KATP Channel Blockade as a Novel Antiarrhythmic Strategy: Evolving From Tachy to Brady Therapy

ATP-sensitive potassium (KATP) channels have been best characterized in pancreatic tissue where they regulate insulin secretion from β islet cells (1). Since their discovery in cardiac cells (2), they have been shown to play a central role in coupling cellular metabolism with cardiac electrophysiology. The KATP channel is a hetero-octamer complex. It consists of tetramers of an inwardly rectifying K channel subunit, the pore-forming subunit, and an outer sulfonylurea receptor subunit, the regulatory subunit. Each of these subunits has different isoforms and differential isoform expression in different organ systems. As a result, their function varies in different tissues, organ systems, and even within a single organ. Under normal physiological conditions, when ATP levels inside cardiomyocytes are replete, KATP channels are closed and do not contribute to action potential configuration. On the contrary, during ischemia (or hypoglycemia) when intracellular ATP levels are depleted, activation of KATP channels results in efflux of potassium to extracellular environment. This can result in shortening of action potential duration (and refractory period) and decreased conduction velocity, creating a substrate for tachy arrhythmias. The roles of KATP channels in cardiac tachy arrhythmogenesis and its modulation to prevent cardiac arrhythmias have been of interest to our laboratory. We have also demonstrated that there is differential expression of KATP channels between epicardium and endocardium in human hearts, contributing to left ventricular transmural dispersion of refractoriness during ischemia that provides a substrate for arrhythmogenesis. Blocking KATP channels using glibenclamide prevents the shortening of action potential (and effective refractor period) caused by ischemia and attenuates the dispersion of refractoriness, contributing to spontaneous termination of ventricular fibrillation (VF) (3). In a biophysically detailed rabbit ventricular computer model, we demonstrated once again that the KATP channel expression heterogeneity led to higher transmural activation rate gradients and sustained VF. The simulated glibenclamide pretreatment could suppress VF by blocking the KATP channels, and an early termination was observed when this drug effect was applied during VF (4). It has been suggested that the expression of KATP channels in heart is not homogeneous. Rather, there is spatial heterogeneity in the expression of KATP channels. Glukhov et al. (5) studied the effect of isoform-specific KATP channel openers in mice and reported that there is differential expression of KATP channel isoforms in mice atria and ventricles that translates into different effects of KATP channel modulation on action potential configuration in these chambers. Additionally, differential expression of KATP channel isoforms has also been demonstrated within the same cardiac chamber in ischemic conditions. Isodoro Taveres et al. (6) demonstrated selectively increased KATP subunit conductance and expression in cardiomyocytes from infarct border zone. Because KATP channels are activated in ischemic conditions, their activation, in the setting of heterogeneous expression, can result in varied effects on action potential duration contributing to spatial heterogeneity of refractory period and arrhythmogenesis. Although there has been some suggestion of KATP channel activation contributing to transient bradyarrhythmias (7), the role of KATP channels, as well as KATP channel modulation, in bradyarrhythmia has not been very well studied. The physiological basis by which KATP channel modulation may lead to bradyarrhythmia is not clear, although efflux of potassium to the extracellular environment can contribute to decreased conduction velocity, predisposing to conduction block and bradyarrhythmias. In the July issue of Endocrinology, Reno et al. (8) investigated the role of KATP channel modulation in hypoglycemia-induced bradyarrhythmias in rats. They demonstrated that hypoglycemia caused by hyperinsulinemia results in first-, second-, and third-degree heart block and increased mortality in Sprague Dawley rats. Glibenclamide, a KATP channel blocker, completely prevented first- and third-degree heart blocks, whereas the incidence of second-degree heart block was significantly reduced. Importantly, hypoglycemia-induced mortality was completely prevented by glibenclamide. On the contrary, diazoxide, a KATP channel opener, had no effect on either bradyarrhythmia incidence or hypoglycemia-induced mortality. These are important findings. The principal reason of limited clinical use of glibenclamide is increased risk of hypoglycemia. This study demonstrated that, despite the increased risk of hypoglycemia, glibenclamide protects against hypoglycemia-induced bradyarrhythmias and mortality. Reno et al. (8) provide the rationale for future studies to understand the role of KATP channel modulation in bradyarrhythmias, in the broader context of new therapeutic advances and the multitude of actions caused by KATP channel modulation. It is important to reiterate that nonselective KATP channel blockade can have undesirable consequences. Most importantly, it can prevent ischemic preconditioning contributing to increased ischemic insult. Thus, the role KATP modulation for bradyarrhythmia prevention has to be balanced with impact on ischemia preconditioning and arrhythmogenesis with carefully planned studies of cardioselective KATP channel blockade. ATP-sensitive potassium ventricular fibrillation Disclosure Summary: The authors have nothing to disclose.

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