ATP- and voltage-dependent electro-metabolic signaling regulates blood flow in heart.

Local control of blood flow in the heart is important yet poorly understood. Here we show that ATP-sensitive K+ channels (KATP), hugely abundant in cardiac ventricular myocytes, sense the local myocyte metabolic state and communicate a negative feedback signal-correction upstream electrically. This electro-metabolic voltage signal is transmitted instantaneously to cellular elements in the neighboring microvascular network through gap junctions, where it regulates contractile pericytes and smooth muscle cells and thus blood flow. As myocyte ATP is consumed in excess of production, [ATP]i decreases to increase the openings of KATP channels, which biases the electrically active myocytes in the hyperpolarization (negative) direction. This change leads to relative hyperpolarization of the electrically connected cells that include capillary endothelial cells, pericytes, and vascular smooth muscle cells. Such hyperpolarization decreases pericyte and vascular smooth muscle [Ca2+]i levels, thereby relaxing the contractile cells to increase local blood flow and delivery of nutrients to the local cardiac myocytes and to augment ATP production by their mitochondria. Our findings demonstrate the pivotal roles of local cardiac myocyte metabolism and KATP channels and the minor role of inward rectifier K+ (Kir2.1) channels in regulating blood flow in the heart. These findings establish a conceptually new framework for understanding the hugely reliable and incredibly robust local electro-metabolic microvascular regulation of blood flow in heart.