrial node cells

Abstract

Whole‐cell currents were recorded in single, spontaneously active cells dissociated from porcine sino‐atrial node, and the conductance and gating properties of the delayed rectifier K+ current (IK) were investigated. The isolated cells exhibited spontaneous action potentials at a rate of 80.5 ± 5.4 min−1 (mean ± s.e.m., n= 11). Under Ca2+ current block, depolarization from ‐40 mV to various potentials activated a time‐dependent outward current (IK). The activation curve of IK showed a half‐activation potential (V½) of 20.5 ± 2.1 mV and a slope factor (S) of 16.4 ± 1.2 mV (n= 8). As the duration of the depolarizing pulse to either +10 or +60 mV was prolonged, the amplitude of the tail current increased in proportion to that of the activated outward current during depolarization. E4031 (2‐5 μM), a selective blocker for the rapidly activating component of IK (IK,r), hardly affected IK, but chromanol 293B, a selective blocker for the slowly activating component (IK,s), inhibited IK with an IC50 of 8.79 μM. The reversal potential of IK was ‐75.2 ± 2.3 mV with 5.4 mM external and 150 mM internal K+. The time courses of activation and deactivation of IK were fitted by the sum of two exponential functions at various potentials. The relationship between the time constants and membrane potential showed a bell‐shaped curve with a peak at around ‐10 mV for both fast and slow components. The results indicate that in porcine sino‐atrial node cells IK is largely derived from IK,s and that IK,s plays a functional role in the slow diastolic depolarization. IK,s may, in part, account for the relatively slower heart rate of pigs than that of rabbit in which IK,r is a functionally dominant component of IK.

Functional role of L-type Ca v 1.3 Ca 2+ channels in cardiac pacemaker activity

“…To this respect, it is also possible that pacemaking in larger mammals such as humans could involve additional ionic channels that may not be expressed in the mouse. For example, the slow component of the delayed rectifier (I Ks ) has been reported to play a significant role in pacemaking in the pig heart (18). Understanding the ionic basis of pacemaking may yield important indications in the development of new drugs that specifically influence heart rate without affecting cardiac inotropism.…”

Creation of a Biopacemaker: Lessons from the Sinoatrial Node

“…In rabbit and mouse SA node cells, blockade of I Kr with E-4031 prolonged cycle length and action potential duration, and depolarized the MDP (Clark et al, 2004;Verheijck et al, 1995). Since I Kr is absent from pig SA node, blocking of I Kr did not have any affect on the action potential or cycle length in this species (Ono et al, 2000).…”

“…I K currents are responsible for repolarization, but the role of the different I K components in the SA node varies between species. I Kr seems to play an important role in rabbits, while, in guinea pig, I K is mainly composed of I Ks (Matsuura et al, 2002); in pig, I Kr appears to be absent altogether (Ono et al, 2000). Functional data about I K in human SA node are lacking, but mRNA for all three channels has been found in human SA node (Chandler et al, 2009).…”

“…No I Ks has been found in mouse SA node (Cho et al, 2003), and, as expected, KCNQ1 knock out mice do not show prolongation of cycle length (Knollmann et al, 2004). Since I Ks is the only I K present in pig, spontaneous activity ceased on blocking I Ks with chromanol 293B (Ono et al, 2000).…”

Pacemaker Mechanism of Porcine Sino-atrial Node Cells.

“…To get insight into the pacemaker mechanism of the hearts of other species including the human heart, we have attempted to isolate the pacemaker cells of the porcine SAN. The porcine heart rate, ranging between 60-80 min -1 in the resting condition, is much slower than that of the rabbit (Shibata et al, 1999;Ono et al, 2000). On the basis of the action potentials and the membrane currents recorded in porcine SAN cells, the ionic mechanisms underlying the species difference in heart rate is discussed.…”