Cyclooxygenase blockade attenuates responses of group III and IV muscle afferents to dynamic exercise in cats

Cyclooxygenase products accumulate in statically contracting muscles to stimulate group III and IV afferents. The role played by these products in stimulating thin fiber muscle afferents during dynamic exercise is unknown. Therefore, in decerebrated cats, we recorded the responses of 17 group III and 12 group IV triceps surae muscle afferents to dynamic exercise, evoked by stimulation of the mesencephalic locomotor region. Each afferent was tested while the muscles were freely perfused and while the circulation to the muscles was occluded. The increases in group III and IV afferent activity during dynamic exercise while the circulation to the muscles was occluded were greater than those during exercise while the muscles were freely perfused (P < 0.01). Indomethacin (5 mg/kg iv), a cyclooxygenase blocker, reduced the responses to dynamic exercise of the group III afferents by 42% when the circulation to the triceps surae muscles was occluded (P < 0.001) and by 29% when the circulation was not occluded (P = 0.004). Likewise, indomethacin reduced the responses to dynamic exercise of group IV afferents by 34% when the circulation was occluded (P < 0.001) and by 18% when the circulation was not occluded (P = 0.026). Before indomethacin, the activity of the group IV, but not group III, afferents was significantly higher during postexercise circulatory occlusion than during rest (P < 0.05). After indomethacin, however, group IV activity during postexercise circulatory occlusion was not significantly different from group IV activity during rest. Our data suggest that cyclooxygenase products play a role both in sensitizing group III and IV afferents during exercise and in stimulating group IV afferents during postexercise circulatory occlusion.     

Group III muscle afferents evoke reflex depressor responses to repetitive muscle contractions in rabbits

Repetitive-twitch contraction of the hindlimb muscles in anesthetized rabbits consistently evokes a reflex depressor response, whereas this type of contraction in anesthetized cats evokes a reflex pressor response in about one-half of the preparations tested. Rapidly conducting group III fibers appear to comprise the afferent arm of the reflex arc, evoking the depressor response to twitch contraction in rabbits because electrical stimulation of their axons reflexly decreases arterial pressure. In contrast, electrical stimulation of the axons of slowly conducting group III and group IV afferents reflexly increases arterial pressure in rabbits. In the present study, we examined the discharge properties of group III and IV muscle afferents and found that the former (i.e., 13 of 20), but not the latter (i.e., 0 of 10), were stimulated by 5 min of repetitive-twitch contraction (1 Hz) of the rabbit triceps surae muscles. Moreover, most of the group III afferents responding to contraction appeared to be mechanically sensitive, discharging in synchrony with the muscle twitch. On average, rapidly conducting group III afferents responded for the 5-min duration of 1-Hz repetitive-twitch contraction, whereas slowly conducting group III afferents responded only for the first 2 min of contraction. We conclude that rapidly conducting group III afferents, which are mechanically sensitive, are primarily responsible for evoking the reflex depressor response to repetitive-twitch contractions in anesthetized rabbits.     

Responses of group III and IV muscle afferents to distension of the peripheral vascular bed.

This study was undertaken to test the hypothesis that group III and IV afferents with endings in skeletal muscle signal the distension of the peripheral vascular network. The responses of these slowly conducting afferents to pharmacologically induced vasodilation and to acute obstruction of the venous drainage of the hindlimbs were studied in barbiturate-anesthetized cats. Afferent impulses arising from endings in the triceps surae muscles were recorded from the L(7) and S(1) dorsal roots. Fifteen of the 48 group IV and 3 of the 19 group III afferents tested were stimulated by intra-aortic injections of papaverine (2-2.5 mg/kg). Sixty-two percent of the afferents that responded to papaverine also responded to isoproterenol (50 microg/kg). Seven of the 36 group IV and 2 of the 12 group III afferents tested were excited by acute distension of the hindlimb venous system. Four of the seven group IV afferents responding to venous distension also responded to papaverine (57 vs. 13% for the nonresponding). Finally, we observed that most of the group IV afferents that were excited by dynamic contractions of the triceps surae muscles also responded either to venous distension or to vasodilatory agents. These results are consistent with the histological findings that a large number of group IV endings have their receptive fields close to the venules and suggest that they can be stimulated by the deformation of these vascular structures when peripheral conductance increases. Moreover, such a mechanism offers the possibility of encoding both the effects of muscle contraction through intramuscular pressure changes and the distension of the venular system, thereby monitoring the activity of the veno-muscular pump.     

