Nutritive and non-nutritive blood flow in skeletal muscle

The vascular structure of mammalian skeletal muscle has been intensively investigated for the last seventy years. Since the early work of Pappenheimer and Barlow, the existence of a parallel dual vascular pathway has been suggested to explain the differences between total flow and clearance rates of a variety of infused substances. Direct microscopy studies using superficial muscles have shown that the microvascular arterioles have very frequent connections with the capillary modules of the associated connective tissue and adipose tissue within skeletal muscle. In more recent times, Clark and colleagues have identified two vascular pathways according to the opposing actions of two groups of vasoconstricting agents. While all increase perfusion pressure, Type A vasoconstrictors (low dose noradrenaline (Nad), vasopressin, angiotensin II) increase oxygen uptake but Type B vasoconstrictors (serotonin, high dose noradrenaline) decrease hindlimb oxygen consumption. The opposing effects on oxygen consumption are thought to arise from selective vasoconstriction of the mircrovasculature. Type A vasoconstrictors redirect blood into muscle tissue capillary beds (termed nutritive bed) whilst Type B vasoconstrictors redirect blood into the associated connective tissue, adipose and septum capillary beds (termed non-nutritive bed). Many of the previous studies are based on variations of an in situ rat, isolated perfused hindlimb model, having low vascular tone and often with insufficient oxygen carrying capacity to support active metabolism. In vivo, skeletal intramuscular blood redistribution during exercise occurs principally via the release of vasodilatory metabolites and the nervous system. This thesis used a novel in vivo model to test the hypothesis that nutritive and non nutritive blood flow distribution can still be observed under conditions of high vascular tone and oxygen delivery at rest and in metabolically active (contracting) muscle. Utilising the high vascular tone, it also tests the hypothesis that the vascular pathways can be differentiated using vasodilators. Male Wistar rats were anaesthetised with sodium pentobarbital (6mg.100g(superscript �1) i.p.). The right femoral artery was cannulated to supply blood to the left femoral artery (perfused) at a constant flow (basal 1ml.min(superscript �1), contraction 2ml.min(superscript �1) via a pump. Perfused hindlimb pressure was recorded distal to the pump and passive venous return occurred from the left femoral vein to the right external jugular vein. Systemic blood pressure was recorded from the left common carotid artery. Polyethylene cannulae were filled with heparinized 0.9% saline containing 6% w/v dextran70. The left sciatic nerve was isolated and stimulated (5Hz) to produce twitch contraction in the lower hindlimb muscle bundle and developed tension was recorded. Vasoactive drugs (2 constrictor, 8 dilator) were prepared with saline and 0.01% ascorbic acid, and injected into the arterial loop. Blood was sampled from the venous and arterial loops and oxygen consumption determined using the Fick equation. In the autoperfused rat hindlimb, the Type B vasoconstrictor increased perfusion pressure and caused a significant decrease in basal hindlimb oxygen consumption, however during muscle contraction this effect on oxygen consumption was diminished. The Type A vasoconstrictor had no significant effect on hindlimb oxygen consumption during significant increases in perfusion pressure. Eight vasodilators with a variety of mechanisms of action were screened at rest but none were observed to decreases hindlimb oxygen consumption in a fashion similar to Type B vasoconstrictors. Increases in oxygen availability at rest via increased nutritive flow by noradrenaline and vasodilator infusion had no effect upon basal metabolic rate. Therefore, during adequate oxygen delivery, increased availability has no effect upon metabolic demand. Isoprenaline and histamine significantly increased hindlimb oxygen consumption during the contraction protocol, whilst there was no significant effect observed at rest. It can be concluded that selective vasoconstriction metabolites can overcome exogenous vasoconstriction. These results confirm the possible existence of a dual vascular pathway however blood flow redistribution via vasodilation is likely determined by the locale of vasodilator release rather than differences in receptor distribution