Coordination of blood flow control in the resistance vasculature of skeletal muscle STEVEN S. SEGAL and DAVID T. KURIIAKA The John B. Pierce Laboratory, Departments of Epidemiology and Public Health, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06519 ABSTRACT SEGAL, S. S. and D. T. KURIAKA. Coordination of blood flow ‘coniol in the resistanee vasculature of skeletal muscle. Med. Sei. Sports Exerc, Vol. 27, No.8 pp. 1158-1164, 1995. The coordination Of blood flow control in exercising skeletal muscle is exemplified by the interaction among muscle fibers, nerves, and the smooth muscle and endothelial eels whieh comprise the resistance vasculature. Dur- ing functional hyperemia in aelive muscle, maximal flow exceeds resting values by 10- to 50-foki, according to muscle fiber type and recruitment pattern The contol of muscle blood flow is coordinated among. many vessel branches, encompassing the resistance arteries external 1 the muscle and the arteriolar network embedded within the tissue, As motor unit recruitment and metabolie demand increase with exercise inensity, the locus of blood flow coniral “ascends” from Aisial arterioles, which govern capillary perfusion and flow diss lion, into the proximal arterioles and feed arteries, which control the volume of flow into a muscle. The organization of vasomotor sponses within and among resistance vessels can be explained by the spread of electrical chemical, and physical signals between endothl and smooth musele cells, These Signals are triggered by substances released from muscle fibers and nerve terminals and by changes in teansmural pressure and luminal flow, Thus fom several perspectives, callto-cll communication eaordinaies blood flow contol in accord with the metabolic domands of active musele Fibers, :D VASODILATION, ENDOTHELIAL CELLS, FUNCTIONAL HYPEREMIA, SYMPATHETIC INNERVATION, ‘VASCULAR SMOOTH MUSCLE CELLS Persie the activity of skeletal muscle and the cardiovascular system. With the onset of muscle activity, oxygen and nutrient delivery to (and metabolite removal from) the active musculature increase in propor- tion to the metabolic requirements of the tissue (3,4,65), Indeed, functional hyperemia and oxygen consumption of active muscle can exceed resting values by 10- to 50-fold (1,31,38,46), according to muscle fiber type and ¢ is the preeminent stimulus for in- [NEDICINE AND SCHENCE IN SPORTS AND EXERCISE ‘ip © 15 te An Cleo Spor Mate ‘eile epson Age 85, 1138 recruitment patterns. The traditional explanation of these responses centers on the metabolic theory of local flow control. This states that vasodilator substances (e.., adenosine, carbon dioxide, potassium), which are re- leased from active fibers in proportion to energy expen- diture, diffuse through the interstitial space to act on the smooth muscle cells of arterioles (18,57). The resulting ‘vasodilation increases blood flow in proportion to meta- bolic demand of skeletal muscle (21,38,46). Studies which have investigated the action of specific vasodilator metabolites have revealed that each substance can con- tribute to functional hyperemia, yet no one influence can explain the integrated response of blood flow to muscle contraction (18,57). For example, in addition to sub- stances acting directly on smooth muscle cells, a variety of stimuli have now been shown to exert their effects on vascular resistance via the stimulation of endothelial cells (15,26,40,43), This brief review addresses relationships among flow control mechanisms inherent to the resistance network, the influence of sympathetic innervation, and explores how microvascular responses may be integrated with the pattern of muscle fiber recruitment; particular attention is given to the role of endothelial cells in mediating vaso- motor activity. Additionally, we point to fundamental ‘gaps in our current understanding of how the vasomotor responses of resistance vessels are actually coordinated with the contractile activity of skeletal muscle fibers. Locus of Blood Flow Control ‘The vascular resistance network begins with the mus- cular “feed” arteties external to the tissue and encom- passes the arteriolar network embedded within the tissue (14,16,50,64; Fig, 1). The wall of resistance vessels con- sists primarily of smooth muscle cells wrapped around the vessel lumen, which is lined by a single layer of ‘endothelial cells in direct contact with the blood (42). At each level of the network, vascular caliber (and therebyCOORDINATION OF BLOOD FLOW CONTROL Official Journal ofthe