Relationship of microvascular flow distribution to skeletal muscle metabolism

Previous research by others led to the proposal that a non-nutritive route in muscle existed in association with the tendon and connective tissue of muscle. This non nutritive route could carry a large proportion of flow directed to it under certain vasomodulatory stimuli including norepinephrine (NE). Research by this laboratory using the perfused rat hindlimb indicated that there are two types of vasoconstrictors, A and B. Type A, of which NE and angiotensin II (All) are typical, increase metabolism, while type B, of which serotonin (5-HT) is representative, decrease metabolism. The perfused rat hindlimb was used to investigate whether flow redistribution plays a role in these vasoconstrictor-mediated changes in metabolism. The infusion of NE at low doses, but not 5-HT caused the release ofred blood cells from the erythrocyte-free perfused hindlimb. NE also recruited a vascular space in the hindlimb and trapped FITC-labeled dextran in that space which was released on subsequent exposure to NE. 5-HT closed off part of the vasculature, which was only reopened when 5-HT was removed. Both these vascular spaces were slowly cleared. In addition, NE significantly increased the extent of filling of the arterial vascular tree, while 5-HT decreased filling as assessed by vascular casts. The redirection of flow caused by 5-HT was not through arterio-venous thoroughfares since the passage 15µm microspheres was not greatly enhanced compared to basal. All these effects were in the absence of redistribution of total flow between individual muscle or between muscle and non-muscle tissues. In order to determine whether the tendon of muscle was involved in the redistribution of flow in the perfused hindlimb, FITC labeled dextran was infused during varying nutritive flow generated by NE and 5-HT. These experiments showed that the fluorescence of the tendon of the biceps femoris was increased by 5 HT and decreased by NE. Photographs of the tendon vessels of the biceps femoris highlighted with Indian Ink showed that there was constriction by NE, but vasodilatation by 5-HT. These data were consistent with the notion that 5-HT increased flow to the tendon region of muscle while NE denied flow to that region. The possibility that 5-HT could be denying access to certain areas of the vasculature, implied that it could deny access of other compounds, specifically type A vasoconstrictors. In a complementary fashion, type A vasoconstrictors may enhance the delivery of type B vasoconstrictors. A ser!es of experiments were conducted to test this idea whereby angiotensin II (All) was infused before or after 5-HT. Data showed that infusion of All before 5-HT enhanced the effectiveness of 5-HT in terms of both its vasoconstrictive and inhibitory metabolic potential. All was significantly less effective when infused after 5-HT. The key to 5-HT denying access to All, was due to its vasodilatory action into the tendon vessels since the metabolic inhibitory effects of the specific 5-HT2 agonist a-methyl 5-HT (a-MT) were not enhanced by prior infusion of AIL Increasing the nutritive flow with NE was found to decrease the microdialysis outflow/inflow (0/1) ratio of 14C-ethanol and 3H20 over a range of perfusion flow rates. Serotonin, however increased the ratio of both tracers. The addition of the vasodilator nitroprusside (NP) restored the effects of the vasoconstrictors on the O/I ratio as well as the constrictive and metabolic changes. These data are consistent with the notion that as the nutritive flow past the microdialysis probe increased with NE, there was more blood to remove 14C-ethanol and 3H20 from the interstitial fluid surrounding the probe and so decrease the 0/1 ratio. In the case of 5-HT, the decrease in nutritive flow led to a decrease in the removal of the tracers by blood and an increase in the O/I ratio. A similar set of experiments were also done to investigate the changes in microdialysis recovery of glucose and lactate in the perfused hindlimb while varying nutritive flow. The recovery of glucose and lactate were both improved by NE and All while the interstitial concentration of glucose and lactate were altered to be closer to their respective arterial values. 5-HT, however, decreased the recovery of glucose and lactate, while altering the interstitial concentration to be further from their respective arterial values. The increased flow around the microdialysis probe with NE and All would allow for greater exchange between the probe, interstitial fluid and blood, whereas 5-HT would decrease exchange. All of these data demonstrate that the blood flow distribution within skeletal muscle has important implications for muscle metabolism with type A vasoconstrictors improving muscle metabolism by increasing nutritive flow and type B vasoconstrictors decreasing muscle metabolism by increasing non-nutritive flow.