Effects of hypoxia on the discharge of group III and IV muscle afferents in cats.

The reflex pressor response evoked by static muscular contraction is widely believed to be caused by the stimulation of group III and IV afferents. Although the specific nature of the contraction-induced stimulus to these thin-fiber afferents is unknown, they are thought to be stimulated in part by a condition arising from a mismatch between blood supply and demand in the exercising muscle. Hypoxia, a condition found in skeletal muscle during such a mismatch, may stimulate these afferents. We have therefore tested the hypothesis that perfusion of the triceps surae muscles with hypoxic blood stimulates group III and IV afferents in barbiturate-anesthetized cats. We found that 3-3.5 min of hypoxia with the triceps surae muscles at rest significantly (P < 0.05) increased the average discharge rate of contraction-sensitive group IV afferents but had no effect on the average discharge rate of contraction-sensitive group III afferents. Hypoxia had only trivial effects on the discharge of contraction-insensitive group III and IV afferents. Hypoxia stimulated 4 of 11 contraction-sensitive group IV afferents and 2 of 13 contraction-sensitive group III afferents. The responses of the afferents stimulated by hypoxia were small in magnitude. Hypoxia with the muscles at rest appeared to have no effect on either hydrogen or lactate ion concentrations in the femoral venous blood. In addition, hypoxia increased the responses to contraction in only 3 of 22 group III and 4 of 21 group IV afferents tested. We conclude that muscle tissue hypoxia is a minor stimulus to afferents that sense a mismatch between blood supply and demand during static contraction.     

Effect of arterial occlusion on responses of group III and IV afferents to dynamic exercise

Our laboratory has shownpreviously that a low level of dynamic exercise induced by electricalstimulation of the mesencephalic locomotor region (MLR) stimulatedgroup III and IV muscle afferents in decerebrate unanesthetized cats(C. M. Adreani, J. M. Hill, and M. P. Kaufman. J. Appl. Physiol. 83: 1811-1817, 1997). In thepresent study, we have extended these findings by examining the effectof occluding the arterial supply to the dynamically exercising muscleson the afferents' responses to MLR stimulation. In decerebrate cats,we found that arterial occlusion increased the responsiveness to a lowlevel of dynamic exercise in 44% of the group III and 47% of thegroup IV afferents tested. Occlusion, compared with the freely perfusedstate, did not increase the concentrations of either hydrogen ion orlactate ion in the venous effluent from the exercising muscles. Weconclude that arterial occlusion caused some unspecified substance toaccumulate in the working muscles to increase the sensitivity of equalpercentages of group III and IV afferents to dynamic exercise.

     

Comparison between the effect of static contraction and tendon stretch on the discharge of group III and IV muscle afferents.

The exercise pressor reflex is evoked by both mechanical and metabolic stimuli. Tendon stretch does not increase muscle metabolism and therefore is used to investigate the mechanical component of the exercise pressor reflex. An important assumption underlying the use of tendon stretch to study the mechanical component of the exercise pressor reflex is that stretch stimulates the same group III mechanosensitive muscle afferents as does static contraction. We have tested the veracity of this assumption in decerebrated cats by comparing the responses of group III and IV muscle afferents to tendon stretch with those to static contraction. The tension-time indexes as well as the peak tension development for both maneuvers did not significantly differ. We found that static contraction of the triceps surae muscles stimulated 18 of 30 group III afferents and 8 of 11 group IV afferents. Similarly, tendon stretch stimulated 14 of 30 group III afferents and 3 of 11 group IV afferents. However, of the 18 group III afferents that responded to static contraction and the 14 group III afferents that responded to tendon stretch, only 7 responded to both stimuli. On average, the conduction velocities of the 18 group III afferents that responded to static contraction (11.6 +/- 1.6 m/s) were significantly slower (P = 0.03) than those of the 14 group III afferents that responded to tendon stretch (16.7 +/- 1.5 m/s). We have concluded that tendon stretch stimulated a different population of group III mechanosensitive muscle afferents than did static contraction. Although there is some overlap between the two populations of group III mechanosensitive afferents, it is not large, comprising less than half of the group III afferents responding to static contraction.     