American Colege of Sports Medicine 1159 the muscle, with corresponding venular netwo across vessels) run along the feed arteries a {o arse from a terminal arteriole (4) ‘of blood flow, Note “stacking” of ex refs. 58,3339 for relevant anor ‘neuromuscular junctions of superficial bers na collecting ven vith corresponding vein; 2) indicates arteriolar network within ary) unit Sympathetie nerve ibers (indicated by diagonal lines wenrteriolar network. In the enlarged portion of figure below, a capillary unt (3) is shown ‘ulaway regan of muscle fer bundle (6; arrows indicate direction unde, with altersating terminal arterioles and collecting venules (see 1 rise to four axon branches, two of Wh other two branches terminate on fibers in respective fiber bundles (the four muscle bers derived, ‘rom the common motor neuron are shaded in eros section). Note that musele fibers ofthe motor unit would he supplied by diferent microvascular units and that each musee fiber is supplied by many microvascular units, blood flow) is regulated by the contraction and relaxation of smooth muscle cells, which is mediated by the endo- thelial cells in response a variety of stimuli (7,15,25, 40,58). In response to muscular activity, muscle fiber oxygen consumption increases (and intracellular PO, falls); the initial vascular response involves dilation of the terminal arterioles, thereby increasing capillary perfusion and aug- menting oxygen extraction (16,21,24,27,47,60). The in- crease in extraction enables oxygen consumption to in- crease before hyperemia can fully develop. The volume of blood flow to active muscle increases with exercise intensity, which is explained by an “ascending” vasodi lation which encompasses more proximal resistance ves- sels (14,16,21,29,50); eg, the large arterioles and feed arteries (Fig. 1). This progressive response indicates that as the severity of metabolic stress increases, vasodilation ascends from the vessels controlling capillary surface area to those controlling the magnitude of blood flow (14,16,29,50). Furthermore, this relationship implies that once the distal branches of the network dilate, the mag~ nitude of perfusion can be increased only by the dilation of more proximal branches. Vasomotor Responses Intrinsic to the Resistance Vessel Wall Changes in the locus of flow control can be most readily explained by cell-to-cell communication within and among branches of the resistance network; endothe- lial cells are central to mediating this interaction (29,50— 52). In recent years, we have shown that vasomotor responses triggered [e.g., via microiontophoresis of the curotransmitters acetylcholine (ACh) and norepineph- ¢ (NE)] at a distinct location can spread rapidly along the arteriolar wall independent of nerve activation (49,53), giving rise to the terms “conducted vasodilation” and “conducted vasoconstriction.” This refers to direct coupling (e.g., via gap junctions) between the endothelial cells and/or smooth muscle cells which comprise the resistance vasculature (42,52). Our working hypothesis is that ACh, perhaps derived from the neuromuscular june- tion (39, and see below) triggers hyperpolarization, which is conducted along the endothelial cell layer (52) resulting in vasodilation along the arteriole network 60,51,53,54). In a similar fashion, conducted vasocon- striction in response to NE likely reflects the spread of depolarization (53,54), perhaps among smooth muscle cells independent of the endothelium (51). For both cases, the central idea is that the movement of an el trical signal between cells coordinates the vasomotor activity of cells within and among branches. In effect, this behavior constitutes a mechanism whereby informa- tion is integrated among regions of the resistance net- work. There are two well-described mechanisms of flow con- trol which are intrinsic to the vessel wall, The myogeni response is ascribed to the sensitivity of smooth muscle cells to tangential wall stress (12). Increases and de- creases in transmural pressure elicit vasoconstriction and vasodilation, respectively (12,28). This mechanism seems particularly suited for responding to skeletal mus- cle contraction; the increase in intramuscular pressure would trigger vasodilation in response to the correspond- ing fall in transmural pressure. Flow-induced vasodil1160 Oficial Joumal ofthe American College of Sports Medicine tion centers on the ability of endothelial cells to act as signal transducers (25,26,40,45); they respond to an in- crease in flow (i.e., shear