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The influence of muscular compression on the blood flow in skeletal muscle has been pondered for many years. Anrep & von Saalfeld (1935) first showed that arterial inflow is reduced during contraction due to compression of the intramuscular vessels, an effect later confirmed by Wesche (1986) in humans. Compression of the veins aids venous return to the heart (Guyton et al. 1962) and has been postulated to increase skeletal muscle perfusion by reducing the downstream venous pressure during relaxation, i.e. the muscle pump effect. Evidence in support of this notion is scanty, but the absence of contraction-induced hyperaemia when vascular smooth muscle relaxation is impaired implies that immediate increases in blood flow are attributable to rapid vasodilatation rather than a muscle pump effect (Hamann et al. 2004). Indeed, there is definitive evidence of rapid vasodilation at the onset of contractions in the rat spinotrapezius muscle (Marshall & Tandon, 1984), hamster cremaster muscle (Mihok & Murrant, 2004), and the hamster retractor muscle (VanTeeffelen & Segal, 2006). An additional way that compression could influence blood flow is through activation of a myogenic-like response. This idea was first put to the test by Mohrman & Sparks (1974) who showed that inflation of a cuff placed around isolated canine gastrocnemius muscle could cause vasodilatation. In addition, they observed that changes in vascular conductance following contraction were related to intramuscular pressure. More recent data demonstrated that brief periods of mechanical compression elicit dilatation in isolated soleus feed arteries (Clifford et al. 2006). The time course of the vasodilatation was remarkably similar to that for the change in blood flow after a brief muscle contraction. In addition, multiple pressure pulses evoked a greater magnitude of dilatation than a singe pressure pulse. On the basis of these results it was suggested that compression of the intramuscular vasculature could provide a mechanism for rapid vasodilatation following contraction. The study by Kirby et al. (2007) in this issue of The Journal of Physiology represents another important landmark in this story. The clever manipulations employed by this group are a superb example of how to study integrative human physiology. Moreover, the results show quite clearly that mechanical compression can elicit hyperaemia in the human forearm. The existence of a dose–response relationship over a range of cuff pressures between 25 and 100 mmHg provides the potential to produce graded vasodilatation in response to graded compression of the vasculature. Importantly, the observation of a temporal dissociation between the peak response to compression and that elicited by contractions argues that mechanical influences do not completely explain contraction-induced vasodilatation. In considering these results, one must keep in mind that it cannot be determined whether the forearm cuff faithfully mimics the compression elicited by forceful muscular contraction. One issue that remains to be resolved is whether this mechanism is operative in all types of muscle under all conditions. Berg et al. (1997) and vanTeeffelen & Segal (2006) maintain that vessel compression is not a factor in thin muscle in situ preparations. However, it must be emphasized that complete collapse of the vessel is not required to evoke this response. In fact, subjects in the study of Kirby et al. with a mean arterial pressure of 89 mmHg exhibited significant dilatation when external pressure was applied at only 50 mmHg. In the in vitro model (Clifford et al. 2006), high extravascular pressures were employed to simulate intramuscular pressures during maximal contraction. More recent experiments (unpublished observations Clifford & Jasperse) reveal that compression-induced dilatation can occur with little discernible reduction in vessel diameter. Substantial dilatation was observed when a brief pressure pulse matching intraluminal pressure was applied to the outside of the vessel. We speculate that contraction of muscle fibres may evoke sufficient vascular compression to elicit dilatation in the in situ muscle preparations. There has been considerable discussion of redundant factors being involved in complex physiological responses such as exercise hyperaemia. The present findings suggest a scenario where there may be temporally distinct phases of vasodilatation. Mechanically induced feed forward vasodilatation could occur with the initial contraction. Vasodilatation could then continue as potassium rapidly accumulates in the interstitium. After sufficient time to allow production and diffusion of metabolites from skeletal muscle, the blood flow could be adjusted by feedback mechanisms to match blood flow with oxygen consumption. A critical challenge for physiologists interested in this topic will be to begin teasing out the time course over which each of these overlapping mechanisms may act. The paper by Kirby et al. (2007) makes a key contribution by demonstrating that mechanically induced vasodilatation is most important in the very initial phase of hyperaemia. Until recently, little consideration has been given to a mechanical mechanism to explain vasodilatation during exercise. Kirby and colleagues have provided the impetus for further study of this mechanism. It seems clear that the influence of mechanical factors must be incorporated into our models for the overall picture of exercise hyperaemia.
