Keeping the heart going: a new role for KATP channels

Abstract

Heart failure is a major cause of death in Western societies. It is usually precipitated by an increased haemodynamic load against which the heart must pump, such as that caused by narrowing of the aorta. For reasons still not understood, some individuals are more susceptible to heart failure. The issue of how the heart adapts to changes in ventricular pressure load is therefore of considerable significance. The paper by Yamada et al. (2006) in this issue of The Journal of Physiology reveals that KATP channels are involved in adaptation to ventricular pressure load and protect against heart failure. KATP channels serve as metabolic sensors that translate changes in cell metabolism into changes in electrical activity. In the heart, KATP channels are normally closed but they open in response to various forms of cardiac stress, including ischaemia, physical exertion, stress hormones such as adrenaline, and mineralocorticoid-induced hypertension (Kane et al. 2005). Opening of KATP channels leads to membrane hyperpolarization and shortening of the cardiac action potential, thereby reducing contractility. In this way, KATP channels serve to reduce calcium influx and ATP consumption at times of metabolic stress. Because the membrane resistance is very high during the plateau of the cardiac action potential, opening of as few as 1% of the KATP channels in the cell can halve the cardiac action potential duration (Faivre & Findlay, 1990). Cardiac KATP channels are composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR2A) subunits. Both contribute to metabolic regulation, with ATP blocking the channel via binding to Kir6.2 and Mg-nucleotides opening it via interaction with SUR2A. The sulphonylurea receptor also confers sensitivity to a variety of drugs, including the sulphonylureas for which it was named. Genetic deletion of Kir6.2 results in the total loss of functional cardiac KATP channels, as both types of subunit are required to form a functional channel. Mice lacking KATP channels due to knockout of Kir6.2 (Kir6.2-KO mice) have previously been shown to exhibit enhanced sensitivity to several forms of cardiac stress, including ischaemia and sympathetic stimuli. Yamada et al. (2006) now use Kir6.2-KO mice to explore the role of cardiac KATP channels in heart failure. In wild-type mice, no change in action potential duration or energetic handling was observed in response to ventricular pressure overload induced by transverse aortic constriction. In contrast, Kir6.2-KO mice showed an abnormal prolongation of the cardiac action potential that resulted in elevation of intracellular Ca2+ and ATP depletion. Similar effects were found in wild-type mice when KATP channels were inhibited with the sulphonylurea glyburide. Within hours of aortic constriction, Kir6.2-KO mice developed biventricular congestive heart failure, characterized by decreased cardiac function, fluid retention, progressive sinus bradycardia and atrio-ventricular conduction block. After 48 h, about half of them were dead. However, wild-type animals showed no evidence of increased mortality or heart failure. Surviving Kir6.2-KO animals exhibited compromised cardiac function and myocardial hypertrophy, which were associated with up-regulation of the transcription factors MEF2 and NF-AT. Precisely how ventricular pressure overload results in opening of KATP channels remains unclear. One possibility is that channels are activated by mechanical stretch of the ventricle wall. In support of this idea, previous studies have shown that KATP channels in atrial myocytes are opened by cell swelling, leading to action potential shortening (Van Wagoner, 1993; Saegusa et al. 2005). Furthermore, disruption of the actin network, as might occur in response to stretch, leads to cardiac KATP channel activation (Terzic & Kurachi, 1996). Thus it seems reasonable to speculate that ventricular KATP channels are activated by stretch, but this remains to be established. In conclusion, Yamada et al. (2006) demonstrate a new functional role for the KATP channel in the heart: protection against left ventricular pressure overload and congestive heart failure. A second intriguing suggestion is that KATP channels may be involved in regulation of gene expression, via their ability to regulate calcium influx. Finally, the discovery that cardiac KATP channels are involved in the response to ventricular overload may have therapeutic implications. Many patients with type 2 diabetes are treated with sulphonylureas. Some of these drugs preferentially block pancreatic β-cell KATP channels, whereas others, like glyburide, block both cardiac and pancreatic β-cell KATP channels. This suggests that sulphonylureas should be administrated with care in patients affected by type 2 diabetes if they also suffer from left ventricle pressure overload. Furthermore, it raises the question of whether K+ channel openers might be helpful in congestive heart failure.