stress) by releasing factors [e.g., nitric oxide (NO)] which relax adjacent smooth muscle cells, causing vasodilation and returning shear stress to- ward control (25,40). Through this mechanism, the initial dilation of downstream vessels will increase flow through upstream vessels, inducing dilation of the upstream ves sels (40,50). Whereas exercise appears to enhance the release of NO from arteriolar endothelial cells (58), the contribution of this mechanism to functional hyperemia remains to be fully clarified. Of particular interest is the recent report that venular endothelial cells can also re~ lease factors which relax adjacent arterioles and thereby contribute to functional hyperemia (45). Nevertheless, myogenic vasoconstriction and flow-induced vasod tion may chronically oppose one another in the mainte- nance of vasomotor tone (28,51) such that the intrinsic contractile state of smooth muscle cells represents a balance between constrictor and dilator forces. With ex- ercise, the production of vasodilator metabolites coupled with the increase in flow pushes this balance toward vasodilation. ‘Sympathetic Innervation and Local Blood Flow Control During Exercise ‘The sympathetic nervous system exerts control over arterial pressure through affecting both the heart and the peripheral vasculature, In response to exercise, the in- crease in cardiac output, together with the flow redisti bution from inactive areas to exercising muscle, are me~ diated largely via efferent sympathetic activity (44). Sympathetic vasoconstriction may even curtail flow to active muscle (14,62), particularly as the total mass of active muscle in the body increases (48). Such reflexive vasoconstriction to active muscles during exercise has recently been confirmed in dogs during treadmill running (37). In essence, as the fraction of cardiac output directed to skeletal muscle increases, the constriction of vessels supplying active muscle becomes the most significant means for controlling arterial pressure (37). Sympathetic adrenergic nerve fibers are located throughout the resistance network, encompassing, feed arteries us well as the entire arteriolar network (11,35; Segal, Walker, and Kurjiaka, unpublished observations). ‘The response to sympathetic nerve stimulation (11,35) nto inhibition by muscle fiber activity (2) appear greatest in distal versus proximal arterioles, which may be a counted for by differences in the distribution of adrener- gic receptor subtypes. “Functional sympatholysis” de- seribes the ability of active muscle to overcome the constriction of its resistance vessels by sympathetic nerves (23,41). In short, the products of muscle contrac~ tion can interfere with NE release as well as induce the MEDICINE AND SCIENCE IN SPORTS AND EXERCISE relaxation of smooth muscle cells directly, thereby pro- moting vasodilation and increasing oxygen delivery to active muscle fibers (2,18,41). Furthermore, NE released during exercise may also stimulate endothelial cells to release vasodilator substances which antagonize smooth muscle cell contraction (7). However, even during in- tense muscular activity, the sympathetic nervous system can effectively limit muscle blood flow (37,44,62) and thereby restrict the rate of oxygen consumption by skel- tal muscle mitochondi Oxygen extraction by skeletal muscle increases when its blood flow is reduced (59,62), suggesting that the surface arca for exchange is not diminished with sympa- thetic nerve activity. This implies that vasodilation is maintained in the arterioles which control the (capillary) surface area for exchange. Since these embedded within the muscle parenchyma, it is likely that metabolite changes in the interstitial milieu (18,7) in- duced by contraction act to maintain these vessels in a dilated state, In light of the present discussion, a critical question concerns the locus in the vascular network where the volume of muscle blood flow is controlled. Because feed arteries are external to the muscle parenchyma, they are removed from the direct effects of the vasoactive prod- Uucts of muscular contraction, Evidence suggest that itis at this level where sympathetic vasoconstriction is most effective during exercise (14,32). We hypothesize that feed arteries can “integrate” vasoconstrictor information “descending” along sympathetic nerves with vasodilator stimuli “ascending” from within the muscle, e.g., via conducted and/or flow-induced, endothelial cell-med ated responses (29,50). Thus, the diameter of feed arter- ies (as well as