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Background: The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K+ current (IK1) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear.Objective: The purpose of this study was to define the effect of IK1 suppression on the cardiac AP and excitability in the normal and failing hearts.Methods: We used electrophysiological and pharmacological approaches to investigate IK1 function in a swine tachy-pacing model of heart failure (HF).Results: Terminal repolarization of the AP (TRAP; the time constant of the exponential fit to terminal repolarization) was markedly prolonged in both myocytes and arterially perfused wedges from animals with HF. TRAP was increased by 54.1% in HF myocytes (P < .001) and 26.2% in HF wedges (P = .014). The increase in TRAP was recapitulated by the potent and specific IK1 inhibitor, PA-6 (pentamidine analog 6), indicating that IK1 is the primary determinant of the final phase of repolarization. Moreover, we find that IK1 suppression reduced the ratio of effective refractory period to AP duration at 90% of repolarization, permitting re-excitation before full repolarization, reduction of AP upstroke velocity, and likely promotion of slow conduction.Conclusion: Using an objective measure of terminal repolarization, we conclude that IK1 is the major determinant of the terminal repolarization time course. Moreover, suppression of IK1 prolongs repolarization and reduces postrepolarization refractoriness without marked effects on the overall AP duration. Collectively, these findings demonstrate how IK1 suppression may contribute to arrhythmogenesis in the failing heart. [ABSTRACT FROM AUTHOR]

Considering the effects of alcohol on cardiac electrical behavior as well as the important role of the inward rectifier potassium current IK1 in arrhythmogenesis, this study was aimed at the effect of acetaldehyde, the primary metabolite of ethanol, on IK1 in rat ventricular myocytes. Acetaldehyde induced a reversible inhibition of IK1 with IC50 = 53.7±7.7 µM at -110 mV; a significant inhibition was documented even at clinically-relevant concentrations (at 3 µM by 13.1±3.0 %). The inhibition was voltage-independent at physiological voltages above -90 mV. The IK1 changes under acetaldehyde may contribute to alcoholinduced alterations of cardiac electrophysiology, especially in individuals with a genetic defect of aldehyde dehydrogenase where the acetaldehyde level may be elevated. [ABSTRACT FROM AUTHOR]

Background: Normal cardiac rhythm is critically dependent on the sinoatrial (SA) node, the natural biological pacemaker. Although recent studies have focused on the development of “artificial” biological pacemakers using gene transfer, less is known about the functional consequences of such interventions. Objective: The purpose of this study was to investigate the electrophysiological consequences of two approaches used to create a biological pacemaker: overexpression of the hyperpolarization-activated cyclic nucleotide gated channel (HCN “pacemaker” channels) and suppression of the inward-rectifier potassium current, IK1. Methods: We used a linear multicellular Luo-Rudy (LRd) AP model consisting of 130 ventricular cells connected by resistive gap junctions. To induce automaticity, IK1 current was reduced or If (HCN) current was introduced in endocardial and midmyocardial (M) cells. Results: Similar to the previously published results for a single LRd model, myocyte IK1 suppression induced automaticity in the fiber. While introduction of If also resulted in automaticity, the main differences between IK1 suppression and If expression were (1) a relatively more gradual phase 4 depolarization with HCN expression, (2) stabilization of cycle lengths during IK1 suppression, but not during HCN expression, and (3) responsiveness to β-adrenergic stimulation during HCN expression, but not during IK1 suppression. Upon further investigation, we found that cycle length instability during HCN expression was primarily due to a gradual reduction of intracellular potassium ([K+]i) from its baseline value of 142 mM to 120 mM in 600 beats and subsequent alteration of potassium-dependent ionic currents. A twofold increase in HCN expression also led to a similar behavior. We attribute this decrease in [K+]i to a large IK1 during phase 4 depolarization. When intracellular [K+]i loss was minimized, cycle lengths stabilized during HCN expression. Conclusions: Our results help to further understand the electrophysiologic consequences as well as some of the challenges associated with the creation of biological pacemakers using HCN and IK1 gene transfer strategies. [Copyright &y& Elsevier]

Abstract: In vivo light-induced and basal hydrolysis of phosphatidyl inositol 4,5-bisphosphate (PIP2) by phospholipase C (PLC) were monitored in Drosophila photoreceptors using genetically targeted PIP2-sensitive ion channels (Kir2.1) as electrophysiological biosensors for PIP2. In cells loaded via patch pipettes with varying concentrations of Ca2+ buffered by 4mM free BAPTA, light-induced PLC activity, showed an apparent bell-shaped dependence on free Ca2+ (maximum at “100nM”, ∼10-fold inhibition at <10nM or ∼1μM). However, experiments where the total BAPTA concentration was varied whilst free [Ca2+] was maintained constant indicated that inhibition of PLC at higher (>100nM) nominal Ca2+ concentrations was independent of Ca2+ and due to inhibition by BAPTA itself (IC50 ∼8mM). Di-bromo BAPTA (DBB) was yet more potent at inhibiting PLC activity (IC50 ∼1mM). Both BAPTA and DBB also appeared to induce a modest, but less severe inhibition of basal PLC activity. By contrast, EGTA, failed to inhibit PLC activity when pre-loaded with Ca2+, but like BAPTA, inhibited both basal and light-induced PLC activity when introduced without Ca2+. The results indicate that both BAPTA and DBB inhibit PLC activity independently of their role as Ca2+ chelators, whilst non-physiologically low (<100nM) levels of Ca2+ suppress both basal and light-induced PLC activity. [Copyright &y& Elsevier]