Analyzing the role of ATP-dependent potassium channels in the regulation of coronary metabolic vasodilation during exercise

Abstract The purpose of this meta-analysis is to compile, integrate, and assess studies that have investigated the role of ATP-dependent potassium channels (K ATP channels) in coronary metabolic vasodilation in vivo. K ATP channels are important modulators of membrane potential and vascular reactivity and are commonly proposed as regulating coronary blood flow in response to myocardial metabolism. For example, the electro-metabolic hypothesis of Lederer and colleagues (Zhao et al., Proc Natl Acad Sci 117:7461–70, 2020) suggests a pathway where myocardial metabolic activity reduces intracellular ATP, thus activating myocardial K ATP channels to elicit vasodilation. The data collected here suggest that K ATP channels are involved in determining resting vascular tone, but that their contribution does not increase with metabolism (a tonic 15% decrease in flow by glibenclamide). Furthermore, inhibiting K ATP channels with glibenclamide impairs cardiac function by reducing coronary flow at rest, a clear indicator of ischemia, but this effect is overcome by endogenous mediators of vasodilation during increases in metabolism. These findings are inconsistent with the negative feedback/K ATP channel version electro-metabolic hypothesis. Other cardiac K + channels remain viable as candidates to mediate the vasodilatory mechanisms in this electro-metabolic paradigm. An amendment to the electro-metabolic hypothesis is proposed whereby the scheme is altered to feedforward. Specifically, we suggest considering the opening of other types of K + channels in direct proportion to heart rate, ones whose activity can be linked directly to the increased frequency of cardiac action potentials or those that respond to mitochondrial factors or increased intracellular Na + . Whether the feedforward mechanism we propose can be supported experimentally remains to be determined.