arterioles within the muscle) would reflect the interaction of these influences at any particular mo- ment, For example, the volume of blood flow (and thereby oxygen consumption) to active muscle could be effectively limited (4,37,44,62) external to the muscle while extraction is maximized by vasodilation of arte- rioles located within the muscle. Furthermore, when con- sidering the preferential distribution of cardiac output to active muscles (or to red vs white regions of individual muscles; 31,34), ascending vasodilation originating in the vicinity of active muscle fibers may attenuate sym- pathetic vasoconstriction in the corresponding resistance vessels. These relationships are currently under investi- gation in our laboratory, Muscle Fiber Type ‘The hyperemic response to exercise differs between red and white skeletal muscles (13,31,34), with blood flow distributed among muscle fiber types in accord with the intensity of exercise (31,34) and motor unit recruit- ment (6). With the onset of exercise, the primary increase in blood flow occurs in slow-twitch, oxidative fibers. As(COORDINATION OF BLOOD FLOW CONTROL exercise intensity increases, flow is elevated to fast- twitch oxidative and then to fast-twitch glycolytic fibers (31). However, the anatomical and physiological basis of such differences has been ambiguous. Recent work from ‘our laboratory has shown differences between slow- twitch (soleus) and fast-twitch (extensor digitorum lon- ‘gus) muscles of the rat with respect to both microvascular architecture (63) and feed artery reactivity (64); arteriolar networks were more dense and feed arteries demon- sirated a greater range of flow control in the soleus muscle compared to the extensor digitorum longus mus- cle. Although these findings are based on only two mus- cles of the rat, we suggest that vascular architecture and functional reactivity may vary in accord with the physi- ological properties of the muscles involved in the exer- cise task. For example, differences in the response of feed arteries supplying respective muscles would facilitate the ribution of cardiac output in accord with muscle re- cruitment patterns (6,31), while differential responses within the arteriolar network could explain the preferen- tial increments in flow to specific regions of a muscle (eg, red vs white gastrocnemius; 31,34) and com- plement the corresponding differences in capillary sur- face area (13,17). An additional (and unanswered) ques tion centers on whether the activity of respective muscle fiber types exerts differential affects on the resistance vasculature, Functional Organization of Microvessels and Muscle Fibers. ‘The functional unit of skeletal muscle is generally considered to be the motor unit, which describes the group of muscle fibers activated by the firing of a single ‘motor neuron in the spinal cord (6). Muscle fibers within a unit may span the entire fength of the muscle, perhaps reaching up to 60 cm in man (5). The fibers within a motor unit are normally dispersed throughout a muscle rather than lying side by side (6; Fig. 1). An alternative definition for the functional unit of muscle is based upon the volume of tissue supplied by a single terminal arte~ le (5); ica the smallest tissue unit of blood flow control (Fig. 1), Note that this definition also corresponds to that of the “microvascular unit” (8,33,47). The essence of this concept is that the provision of oxygen to this volume of muscle (~1 mm; ref. 5) is controlled by a group of capillaries originating from a common terminal arteriole (5,10). In parallel-fibered muscles, microvascu- lar units tend to be arranged in series along the length of muscle fibers (5,6,33), with each spanning ~1 mm of muscle fiber length (Fig. 1). The volume of muscle within this unit is comprised of segments of up to 500 muscle fibers (5) which may derive from 50 or more ‘motor units. A capillary within a microvascular unit may Offical Journal ofthe American Colege of Sports Medicine 1161 thereby have none, one, or all of the adjacent muscle fibers drawing oxygen from it at any given moment. ‘These anatomical relationships imply that the metabolic demand within a microvascular unit varies both spatially and temporally. Given the close coupling between muscle work, blood flow, and oxygen consumption (1,21,38,46,65), the con- trol of motor units of striated muscle must somehow interact with that of the microvascular units perfusing muscle fibers. However, there is a paucity of information concerning how the activation