Blood Flow Control of the Microcirculation by KATP Channels in Ventricular Myocytes

Abstract

The metabolic demands of the working myocardium underlies the control of blood flow to the cardiac myocytes. However, little is known about the details of the signals that are generated by metabolic need and how these signals are linked into a rapid‐response negative feedback control of blood flow. Here, using the state‐of‐the‐art confocal microscopy and whole mount immunostaining techniques and other fluorescent labels, we have investigated both the anatomic organization of the vasculature and the control mechanisms of blood flow. Our results show the key cellular elements of the system are connected to each other electrically by means of gap junctions (Connexin 43). They connect ventricular myocytes to capillary endothelial cells which are connected to pericytes and the small artery endothelium. Gap junctions thus allow the time‐averaged hyperpolarization of ventricular myocytes (due to the opening of ATP‐sensitive K+ channels (KATP) following metabolic need) to produce hyperpolarization in the rest of the system. By this means relaxation of the pericytes and the smooth muscle cells could produce an increase in blood flow with O2 and nutrition to the ventricular myocytes. Initial results showing this physiological feedback control system that appear to manage blood flow control in heart were tested in a perfused mouse cardiac papillary muscle preparation. The functional changes of arterioles and capillaries in the ex vivo heart were monitored using high‐speed confocal microscopes that include a combination of XY (Nipkow disk) and point‐scanner confocals. Our results suggest that KATP opener pinacidil caused perfusion pressure decrease (blood flow increase) while KATP blocker glibenclamide causes perfusion pressure increase in paced or quiescent heart, indicating the functional involvement of KATP channels in local blood flow control. Pinacidil‐induced perfusion pressure reduction does not differ on smooth muscle specific Kir6.1 mutated mice, suggesting the least role of smooth muscle KATP in the local blood flow regulation. An additional contribution to blood flow elevation may be attributed to extracellular K+ ([K+]o) increases (from ventricular myocyte KATP and other K+ channels), which leads to the hyperpolarization of capillary endothelial cells through the activation of inward rectifier K+ channels (Kir). Thus, the activation of KATP in cardiomyocytes caused by metabolic increase links to the local increase in blood flow. Taken together, these data provide compelling evidence that blood flow control in the mammalian heart is a classic negative‐feedback signaling mechanism that links the metabolism of ventricular myocytes to locally increased blood flow through an electrically controlled signaling system.