Effects of blood pressure on force production in cat and human muscle

In anesthetized cats reducing local arterial pressure from 125 to 75 Torr decreased blood flow (53 +/- 5%) and force production (57 +/- 7%) in soleus and medial gastrocnemius. Force was produced in these muscles by aerobic, slowly fatiguing fibers. Similar reductions in arterial pressure did not affect force production in caudofemoralis, which contains mainly fast-fatiguing fibers. In human subjects the electromyogram produced by the ankle extensors during rhythmic constant-force contractions increased as the contracting muscles were raised above the heart during legs-up tilt. This suggests that force production of active muscle fibers at a given level of activation fell with muscle perfusion pressure, thus requiring augmentation of muscle activity to sustain the standard contractions. Because aerobic fibers contributed to these contractions, it appears that force production of human muscle fibers is sensitive to small changes in perfusion pressure and, presumably, blood flow. The critical dependence of developed muscular force on blood pressure is of importance to motor control and may also play a significant role in cardiovascular control during exercise.     

Effect of phentolamine on the reflex increase in arterial pressure

Experiments were carried out in anaesthetized and curarized cats to study the effects of the alpha-blocker phentolamine on arterial pressor response to stimulation of group I afferent fibers from gastrocnemius-soleus muscles. It has been found that increasing doses of phentolamine given i.v. cause a decreasing pressor response until complete disappearance occurs at 2.5 mg/Kg. It is concluded that pressor response is present only when the adrenergic control system is effective and, therefore, it is due mainly to an increase in peripheral vascular resistances.     

Effect of metabolic products of muscular contraction on discharge of group III and IV afferents

Static muscular contraction has been firmly established to reflexly increase cardiovascular and ventilatory function. Although group III and IV fibers with endings in muscle have been shown to comprise the afferent arm of this reflex arc, little is known about the nature of the contraction-induced stimulus causing the activation of these fibers. This stimulus has often been suggested to be a metabolic product of muscular contraction. We have therefore recorded the impulse activity of group III and IV afferents with endings in the triceps surae muscles of barbiturate-anesthetized cats while we injected into the femoral artery substances believed to be metabolic products of muscular contraction. We found that lithium and sodium lactate (400 mM; 1 ml) had little or no effect on the discharge of group III and IV afferents. Likewise, monobasic sodium phosphate (20 and 400 mM; 1 ml) and 2-chloroadenosine (50-100 micrograms) had only trivial effects on the discharge of these afferents. By contrast, lactic acid (25 and 400 mM; 1 ml) and arachidonic acid (0.5-2.0 mg) caused significant increases in the activity of group III and IV afferents. Most of the excitatory effect of arachidonic acid on the discharge of the afferents was prevented by indomethacin, a cyclooxygenase inhibitor. We conclude that of the substances tested in our experiments, lactic acid and some cyclooxygenase products, such as prostaglandins and thromboxanes, are the most likely to be responsible for any metabolic stimulation of group III and IV afferents during muscular contraction.     