3Commentaries on Viewpoint: A paradigm shift for local blood flow regulation
# COMMENT ON “A PARADIGM SHIFT FOR LOCAL BLOOD FLOW REGULATION” {#article-title-2} to the editor: The proposed role of O2− produced by NAD(P)H oxidase acting in concert with changes in mitochondrial O2 on regulating local blood flow hypothesized by Golub and Pittman ([5][1]) could very well
Read more3Effects of dopamine and dobutamine on the myocardial and systemic circulation during and following cardiopulmonary bypass in dogs.
The effect of dopamine (Dp) and dobutamine (Db) on myocardial and systemic blood flow (BF) distribution was compared in dogs being weaned from cardiopulmonary bypass (CPB) after 20 min of normothermic global myocardial ischemia. Drug infusions (10 mcg/kg/min) were begun and BF was measured (radiolabeled microspheres) prior to weaning and 60 min off CPB. On CPB: Pump flows, by design, were similar (100 ml/kg/min) in Dp, Db, and saline control (NS) dogs. Dp and Db significantly (p less than 0.05) increased myocardial BF. Dp did not alter renal, visceral, and skeletal muscle BF and only increased BF to the cervical spinal cord and medulla. Db, however, significantly reduced renal (-49%), splenci (-58%), pancreatic (-27%), and colonic (-47%) BF but increased perfusion in essentially all of the central nervous system. Off CPB: Cardiac output during Dp and Db infusions was significantly greater than NS dogs (107 +/- 7 vs 152 +/- 12 vs 82 +/- 10 ml/kg/min resp.); the greater increase for Db resulting from a larger stroke volume. Dp and Db significantly increased myocardial BF. Dp increased splenic (+77%), gastric (+139%), and gallbladder (+125%) BF but had no effect on renal, hepatic, skeletal muscle, and intestinal BF. Db infusion maintained renal BF similar to NS and elevated BF to most visceral organs. The results of this study show that the myocardium responded to inotropic stimulation despite the previous ischemic insult but the BF changes varied among regional vascular beds with Dp and Db infusions during and following CPB. Of the 2 drugs, Db showed the greater inotropic response off CPB, a similar increase in myocardial perfusion and greater visceral organ bloodflow.
Read moreSustained Skeletal Muscle Blood Flow Elevations Following Prolonged Passive Leg Movement
Passive limb movement results in up to a threefold increase in skeletal muscle blood flow following movement. The increased blood flow occurs independently of local tissue metabolism, but is likely related to changing sheer patterns from mechanically‐induced blood flow, tissue distortion, and afferent feedback from group III/IV nerves. Prior research suggests that following acute bouts of passive limb movement, blood flow is only elevated transiently, and returns to baseline within minutes. Whether increased duration of passive movement could extend the duration of increased blood flow after movement, generating a sustained elevation in skeletal muscle blood flow that is similar to sustained postexercise vasodilation, is unknown. However, if passive movement can elicit a sustained vasodilation, the underlying mechanisms could contribute to the sustained postexercise vasodilation. Therefore, the purpose of this experiment was to determine the duration of elevated skeletal muscle blood flow in response to an extended duration (60 min) of passive movement. It was hypothesized that 60 min of passive leg movement would increase skeletal muscle blood flow for up to 60 min following movement. Four young, healthy, recreationally active individuals (3M, 1F) volunteered for this study. Limb blood flow and muscle perfusion were assessed in the supine position in both the right (Passive) and left (Control) legs 30 min prior to and 60 min following passive movement. Limb blood flow was estimated via Doppler ultrasound at the femoral artery, and muscle perfusion was estimated in the vastus lateralis using the near‐infrared spectroscopy response to intravenous infusion of indocyanine green (IC‐Green, Akorn). Passive movement of the volunteer's right leg (Passive) consisted of knee flexion from 45 to 90 degrees, completed at a cadence of 45 flexions per min for 60 min. To confirm limb movement was passive, muscle activity was monitored via surface electromyography. Heart rate and blood pressure were recorded throughout the study by electrocardiogram and an automatic acoustic sphygmomanometer. At 60‐min following passive movement, limb blood flow tended to remain elevated in the Passive leg (25.5±6.4% P=0.06), but not in the Control leg (+9.1±5.4%, P=0.22) when compared to