Bang-bang model for regulation of local blood flow.

The classical model of metabolic regulation of blood flow in muscle tissue implies the maintenance of basal tone in arterioles of resting muscle and their dilation in response to exercise and/or tissue hypoxia via the evoked production of vasodilator metabolites by myocytes. A century-long effort to identify specific metabolites responsible for explaining active and reactive hyperemia has not been successful. Furthermore, the metabolic theory is not compatible with new knowledge on the role of physiological radicals (e.g., nitric oxide, NO, and superoxide anion, O2 (-) ) in the regulation of microvascular tone. We propose a model of regulation in which muscle contraction and active hyperemia are considered the physiologically normal state. We employ the "bang-bang" or "on/off" regulatory model which makes use of a threshold and hysteresis; a float valve to control the water level in a tank is a common example of this type of regulation. Active bang-bang regulation comes into effect when the supply of oxygen and glucose exceeds the demand, leading to activation of membrane NADPH oxidase, release of O2 (-) into the interstitial space and subsequent neutralization of the interstitial NO. Switching arterioles on/off when local blood flow crosses the threshold is realized by a local cell circuit with the properties of a bang-bang controller, determined by its threshold, hysteresis, and dead-band. This model provides a clear and unambiguous interpretation of the mechanism to balance tissue demand with a sufficient supply of nutrients and oxygen.