Theoretical simulation of metabolic mechanisms for regulating capillary perfusion in working skeletal muscle

Capillary perfusion in skeletal muscle is highly coordinated both spatially and temporally with the level of muscle fiber activity. Increased oxygen demand in working muscle is met by increasing capillary perfusion. Blood flow to skeletal muscle increases proportionally with exertion during exercise, and returns to resting levels almost immediately after cessation of activity. Matching blood flow with fiber activity is the result of multiple mechanisms working in combination to dilate and constrict smooth muscle in the arteriolar walls. In this study, theoretical models were used to examine the regulation of capillary perfusion based on arteriolar vasodilation in response to local metabolic changes in the muscle tissue. The level of tissue oxygenation in working muscle was predicted for mechanisms of blood flow regulation based on vascular sensing of decreased tissue PO₂ and of increased interstitial [K⁺]. Two hypothetical mechanisms for vascular sensing of PO₂ and interstitial [K⁺] were considered: direct sensing by arterioles, and sensing by capillaries with stimulation of feeding arterioles via conducted responses. Grouping of capillaries into functional units called microvascular units (MVUs) increased the predicted fraction of capillaries necessarily perfused to maintain adequate oxygenation relative to control by individual capillaries. Control by arteriolar sensing of oxygen and K⁺ resulted in poor control of tissue oxygenation at high levels of muscle activation. At higher levels of muscle activity, the terminal feeding arteriole for a MVU typically flows through a region perfused by another MVU such that the metabolic conditions near the arteriole is not sufficient to trigger vasodilation. Control of microvascular unit perfusion by capillary sensing of oxygen and K⁺ resulted in adequate tissue oxygenation over the full range of activation, without a significant increase in the number of perfused MVUs relative to control by individual capillaries. Oxygen consumption in active muscle fibers does not reach a maximal rate until 15 to 25 seconds after initial recruitment, but increased blood flow to MVUs is observed within 5 seconds after initial recruitment. A simulation of the time course of the response mechanisms suggests that vascular sensing of tissue PO₂ does not fully trigger MVU perfusion until 15 seconds after initial recruitment. Increased interstitial [K⁺] can trigger MVU perfusion within 2 seconds after initial recruitment. During the initial 10 seconds of muscle activation, increased perfusion in the absence of an increased rate of oxygen consumption may function to minimize the build up of interstitial [K⁺], which is important in maintaining fiber excitability and avoiding early onset of fatigue. MVU perfusion triggered by capillary sensing of local metabolic conditions resulted in a lower mean [K⁺] across the muscle tissue over the range of activity levels than mechanisms based on arteriolar sensing