Femoral artery occlusion augments TRPV1-mediated sympathetic responsiveness

Muscle metabolic by-products stimulate thin fiber muscle afferent nerves and evoke reflex increases in blood pressure and sympathetic nerve activity. Previous studies reported that chemically sensitive transient receptor potential vanilloid type 1 (TRPV1) channels present on sensory muscle afferent neurons have an important impact on sympathetically mediated cardiovascular responses. The reflex-mediated reduction in blood flow to skeletal muscle leads to limited exercise capacity in patients with peripheral arterial occlusive disease. Thus, in this study, we tested the hypothesis that the expression of enhanced TRPV1 receptor and its responsiveness in primary afferent neurons innervating muscles initiate exaggerated reflex sympathetic responses after vascular insufficiency to the muscle. Muscle vascular insufficiency was induced by the femoral artery ligation in rats for 24 h. Our data show that 1) the ligation surgery leads to the upregulation of TRPV1 expression in the dorsal root ganglion; 2) the magnitude of the dorsal root ganglion neuron TRPV1 response induced by capsaicin is greater in vascular insufficiency (4.0 +/- 0.31 nA, P < 0.05 vs. sham-operated control) than that in sham-operated control (2.9 +/- 0.23 nA); and 3) renal sympathetic nerve activity and mean arterial pressure responses to capsaicin (0.5 microg/kg body wt) are also enhanced by vascular insufficiency (54 +/- 11%, 9 +/- 2 mmHg in sham-operated controls vs. 98 +/- 13%, 33 +/- 5 mmHg after vascular insufficiency, P < 0.05). In conclusion, sympathetic nerve responses to the activation of metabolite-sensitive TRPV1 receptors are augmented in rats with the femoral artery occlusion compared with sham-operated control animals, due to alterations in the expression of TRPV1 receptor and its responsiveness in sensory neurons.     

Cardiovascular regulation by skeletal muscle reflexes in health and disease

Heart rate and blood pressure are elevated at the onset and throughout the duration of dynamic or static exercise. These neurally mediated cardiovascular adjustments to physical activity are regulated, in part, by a peripheral reflex originating in contracting skeletal muscle termed the exercise pressor reflex. Mechanically sensitive and metabolically sensitive receptors activating the exercise pressor reflex are located on the unencapsulated nerve terminals of group III and group IV afferent sensory neurons, respectively. Mechanoreceptors are stimulated by the physical distortion of their receptive fields during muscle contraction and can be sensitized by the production of metabolites generated by working skeletal myocytes. The chemical by-products of muscle contraction also stimulate metaboreceptors. Once activated, group III and IV sensory impulses are transmitted to cardiovascular control centers within the brain stem where they are integrated and processed. Activation of the reflex results in an increase in efferent sympathetic nerve activity and a withdrawal of parasympathetic nerve activity. These actions result in the precise alterations in cardiovascular hemodynamics requisite to meet the metabolic demands of working skeletal muscle. Coordinated activity by this reflex is altered after the development of cardiovascular disease, generating exaggerated increases in sympathetic nerve activity, blood pressure, heart rate, and vascular resistance. The basic components and operational characteristics of the reflex, the techniques used in human and animals to study the reflex, and the emerging evidence describing the dysfunction of the reflex with the advent of cardiovascular disease are highlighted in this review.     

Localization of different types of collagen (I, III, IV, V) in the connective tissue of the popliteal artery and skeletal muscle of man (immunoelectronmicroscopic analysis)

By means of immunoperoxidase and immunoferritin techniques collagen of the I, III, IV and V types has been revealed in cryostat sections of the popliteal artery and in the musculus quadriceps of the femur. Areas of the vascular wall without any macroscopical signs of lesions have been investigated. They have been obtained from amputated extremities of young persons (17-22 years old), and muscle pieces have been taken during operations performed in the knee joint. After certain immunocytochemical procedures the cryostat slices are embedded in mixture of epon 812 and araldit, non-contrasted ultrathin slices are examined in the electron microscope JEM 100CX. Collagen of the I and III types is revealed in fibrills 20-80 nm thick either with or without cross striation, as well as in microfibrills. Collagen of the III type in the intercellular substance of the arterial wall occurs in nonfibrillar form. Collagen of the IV type is revealed in basal membranes of the smooth muscle cells of the arterial wall, of the muscle fibers and of endothelium of blood capillaries of the skeletal muscle. Collagen of the V type is found as accumulations having various size and form; they localize in many places of the intercellular substance of the arterial wall. A tight contact is revealed between the formations including collagen of the V type with drops of elastin and elastic fibers. A suggestion is made that collagen of the V type participates in formation of elastic fibers.     

