Chapter 14 Organization and control of circulation to skeletal mucsle

1. Chapter 14Organization and control of circulation to skeletal mucsle

2. Introduction • Blood flow in microcirculation • Degree to which muscle blood flow can increase • Relationship between metabolism, blood flow and Vo2 • Coupling between skeletal muscle and vascular supply • Role of SNS

3. Organization and control of circulation to skeletal muscle • Conduit arteries: • Large, act like pipes to convey large amounts of blood to areas in bulk • Feed arteries: • Muscular, act as resistance vessels • Constrict or dilate to control blood flow into microvascular networks • Both are external to muscle • Not directly responsive to vasoactive stimuli produced within muscle fibers

4. Organization and control of circulation to skeletal muscle • Primary arterioles: • Within skeletal muscle • Branch into 2cd and 3rd order arterioles • Distribute blood within muscle • 4th order and terminal arterioles • Control perfusion of capillaries • Collecting venules • Receive effluent blood from capillary bed • These empty into progressively larger venules Arteriolar diameter: 10-100 μm

5. Resistance vessels • Arteriolar control of blood flow • Smooth muscle contraction • VC and VD • Smooth muscle cells encircle arterioles • Capillaries do NOT have smooth muscle • Exchange vessels • While diameter of caps is smallest (maybe 5 μm), there are many of them • Low resistance and high total surface area • Venules • Have smooth muscle • Regulates capacitance of these vessels

6. Resistance Vessels • Intimal surface • Continuous layer of endothelial cells (50-100 microns long and 5-10 microns wide) • Direct contact with blood • Smooth muscle and endothelium • Separated by elastic lamina • Sympathetic nerves • Surround feed arteries and arterioles

7. Resistance vessels and their innervation

8. Capillaries: microvascular units • Microvascular unit • All the caps that arise from a given terminal arteriole • TA’s run perpendicular to fiber, to caps run along fiber • About 1 mm in length • Maybe 20 caps arise from each TA • Cover about 0.1 mm3 • Each MVU supplies 20-30 fibers

9. Capillaries: muscle fiber and MVU recruitment • Perfusion is controlled at the level of the TA • Constriction: shuts off MVU • Dilation: opens MVU • RBC distribution within MVU • Not uniform • Determined in part by metabolism of contraction fibers and hemodynamics

10. Muscle fiber-MVU relationships • Muscle fibers are several cm long (order of magnitude longer than MVU) • Multiple MVUs supply each fiber • Muscle fibers of a motor unit are dispersed within muscle (not spatially organized) • Thus, firing of a motor unit will result in the perfusion of more MVUs than needed (particularly at low levels of recruitment) • Flow is both concurrent and counter-current • Offsets heterogeneities in O2 delivery within and between fibers

11. O2 Diffusion: from microvessel to myocyte • Capillary density • Principle determinant • Early thought • Krogh cylinder • Each capillary supplies fibers surrounding it • Theory arose from cross-sectional (2D) analyses • Thus, capillary density (# of caps/mm2) or cap-to-fiber ratio dominated early work • Cap-to-fiber ratio can be constant over training states; how? • 3D models are more insightful • Cap volume per muscle fiber volume • Accounts for tortuosity and branching not noted in 2D modelling

12. Diffusion • According to Krogh model • Inc in metabolic rate will reduce intracellular Po2 • Increases gradient (PcapO2-PiO2) • At this point, Vo2 is limited by flow through capillary bed • Best, to have many MVUs perfused at onset of contractions

13. Red Blood Cell Transit Time: determinant of extraction? • Proportional to the length (TA to CV) and inversely proportional to velocity • Transit time • Increased length • Determined by tortuosity, number of caps perfused and RBC spacing • Velocity • Determined by total capillary volume density • However • Blood flow is NOT homogeneous throughout caps • Caps are not straight tubes • Difficult to determine transit time

14. Altered capillary hematocrit • Capillary hematocrit varies greatly from rest to exercise • Number of RBCs per unit capillary length • May double from rest to exercise (20 to 40%) • Reduces RBC spacing with augments diffusion of O2 • Caused by glycocalyx which retards plasma flow to a greater degree at rest

15. Oxygen diffuses out of arterioles and between microvessels • Major gradient is between cap and myocyte • Mean cap Po2 20-40 mmHg • Intramyocyte Po2 <5 mmHg • However, may be some cap to cap O2 transfer, particularly betw O2 depleted caps and “fresher” caps • May also be some arteriolar and venular diffusion • Likely small % of total • All these diffusional relations (cap-to-cap; arteriolar-venular) • Likely reduce heterogeneity of O2 delivery to muscle

16. What determines O2 supply? • Tissue demand clearly results in changing O2 supply • Is there an O2 sensor? • Tissue Po2 varies • Myoglobin tends to smooth this out • Likely that tissue Po2 determines metabolic state of cell • Upstream sensor? • Capillary Po2 • RBC • Likely a combination • Lowered tissue Po2 mandates increased non-aerobic metabolism, which stimulates increased blood flow (baroreceptors, NO-signalling) • This serves to match supply to demand

17. Blood flow controlled in response to metabolic demand in muscle fibers • Blood flow • Proportional to oxidative capacity • Fiber type • Type of activity • Locomotor muscles vs postural • Diffs in NOS

18. Meeting demand: Motor unit recruitment promotes capillary perfusion • Muscles fibers larger than microvascular units which supply them • Muscle fibers of a particular motor unit are dispersed throughout muscle • May seem wasteful, but this feed forward type mechanism may prevent large scale supply-demand mismatches • Also, helps explain why adjustment to higher exercise intensities is facilitated by prior warm-up exercise

19. Ascending Vasodilation • At rest • Resistance is high • Blood flow is low • O2 Extraction is relatively low (~20%) • Exercise • First: increase extraction (extraction reserve) • Fall in intracellular Po2 • Increase in capillary perfusion (dilation of terminal arterioles) • Vasodilations then spreads up the vascular tree • TA, distal arterioles, larger arterioles, feed arteries • These upstream events occur in concert with greater motor unit recruitment

20. Functional hyperemia • Multiple signals • Vasoconstriction • Inc in free Ca2+ • Voltage-modulated Ca2+ channels • Dependent upon K+ channels • Also intracellular Ca2+ stores (ER) • Second messenger systems (IP3) • Vasodilatory signals • Hyperpolarization • Nitric oxide

21. Myogenic autoregulation • Increase in wall stress (proportional to transmural pressure X luminal radius and inversely proportional to wall thickness) • Stimulate smooth muscle contraction • Maintains constancy of tissue blood flow • During muscular contractions • When muscle relaxes • Reduces transmural pressure and causes vasodilation

22. Local metabolic vasodilation • Increase in metabolic rate causes the release of vasodilatory substances • These help to match O2 supply and demand • Thus, while SNA and autoregulation will tend to VC areas that are inactive; vasodilatory substances will do the opposite • Potassium • EIHF (ex-induced hyperpolarizing factor) • NO (increased via shear stress) • Adenosine • ALL increase with muscle activity

23. Muscle pump • Rhythmic changes in intramuscular pressure with dynamic exercise • Veins fill when muscle relaxes • Blood is expelled when muscle contracts • Valves maintain uni-directional flow