of muscle fibers or motor units is coordinated with the recruitment of microvascu- Jar units along the length of the muscle fiber. Although additional research is required to address this question in detail, we suggest that the conduction of vasodilation among terminal arterioles and their parent branches is ‘one mechanism for coordinating red blood cell perfusion among microvascular units (49). Acetylcholine and Microvascular Perfusion: A Hypothesis Acetylcholine dilates arterioles of striated muscle by activating muscarinic receptors on endothelial cells (15,43). However, the physiologic source of ACh which may activate these receptors is unclear. The neuromus- cular junction of motor nerves synthesizes, stores, and releases ACh in skeletal muscle and is the apparent physiologic source of ACh in this tissue. Although spec- ulative, the dilatory action of ACh on arterioles suggests a mechanism by which neural activation of muscle fibers may be coupled to the local control of blood flow (20,39). Acetylcholine release from motor nerve terminals oc- ‘curs both spontaneously and via action potentials (22,61). We reasoned that the distances between neuromuscular junctions and microvessels could influence the likelihood of ACh derived from neuromuscular junctions to act as a paracrine substance on the microvasculature. To test this hypothesis, the spatial relationships between neuromus- cular junctions and microvessels were evaluated in the hamster cremaster muscle (39). In short, our findings suggest that if substances derived from neuromuscular junctions have a physiological role in the local control of blood flow, capillaries are the most accessible target, followed by distal branches of the arteriolar network. Several studies have indicated that stimulation of capil- laries affects the diameter of terminal arterioles (9,49,56); i.e, those which control the perfusion of microvascular (capillary) units (47,49,60). We therefore speculate that the activation of neuromuscular junctions may contribute to coordinating blood flow distribution in order to perfuse microvascular units in accord with muscle fiber recruit- ment. Nevertheless, a fundamental constraint on this re- lationship is the fact that each fiber typically has only a1162 Offical Journal ofthe American Cotege of Sports Medicine single neuromuscular junction, whereas many microvas- cular units are required to encompass the length of a single muscle fiber (Fig. 1). Thus, the fundamental ques- tion of how (or even if) the recruitment of microvascular Units is coordinated with that of motor units remains to be answered. Integration of Processes and Hypotheses This review is concerned with how the contraction of muscle fibers can give rise to vasodilator responses, which encompass progressively greater portions of the resistance network as metabolic demand increases, and how the interaction between smooth muscle and endo- thelial cells (in response to impinging stimuli) give rise to appropriate blood flow responses. Recall that the micro- circulation is embedded in the tissue, separated from parenchymal cells only by the interstitial space. There- fore, local production of vasodilator metabolites. will cause dilation of arterioles: directly via acting on smooth muscle cells, and indirectly via stimulating endothelial cells or impairing NE release from sympathetic nerves. ‘The distal (terminal) arterioles appear most sensitive and are the first to respond, thereby increasing capillary per- fusion (14,16,24,29,50). This explanation is entirely con- sistent with the metabolic theory described earlier, but {alls well short of completely explaining the local contro! of blood flow. The dilation of terminal arterioles will increase blood flow not only locally, but also through upstream branches; such a cumulative affect could trigger endothelial-mediated, flow-induced dilation in more proximal segments of the network (29,40,50). Addition- ally, vasodilator metabolites carried in venous blood (19) or released from venular endothelial cells (45) can diffuse from the venules to adjacent arterioles and induce vaso- dilation in proximal branches. Such responses throughout the network may be graded with metabolic requirements and oxygen demand. Nevertheless, metabolic and flow- induced vasodilation require several seconds to develop. ‘Therefore, these processes are too slow to account for the rapid (~1-2 s) onset of functional hyperemia (20,50). Vasodilation triggered on terminal arterioles (e.g, with ACh) can be rapidly (<1 