Confluence of barosensory and nonbarosensory inputs at neurons in the ventrolateral medulla in rabbits

In urethane-anesthetized rabbits, 209 spontaneously active neurons that responded to stimulation of aortic nerve A fibers were found within the ventrolateral medulla (VLM). The neurons, termed barosensory VLM neurons, were inhibited, except for three instances, by stimulation of A fibers. Forty-seven percent of barosensory VLM neurons tested (74 of 159) were activated antidromically by electrical stimulation of the dorsolateral funiculus at the C2 level. Activity of barosensory VLM neurons was enhanced by stimulation of carotid body chemoreceptors or the posterior hypothalamic area, whereas it was diminished by increases in arterial pressure elicited by injection of phenylephrine. Barosensory VLM neurons responded variously to stimulation, with two to three pulses at 40 or 100 Hz, of spinal afferents of cutaneous and muscle origins and the spinal trigeminal complex. Although stimulation of one group of somatosensory fibers could evoke different patterns of neuronal responses consisting of excitatory and inhibitory components, the following responses were most often encountered. Group II cutaneous afferents caused an inhibition. Recruitment of group III afferents brought about a brief excitatory component preceding it. Activation of group IV cutaneous fibers added a long latency excitatory component. Excitation of groups III and IV muscle afferents most often resulted in an inhibition, whereas stimulation of the spinal trigeminal complex elicited various combinations of excitatory and inhibitory components. These results are consistent with the view that neurons in the ventrolateral medulla receive barosensory and nonbarosensory inputs from various peripheral and central sources and participate in the control of sympathetic vasomotor activity and arterial pressure.     

Chronically ischemic mouse skeletal muscle exhibits myopathy in association with mitochondrial dysfunction and oxidative damage

A myopathy characterized by mitochondrial pathology and oxidative stress is present in patients with peripheral arterial disease (PAD). Patients with PAD differ in disease severity, mode of presentation, and presence of comorbid conditions. In this study, we used a mouse model of hindlimb ischemia to isolate and directly investigate the effects of chronic inflow arterial occlusion on skeletal muscle microanatomy, mitochondrial function and expression, and oxidative stress. Hindlimb ischemia was induced by staged ligation/division of the common femoral and iliac arteries in C57BL/6 mice, and muscles were harvested 12 wk later. Muscle microanatomy was examined by bright-field microscopy, and mitochondrial content was determined as citrate synthase activity in muscle homogenates and ATP synthase expression by fluorescence microscopy. Electron transport chain (ETC) complexes I through IV were analyzed individually by respirometry. Oxidative stress was assessed as total protein carbonyls and 4-hydroxy-2-nonenal (HNE) adducts and altered expression and activity of manganese superoxide dismutase (MnSOD). Ischemic muscle exhibited histological features of myopathy and increased mitochondrial content compared with control muscle. Complex-dependent respiration was significantly reduced for ETC complexes I, III, and IV in ischemic muscle. Protein carbonyls, HNE adducts, and MnSOD expression were significantly increased in ischemic muscle. MnSOD activity was not significantly changed, suggesting MnSOD inactivation. Using a mouse model, we have demonstrated for the first time that inflow arterial occlusion alone, i.e., in the absence of other comorbid conditions, causes myopathy with mitochondrial dysfunction and increased oxidative stress, recapitulating the muscle pathology of PAD patients.     