pre‐movement measures. Additionally, at 60‐min after passive movement, limb blood flow tended to be higher in Passive leg than in Control (P=0.09). Alternatively, muscle perfusion was elevated in the Passive leg (50.2±7.8%, P=0.03) and tended to be elevated in the Control leg (39.7±6.1%, P=0.09) at 60‐min following movement compared to pre‐movement measures, and did not differ between the Passive and the Control legs (P=0.62). Heart rate and blood pressure did not change from baseline, to passive movement, and during recovery from movement. These results indicated that prolonged passive movement can cause a sustained elevation in skeletal muscle blood flow in the moved limb, but may have broader impacts on microvascular perfusion. We suggest that the underlying mechanism(s) for this response, which remain to be identified, could contribute to the sustained postexercise vasodilation.Support or Funding InformationSupport provided by NIH grant HL115027This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Read more18Oxytocin selectively reduces blood flow in uterine fibroids without an effect on myometrial blood flow: a dynamic contrast enhanced MRI evaluation
Introduction Uterine fibroids are the most common benign neoplasms in women. The administration of intravenous oxytocin is known to increase the efficacy of a non-invasive thermal ablation method (MR-HIFU) for treating fibroids. However, it is not known whether this phenomenon is caused by the effect of the oxytocin on the myometrium or the fibroid itself. The objective of this study was to evaluate the influence of oxytocin on the blood flow of fibroids, myometrium and skeletal muscle using a quantitative perfusion MRI technique. Materials and methods 17 premenopausal women with fibroids considered to be treated with MR-HIFU and 11 women with no fibroids were enrolled in the study. An extended MRI protocol of the pelvis was acquired for each subject. Later another MRI scan was performed with continuous intravenous infusion of oxytocin. The effect of oxytocin was analyzed from quantitative perfusion imaging. The study was registered in clinicaltrials.gov NCT03937401. Results Oxytocin decreased the blood flow of each fibroid; the median blood flow of fibroid was 39.9 ml/100 g tissue/min without and 3.5 mL/100 g/min with oxytocin (p ≤ 0.0001). Oxytocin did not affect the blood flow of the myometrium in either group. Oxytocin increased the blood flow of the skeletal muscle in both groups (p = 0.04). Conclusion Oxytocin is effective in decreasing the blood flow in fibroids while having minor or no effect on the blood flow of normal myometrium. Routine use of oxytocin in HIFU therapy may make the therapy suitable to a larger group of women in a safe manner.
Read more18Evidence that the arterial baroreceptors influence muscle blood flow and not subcutaneous flow in man.
Studies in man indicate that skeletal muscle blood flow is modulated via high pressure baroreceptors located in the carotid body. However, whether subcutaneous blood flow is influenced in this way remains controversial. Therefore, the aim of the present study was to determine whether subcutaneous as well as skeletal muscle blood flow was influenced by direct carotid body stimulation; this was done by means of neck suction. Six young healthy males were investigated. Subcutaneous and skeletal muscle blood flow in the forearm was measured by the local 133Xe washout technique. Neck suction of -20 mmHg was applied through a tight helmet covering the head and neck. In the supine position heart rate increased about 10%, mean arterial pressure was unchanged, subcutaneous blood flow was unchanged, but skeletal muscle blood flow increased about 70%. Measurements were repeated during neck suction, -20 mmHg, and 45 degrees head-up tilt (which is known to decrease subcutaneous blood flow and skeletal muscle blood flow by increasing sympathetic vasoconstrictor activity). Heart rate increased by about 20%, mean arterial pressure was unchanged, subcutaneous blood flow was unchanged and skeletal muscle blood flow increased about 100%. These results indicate that skeletal muscle blood flow is modulated through carotid baroreceptors. Subcutaneous blood flow seems not to be influenced by high pressure baroreceptor modulation, although a vasoconstrictor response to head-up tilt was demonstrated in this as well as other recent studies.
Read more100Preserved relative dispersion but blunted stimulation of mean flow, absolute dispersion, and blood volume by insulin in skeletal muscle of patients with essential hypertension.