s) conducted into proximal branches to increase capillary perfusion (49). ‘Thus, con- ducted vasodilation could explain the early portion of the hyperemic response, with flow-induced and metabolic dilation contributing thereafter. Furthermore, conducted responses that are initiated on distal branches can be tegrated in parent vessels (53), resulting in a graded erease in network perfusion. In light of the established role of ACh in defining cell-to-cell communication be- tween endothelial cells and smooth muscle cells (15,43,51), it seems possible that ACh released at the neuromuscular junction may be vasoactive (und would MEDICINE AND SCIENCE IN SPORTS AND EXERCISE increase with exercise intensity); however, this hypoth- esis (39) requires further study. ‘An additional source of integration may derive from the physical forces associated with movement. With dy- namic exercise, the mechanical action of skeletal muscle fibers (ie., the muscle pump; 30,55) could initiate the rapid onset of hyperemia via two mechanisms. The in- termittent compression and relaxation of muscle fibers surrounding venules would lower postcapillary pressure, thereby increasing the driving force for flow through the mictocirculation (30). Additionally, compression of ar- terioles during contraction would reduce their transmural pressure and could thereby induce myogenic relaxation (12) between contractions, which would further promote blood flow. Such “mechanical” coupling between muscle fibers and both venules and arterioles could rapidly in- crease muscle perfusion with the onset of exercise (55), Recent observations show that muscle length has a pro- found influence on the geometry of arterioles and venules in vivo (36). However, it remains to be shown whether resistance vessels actively respond to excursions in skel- etal muscle length and/or tension. Thus, potentially “new” mechanisms of cell-to-cell coupling remain to be explored. ‘Summary The coordination of vasomotor activity among branches of the resistance vasculature can be explained by the response of endothelial and/or smooth muscle cells to neural activation and the recruitment of skeletal mus- cle fibers. The influence of each stimulus to the control of blood flow is such that the distribution of flow is coor- inated among distal branches whereas flow magnitude is governed in proximal branches. The interaction between multiple mechanisms of flow control, coupled with the coordination of vasomotor activity among resistance seg- ments, adjusts the perfusion of muscle to its level of energy expenditure, Nevertheless, it is not understood how the perfusion of particular regions of the micro- vascular network is adjusted to the needs of individual ‘muscle fibers nor to the pattern of motor unit recruit- ment. Answers to these questions will impact greatly ‘on our understanding of blood flow control in health and disease, We are grateful to Drs. Andrew Fuglevand and Donald Welsh for ther critique ofthis manuscript. The work upon which this review is based was supported by Grant-In-Aid from the American Heart Association (8.8.8), an Established Investigatocship Award from the ‘AHA and Genentech, Inc. (S.S.S), a postdoctoral fellowship from the Connecticut Affiate of the AKA (O.T.K), and grant R29- HL41026 from the National Institutes of Heaith (8.8.8) ‘Address for correspondence: Steven 8. Segal, Ph.D., The John B, Pierce Laboratory, Yale Univesity School of Medicine, 290 Con- tess Avenue, New Haven, CT 06518,COORDINATION OF BLOOD FLOW CONTROL, 10. 24 2 24, REFERENCES Avon, P. and B, Snr, Maximal perfusion of skeletal muscle in man, J. Physiol 366:233-249, 1985, ‘Awouas0n, Kani, Fant, Differential sensitvily of arteriolar srenoceptor eonsrition to metabolic inhibition dur- ing rat skeital muscle contraction. Cire, Res. 69:174~184, 1991, Baseuay, J. K. A delivery-independent blood flow effect on skel- al muscle fatigue. J. Appl. Physiol, 61:1084-1090, 1986, Banetay, J. K. and W. N. Stansny. The role of blood flow in Tinting maximal metabolic rate in muscle, Meu. Sei. Sports TAN6=119, 1995. oct, E and A Tusa. Toward a concept of the functions unit of ‘mammalian skeletal muscle, Am. J. Physiol. 