Group III and IV receptors of skeletal muscle

The single largest group of sensory fibres leaving skeletal muscles are small myelinated or unmyelinated (groups III and IV) fibres. The receptors served by these small fibres have not been subjected to the same intensive study that receptors served by group I and II fibres have received. The evidence so far available suggests that receptors with group III and IV axons play a particular role in nociception and also subserve a wide range of sensory modalities. Despite their role in nociception, the primary afferent fibres from these receptors do not project to the substantia gelatinosa. A significant percentage of group III receptors are sensitive to stretch and have been thought to be the receptor source that initiates the clasp-knife reflex. Other group III receptors respond to chemical change within the muscle and have been implicated in the initiation of cardiovascular reflexes and the changes in muscle blood flow that accompany exercise. Group IV receptors also include high threshold mechanoreceptors and nociceptors. It is well known that encapsulated receptors are quite unevenly distributed within skeletal muscles and in different skeletal muscles. Preliminary evidence suggests that the variation in receptor content is not confined to encapsulated receptors, but that the receptors served by group III and IV afferents may have receptive properties that vary from muscle to muscle.     

Efficacy and specificity of bFGF increased collateral flow in experimental peripheral arterial insufficiency

Angiogenic growth factors could prove to be useful in managing peripheral arterial insufficiency. The present study was designed to evaluate the dose response of basic fibroblast growth factor (bFGF), the efficacy of critical routes and dosing regimens, and the specificity of action in rats with peripheral arterial insufficiency. Bilateral ligation of femoral arteries greatly reduces blood flow capacity to the calf muscles but does not impair resting flow needs. Collateral blood flow to calf muscles was determined 16 days postocclusion, during treadmill running, with (85)Sr and (141)Ce microspheres, in blinded-randomized trials that included intra-arterial and intravenous infusions and subcutaneous injections of recombinant human bFGF. Peak blood flow of 75-80 ml. min(-1). 100 g(-1) for calf muscle was observed at a bFGF dose of 5 microg. kg(-1). day(-1) (ia for 14 days) compared with 50 ml. min(-1). 100 g(-1) for vehicle groups. Similar increases in collateral blood flow were observed with short-term or prolonged and continuous or intermittent delivery of bFGF by any route. Collateral blood flows were similar in corresponding muscles across both limbs. Vascular remodeling induced by bFGF required attendant vascular occlusion, inasmuch as vessels in the normal nonoccluded vascular tree were unresponsive to circulating bFGF. Improvement in collateral blood flow with exogenous bFGF is robust, amenable to short-term administration, and requires vascular occlusion to be effective.     

Cerebral perturbations during exercise in hypoxia

Reduction of aerobic exercise performance observed under hypoxic conditions is mainly attributed to altered muscle metabolism due to impaired O(2) delivery. It has been recently proposed that hypoxia-induced cerebral perturbations may also contribute to exercise performance limitation. A significant reduction in cerebral oxygenation during whole body exercise has been reported in hypoxia compared with normoxia, while changes in cerebral perfusion may depend on the brain region, the level of arterial oxygenation and hyperventilation induced alterations in arterial CO(2). With the use of transcranial magnetic stimulation, inconsistent changes in cortical excitability have been reported in hypoxia, whereas a greater impairment in maximal voluntary activation following a fatiguing exercise has been suggested when arterial O(2) content is reduced. Electromyographic recordings during exercise showed an accelerated rise in central motor drive in hypoxia, probably to compensate for greater muscle contractile fatigue. This accelerated development of muscle fatigue in moderate hypoxia may be responsible for increased inhibitory afferent signals to the central nervous system leading to impaired central drive. In severe hypoxia (arterial O(2) saturation <70-75%), cerebral hypoxia per se may become an important contributor to impaired performance and reduced motor drive during prolonged exercise. This review examines the effects of acute and chronic reduction in arterial O(2) (and CO(2)) on cerebral blood flow and cerebral oxygenation, neuronal function, and central drive to the muscles. Direct and indirect influences of arterial deoxygenation on central command are separated. Methodological concerns as well as future research avenues are also considered.     

