Characteristics of the Delayed Rectifier Current (I _Kr and I _Ks ) in Canine Ventricular Epicardial, Midmyocardial, and Endocardial Myocytes

Abstract

Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine, feline, rat, guinea pig, and human hearts. In this study, we use standard microelectrode and whole-cell patch-clamp techniques to examine the characteristics of the action potential and the delayed rectifier K+ current (IK) in epicardial, M region (deep subepicardial to midmyocardial), and endocardial cells isolated from the canine left ventricle. Cells from the M region displayed much longer action potential durations (APDs) at slow rates. At a basic cycle length of 4 s, APD measured at 90% repolarization was 358 +/- 16 (mean +/- SEM), 262 +/- 12, and 287 +/- 11 ms in cells from the M region, epicardium, and endocardium, respectively. Steady state APD-rate relations were steeper in cells from the M region. In complete Tyrode's solution, IK was smaller in myocytes from the M region when compared with those isolated from the epicardium or endocardium. Further characterization of IK was conducted in a Na(+)-, K(+)-, and Ca(2+)-free bath solution to isolate the slowly activating component of the delayed rectifier (IKs) from the rapidly activating component (IKr). IKs was significantly smaller in M cells than in epicardial and endocardial cells. With repolarization to -20 mV, IKs tail current density was 1.99 +/- 0.30 pA/pF (mean +/- SEM) in epicardial cells, 1.83 +/- 0.18 pA/pF in endocardial cells, and 0.92 +/- 0.14 pA/pF in M cells. Voltage dependence and time course of activation and deactivation of IKs were similar in the three cell types. The relative contribution of IKr and IKs among the three cell types was examined by using 6 mmol/L [K+]o Tyrode's solution with and without E-4031, a highly selective blocker of IKr. An E-4031-sensitive current was observed in the presence but not in the absence of extracellular K+. This rapidly activating component showed characteristics similar to those of IKr as described in rabbit and cat ventricular cells. Deactivation of IKr was significantly slower than that of IKs. IKr (E-4031-sensitive component) tail current density was similar in the three cell types, whereas IKs (E-4031-insensitive component) tail current density was significantly smaller in the M cells. Our results suggest that the distinctive phase-3 repolarization features of M cells are due in part to a lesser contribution of IKs and that this distinction may also explain why M cells are the main targets for agents that prolong APD in ventricular myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)

Density and Kinetics of I Kr and I Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

“…It is larger in epicardium and endocardium than in midmyocardium, 7 in the right than in the left canine ventricle, 8 and at the base than the apex in the rabbit ventricles. 9 The removal of these 3 types of regional inhomogeneities by pharmacological blockade may render the heart electrically more homogeneous.…”

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

“…Though controversial (online-only Data Supplement section J), CaMKII phosphorylation is thought to promote RyR channel opening. 5,14,20 Accordingly, the I rel inactivation time constant ( ri ) depends on CaMKII activity. A 10-ms maximal CaMKII-dependent increase in ri yields a steady-state CaT amplitude (CaT amp ) 95% 20 greater for control than with CaMKII suppressed at rapid pacing (CLϭ300 ms).…”

“…Our model represents an important advance in the physiologic representation of ratedependent cell processes through its inclusion of the CaMKII regulatory pathway, shown experimentally to play a role in the force-frequency relation and rate-dependent CaT abbreviation. 14,20,40 "Local-control" 41 Ca 2ϩ release has been integrated into a canine AP model, 42 wherein SR Ca 2ϩ release involves statistical recruitment of individual Ca 2ϩ release units. Although this model reproduces macroscopic release based on individual diadic events, computational demands discourage its use in modeling cardiac arrhythmias.…”

The role of transmural ventricular heterogeneities in cardiac vulnerability to electric shocks

“…Experimental studies using isolated endocardial, midmyocardial and epicardial myocytes report transmural differences in I to in canine, rabbit, guinea pig and human (Li et al, 1998;McIntosh et al, 1998;Antzelevitch et al, 1999a, b), in I Na in canine (Antzelevitch et al, 1999a, b), in I Ks in canine and rabbit (Liu and Antzelevitch, 1995;Xu et al, 2001;Yan et al, 2001), and to a smaller extent, in I Kr in rabbit ). In our study, transmural heterogeneities in ionic currents have been incorporated based on rabbit experimental data (McIntosh et al, 1998(McIntosh et al, , 2000Xu et al, 2001), as done in a previous simulation study (Saucerman et al, 2004).…”