242:R411-R420, 1982, Burt, R, Motor units: anatomy, physiology, and Faction organi zion’ Handbook of Physiology, Vol. 2, V. B. Brooks (Ed). Be- thesda, MD: American Physiological Scciety, 1981, pp. 345-422. Cocks, T. Mand J. A. Axcus. Endothatium-dependent relaxation of coronary arteries by noradrenaline and serotonin, Nature 305: 627-630, 1983. Datasiny, J. B. and BR. Duuinc. A study of the functional ements regulating capillary perfusion in striated muscle. Miro ase, Res, 36:162=171, L988, Disincn, H. H. Etfee of locally applied epinephrine and norepi replirine on bload flow and diameter in capillaries of ral mesen= ery. Mierovase. Res. 38:125-135, 1989, Eniksson, E. and Re Mviaact. Microvascular dimensions and blood flow in skeletal musele, Acta Physiol. Scand, N6:211-222, 197. Fuewine, B. P., K. W. Basnos, T. W. Howes, and J. K. Swim. Response of the microcirculation in rat cremaster muscle 10 pe= ripheral and central sympathetic stimulation, Cire, Res. (Suppl Hp:i-26-1131, 1987. Fo.xow, B. Description of the myogenic response, Cire, Res 15:279-287, 1964, Fo.xow, B. and H. Hauicxa. A comparison between “red and “white” muscle with respec o blood supply, capillary susface area and oxygen uptake during rest and exercise. Mierovase. Rex 11-14, 1968, Foukow, B., RR. Soxwenscntis, and D. L. Wacit Leck of ncurogenie and metabolic effects on precapillary vessels of skel sta muscle, Acta Physiol Scand. 81:459~471, 1971 Fuxeuoorr, R. F. and J. V. Zawapext, The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine, Naure 288:373-376, 1980, 1 Gaawan, H. J, A. H. Gooowas, and D, N. Geanack. Role of resistance and exchange vessels in local microvascular contal of skelotal muscle oxygenation in the dog Cine, Res. 38:379-385, 1976, Gray, S. D. and E. M. Riss. Microvascular supply in relation 10 fiber metabolic type in mixed skeletal muscle of rabbits, Miera- vase. Res, 16:06~425, 1978 Haoov, F. J. and J.-B, Scorr. Metabolic factors in peripheral circulatory regulation, Fed, Proc, 34:2001~2006, 1975 sree, R. L. Venular-arcriolar diffusion of adenosine in hamster remaster microcirculation. Am. J. Physiol. 258:H1918-H1S. 1990, Howto, C. R. and J. L. Frietsox. Neurons intrinsic to arterioles initiate postcontaction vasodilation, An. J. Physiol, 230:493-507, 1976, Howto, C. R.,C. L, Ovowory, and J Ls Frison, Capilary recite ‘ment in exereise: rate, extent, uniformity, and relation to blood Now. Am. J. Physiol. 238:H31-H42, 1980, Karz, B. and R. Miteot The binding of acstyleholine 1 receptors and its removal fom the synaptic cleft J. Physiol, 213:549-574, 1973, KELiME, 1, On the competition between metabo vasodilatation and neurogenic vasoconsrition in skeletal muscle. Acta Physiol Sean, 63:851)~459, 1965, Kisraaan, By, D. N. Dawn, RJ. Goncevass, and B, R, Dune. Official Journal ofthe American College of Spars Medicine 2%, 30 3h 22 2 34, 35 36, », 38 30 40, 41 2 43, 44, 45, 46 4. 1163 Augmented tissue oxygen supply during striated musele contrac: ‘ion in the hamster: Relative contibutions of eapillary reeriiment, functional dilaton, and reduced tissue POs. Circ, Res. S1:TH— 721, 198 Koulie, A. and G, Katzy, Endothelial regulation of wall shear stress and blood flow in sKelotal musele mieracireuation, Am. J Physiol. 260:H862-H868, 1991 Kote, A. D. Sux, A. Huave, and G. Karty. Corelease of nitie ‘oxide and prostaglandins mediates flow-dependent dilation of rat gracilis arterioles. Am. J. Physiol. 2671H226-H332, 1994, . Kava, A. The supply of oxygen tothe tissues and ihe revlon of the capillary circulation. J. Physiol, $2:487-474, 1919, Kuo, Le, W. M. Cinuiax, and M. J. Dav, Interaction of pressure and flow-indced responses in porcine coronary resistance vessels, Ant J. Physiol. 261:H1706-111715, 1991 Kuo, L, M.J. Dau, and W. M. Chass, Endothelial regulation of arteriolar tone. News Physiol. Sei 75-9, 1991 Lavaitin, M.-H. Skeletal musele blood flow capacity: role of muscle pimp in exercise hyperemia, Am, J. Physiol. 253:1993— Huns, 1987, Laucitas, MH. and R, B. Annstions, Muscular blood flow distribution pattems as 4 function of running speed in rats, Am, J. Physiol. 243:11296-H306, 1982, Lino, A. Rand C. A. Winuats. The coneo of blood flow through human forearm muscles following brief isometeic contractions J. Physiol, 288:529-S47, 1979, AN, Nu D. N. Dano, and B. R. Dut. Capillary grouping in hamster tibialis anterior muscles: low patterns, and physiological significance, In. J. Microcire.: Cli, Exp, 5:389-372, 1987 Mack, B.G. and R. L. Texuns. Blood flow to differen skeletal musele iber types during contraction, An. J Physiol. 245:H265— 1275, 1583, Massitau. J. M. The influence of the sympathetic nervous system ‘on individual vessels ofthe microcirculation of skeletal musele of the ra. J. Physiol 332:169-186, 1982. Nakao, M. and S.'S. Seoat. Muscle length alters geometry of ateroles and venules in hamster retractor. Am. J. Physiol. 