Lesions in the rat soleus muscle following eccentrically biased exercise

Morphological changes in skeletal muscle related to lengthening (eccentric) contractions have been noted by several laboratories. However, a systematic examination of skeletal muscle following repetitive eccentric contractions is lacking. This study was undertaken to study lesions and determine their relative densities in rat soleus muscle 30 min following level or downhill treadmill exercise. Following fixation in situ by vascular perfusion, toluidine-blue-stained 1-micron sections of the muscle samples selected at 73-micron intervals were scanned with a light microscope. Three types of lesions were noted: focal disruptions in the A-band, localized dissolution of Z-lines, and clotting of muscle fibers. Soleus muscle from the caged controls and the tibialis anterior muscle from downhill-exercised rats were essentially free of lesions. Eighty-nine percent of the soleus m. lesions in the downhill runner group and 97% of those in the level runner group were A-band disruptions. A-band lesion density was significantly higher in the soleus muscle of the downhill runners compared to level runners with the highest incidence in the distal half. A-band lesion density was lower in soleus muscles from level runners; however, the highest intramuscular incidence was in the proximal rather than the distal end. The results indicate that a disruption of the A-band is a principal change within some skeletal muscle fibers 30 min following repetitive eccentric contractions.     

MRI measures of perfusion-related changes in human skeletal muscle during progressive contractions.

Although skeletal muscle perfusion is fundamental to proper muscle function, in vivo measurements are typically limited to those of limb or arterial blood flow, rather than flow within the muscle bed itself. We present a noninvasive functional MRI (fMRI) technique for measuring perfusion-related signal intensity (SI) changes in human skeletal muscle during and after contractions and demonstrate its application to the question of occlusion during a range of contraction intensities. Eight healthy men (aged 20-31 yr) performed a series of isometric ankle dorsiflexor contractions from 10 to 100% maximal voluntary contraction. Axial gradient-echo echo-planar images (repetition time = 500 ms, echo time = 18.6 ms) were acquired continuously before, during, and following each 10-s contraction, with 4.5-min rest between contractions. Average SI in the dorsiflexor muscles was calculated for all 240 images in each contraction series. Postcontraction hyperemia for each force level was determined as peak change in SI after contraction, which was then scaled to that obtained following a 5-min cuff occlusion of the thigh (i.e., maximal hyperemia). A subset of subjects (n = 4) performed parallel studies using venous occlusion plethysmography to measure limb blood flow. Hyperemia measured by fMRI and plethysmography demonstrated good agreement. Postcontraction hyperemia measured by fMRI scaled with contraction intensity up to approximately 60% maximal voluntary contraction. fMRI provides a noninvasive means of quantifying perfusion-related changes during and following skeletal muscle contractions in humans. Temporal changes in perfusion can be observed, as can the heterogeneity of perfusion across the muscle bed.     

Theoretical simulation of K(+)-based mechanisms for regulation of capillary perfusion in skeletal muscle

Muscle fibers release K(+) into the interstitial space upon recruitment. Increased local interstitial K(+) concentration ([K(+)]) can cause dilation of terminal arterioles, leading to perfusion of downstream capillaries. The possibility that capillary perfusion can be regulated by vascular responses to [K(+)] was examined using a theoretical model. The model takes into account the spatial relationship between functional units of muscle fiber recruitment and capillary perfusion. Diffusion of K(+) in the interstitial space was simulated. Two hypothetical mechanisms for vascular sensing of interstitial [K(+)] were considered: direct sensing by arterioles and sensing by capillaries with stimulation of feeding arterioles via conducted responses. Control by arteriolar sensing led to poor tissue oxygenation at high levels of muscle activation. With control by capillary sensing, increases in perfusion matched increases in oxygen demand. The time course of perfusion after sudden muscle activation was considered. Predicted capillary perfusion increased rapidly within the first 5 s of muscle fiber activation. The reuptake of K(+) by muscle fibers had a minor effect on the increase of interstitial [K(+)]. Uptake by perfused capillaries was primarily responsible for limiting the increase in [K(+)] in the interstitial space at the onset of fiber activation. Vascular responses to increasing interstitial [K(+)] may contribute to the rapid increase in blood flow that is observed to occur after the onset of muscle contraction.