Vascular system involvement in skeletal muscle oxygen consumption

Among tissues considered to be involved in facultative thermogenesis brown adipose tissue has been regarded as the major thermogenic tissue in rat and other mammals in the past two decades. However, catecholamine stimulated oxygen consumption using perfused in vitro and in vivo skeletal muscle in rat and man strongly suggested a substantial role for skeletal muscle in thermogenesis. The perfused rat hindlimb at 25°C was validated as a model for skeletal muscle metabolism by its metabolic integrity and viability and used in the following studies. The vasoconstrictors vasopressin and angiotensin II were unexpectedly found to markedly stimulate oxygen consumption in the perfused resting rat hindlimb. The increase due to each agonist approached 70% of the basal rate, and was greater than that produced by a maximal concentration of norepinephrine. For each agonist, the dose dependent increase in oxygen consumption coincided with a dose dependent increase in perfusion pressure as previously seen with norepinephrine and other catecholammes. The relationship between oxygen consumption and perfusion pressure was observed under conditions of increased flow through the hindlimb. The agonist and flow induced increase in oxygen consumption and perfusion pressure was blocked by various vasodilators indicating a key role for the vascular system either in the control or actual utilization of rat hindlimb oxygen uptake. An increased release of lactate was also observed in the perfused rat hinillimb preparation which coincided with agonist mediated increase in oxygen consumption and perfusion pressure and was blocked by the vasodilator nitroprusside indicating a vascular origin. Studies using isolated incubated skeletal muscle and aorta preparations provided further evidence for its vascular origin. The lactate may act as an additional fuel for whole body thermogenesis, by being metabolized in the liver or other gluconeogenic tissues. Finally, the perfused rat hindlimb system was utilised to investigate the thermogenic capabilities and the target tissue of some reputed and potential slimming agents such as l-ephedrine, l-norephedrine and the spice principle capsaicin. The evidence obtained indicated that these drugs can act as peripheral thermogenic agents which caused substantial increases in oxygen consumption. l-Norephednne the most active isomer of the racemic mixture (phenylpropanolamine) was much more potent than l-ephedrine, produced a dose dependent increase in oxygen uptake, perfusion pressure and increased lactate production. Nitroprusside substantially inhibited all the effects of these agents suggesting that the vascular system may act as the target tissue. In summary, the data indicates that the vascular system may play a substantial role in skeletal muscle oxygen consumption. The data also provide direct evidence to indicate that the lactate release during vasoconstriction in the perfused rat hindlimb is of vascular origin and that some thermogenic drugs act at least in part on the vasculature in this model