268 H336-H44, 1995, O'Lewy, D. S, L. B. Rowen, and A. M, Scie, Baroreflex- induced vasoconstriction in active skeletal muscle of conscious dogs. Am. J. Physiol, 260:H37-HA1, 1991, Oapwav,G. A, D.L, Fuovo, 1. C. Lonenunst and J H Merc Oxygen consumption and hemodynamic responses during graded ‘readmill exercise in the dog. J- Appl Physiol, 57:601~607, 1984, Prsezca, J. M. and S. $. Secat. Spatial relationships between neuromuscular junctions and microvessels in hamster remaster muscle. Microvase. Res, 48:50 -67, 1994, Pout, U., J. Ho.r7, R. Buss, and E, BASsehoe. Crucial role of ‘endothelium in the vasodilator response to increased flow in viva. Hypertension 837-46, 1986, Rewexswyonn, J.P. J. H. Mrreuts, and S.J. Saesorr. Functional sympatholysis during muscular activity. Cire. Res. 11:370~380, 1962, Ruodiy J. A, G. The ultrastructure of mammalian arterioles snd precapilary sphincters. J. Ulrastuc, Res. 8:181-223, 1967 Rivers, RJ. and B. R. Duuno. Artriolar endothelial eoll barrier separates two populations of muscarini recepiors. Am. J. Physiol 262:H1311-H1316, 1992. Rowsts, L. B. Human Circulation, Regulation During Physical Siress. New York: Oxford University Press, 1986, pp. 213-256, Samo, ¥., A. Baasian, V. Lockann, and RL. estan. Role of venular endothelium in contol of arteriolar diameter during func- tional hyperemia. Am. J. Pysok, 267:H1227-H1231, 1994, ‘Sut B, Hemodynamic adaptations to exercise. Am. J. Cardiol 35:42D-47D, 1985, ‘Sawuus, I. H. Cell and oxygen flow in arterioles controlling capillary perfusion, Am. J. Physiol. 265:81682-H1687, 1994,1164 48, 49, 50, 51 2 3 54 5, 3. Official Journal of the American College of Sports Medicine Seats, D. R. Influence of muscle mass on sympathetie neural activation during isometic exercise. J. Appl. Physiol, 67:1801— 1806, 1989, Srpal, S$. Microvesculrreruiment in hamster sisted muscle: role for conducted vasodilation. Am. J. Plysiol. 261:H181-H189, 1991 Scant, 8. 8. Communication among endothelial and smooth mus clo cells coordinates blood flow contra during exercise. News Physio. Sei, 7:152-156, 1992. Steal, S. 8. Cel-to-cell communication coordinates blood flow conte. Hypertension 23(part2):1113-1120, 1994 Secat, 8. S. and JL, BiNy. Inacllular recording and dye Atansfer in anteroles during blood flow contol. Am. J. Physiol. 263:HI-H7, 1902 StoAL, 5. 8. D. N. Dawos, and B, R, Dune. Propagation of vasomotor responses coordinates ateriolar resistances. Am. J Physiol, 256:H832-H837, 1989. Secat, $..and B. R. Dune. Conduction of vasomotor responses in arterioles: a role for collto-cll coupling? Am, J. Physio. 256:11838-11845, 1989, Shier, D. D., L. B, Roweut, and A. M, Scuex, Is api rise in ‘vascular conductance at onset of dynamic exercise due to musele pump? Am. J. Physiol. 265:H1227-H1234, 1993, Son, H. and K. Ta. Evidence for sensing and integration of biological sipnais by the eapilary network. Am. J. Physiol 265 H1235-#11242, 1998, Srwuss, HV. Effect of local metabolic factors on vascular smooth ruscle, Handbook of Physiology, Section 2: The Cardiovascular 58 59, o. 61 6, 64, 65. MEDICINE AND SCIENCE IN SPORTS AND EXERCISE ‘System, D.F.Bobr, AP. Somlyo, and H. V. Sparks (Eds). Bethesda, MD; American Physiological Society, 1980, pp. 475-513. Sur, D., A. Huanc, A. Kouusk, and G. Katey. Short-term daily exercise activity enhances endothelial! NO synthesis in skeletal muscle arterioles of mts. J. Appl. Physiol. 76:2241-2247, 1994, Stansoy, W. Nand A. B. Ons, Blood flow, blood oxygen tension, oxygen tptake, and oxygen transport in skeletal muscle Ant J. Physiol 206:858-866, 1964. Sweeney, T. E. and I. H. Sanctius. Anteriolar control of capillary cell flow in striated msele, Cire. Res. G4:112-120, 1989, ‘Tuesusrr, $. Funetional aspeets of quantal and_non-quantal release of acetylcholine al the neuromuscular junction, In: Progress in Braln Research, Vol. 84, 8. M. Aquinonivs andP. G. Gillberg (Eds.). Amsterdam: Elsevier Science Publishers, 1990, pp. 93-98. ‘Tuowrson, L. P. and D. E. Mouax, Blood flow and oxygen consumption in skeletal muscle during sympathetic stimulation Am J. Physiol, 25:H66-H71, 1983, Wattiass, D. A and 8, . Seo. Microvaseular architect in ra soleus and extensor digitorum longus muscles, Microvare. Res, 43:192-204, 1992, Witunws, D. A. and S. S. SucaL. Feed artery role in blood flow contro to rat hindlimb skeletal muscles. Physiol. 463:031~646, 1993, Wasson, B. A. and W. N, Sransiy, Relation between oxygen vuplake and developed tension in dog skeletal muscle. J. Appl. Physiol. 45:234-237, 1978,