We examined the integrity of the effects of insulin on mean muscle blood flow, flow heterogeneity, and blood volume in essential hypertension. Positron emission tomography, combined with [15O]H2O and [15O]CO as tracers for direct measurement of blood flow and volume in skeletal muscle, and a new bayesian iterative reconstruction algorithm allowing pixel-by-pixel quantitation of blood flow and flow dispersion, were used. Measurements were performed basally after an overnight fast and under normoglycemic hyperinsulinemic conditions in 11 newly diagnosed, untreated mildly hypertensive men (age, 35 +/- 1 years; body mass index, 25.2 +/- 0.4 kg/m2, blood pressure 141 +/- 4/96 +/- 2 mm Hg, mean +/- SE) and 11 matched normotensive men. Insulin-stimulated whole body glucose uptake was significantly decreased in the hypertensive men (41 +/- 4 mumol/kg per minute) compared with the normotensive (59 +/- 4 mumol/kg per minute, P < 0.005) men. Mean blood flow in skeletal muscle was significantly lower in the hypertensive than the normal subjects basally (1.7 +/- 0.2 versus 2.7 +/- 0.4 mL/0.1 kg per minute, P < 0.05) and during hyperinsulinemia (2.3 +/- 0.2 versus 4.2 +/- 0.8, P < 0.05). The flow response to insulin (0.6 +/- 0.2 versus 1.9 +/- 0.5 mL/0.1 kg per minute, hypertensive versus normal subjects, P < 0.05) was also significantly blunted. Muscle blood volume was significantly lower in the hypertensive than in the normal subjects, both basally (3.0 +/- 0.2 versus 3.5 +/- 0.2 mL/0.1 kg, P < 0.05) and during hyperinsulinemia (3.1 +/- 0.2 versus 4.0 +/- 0.2 mL/0.1 kg muscle, P < 0.02). The increase in muscle blood volume by insulin was significant in the normal (P < 0.05) but not the hypertensive subjects. Regional pixel-by-pixel analysis within femoral muscles revealed significant spatial heterogeneity of blood flow. Insulin increased absolute dispersion of blood flow significantly more in the normal subjects than in the hypertensive subjects (P < 0.05). True flow heterogeneity, as judged from the coefficients of variation (relative dispersion), was comparable between the groups basally and during hyperinsulinemia. We conclude that mean flow, its absolute dispersion, and blood volume exhibit insulin resistance in patients with essential hypertension.
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1Mechanisms of exercise-induced reduction in peripheral arterial stiffness.
Peripheral arterial stiffness measured with pulse wave velocity (PWV) is reduced 5-min after an acute bout of dynamic exercise. The mechanism for the reduction in peripheral arterial stiffness is unknown. We hypothesized that increased blood flow and compression of the vasculature are potential mechanisms involved in post-exercise reduction in peripheral arterial stiffness. Brachial-radial PWV was measured with tonometers on the exercising arm of 20 healthy young volunteers (10 females, 30 ± 5 yrs, mean ± SD) before and after 5min of rhythmic handgrip exercise at 30% of maximal voluntary contraction (MVC), 50% MVC, and a 5min set of passive forearm compressions. Brachial blood flow was monitored with Doppler ultrasound during exercise/compression. Brachial-radial PWV was lower than baseline at 5min post (p < 0.001) for 30% MVC, 50% MVC, and compression, with responses similar among all conditions (p > 0.05). PWV remained lower than baseline at 15min and 30min only for 50% MVC. Blood flow and changes in brachial diameter during exercise/compression were not factors in the PWV reduction (p > 0.05). These findings suggest that compression of the forearm vasculature contributes to the initial reduction in peripheral PWV after handgrip exercise, but the reductions in peripheral PWV are not associated with changes in blood flow.
Read more101Influence of desflurane, isoflurane and halothane on regional tissue perfusion in dogs.
The actions of desflurane, isoflurane and halothane on regional tissue perfusion were studied using radioactive microspheres in dogs chronically instrumented for measurement of arterial and left ventricular pressure, global (left ventricular dP/dtmax) and regional (percent segment shortening) contractile function, and diastolic coronary blood flow velocity. Systemic and coronary haemodynamics and regional tissue perfusion were measured in the conscious state and during anaesthesia with equihypotensive concentrations of desflurane, isoflurane, and halothane. All three volatile anaesthetics (P < 0.05) increased heart rate and decreased mean arterial pressure, left ventricular systolic pressure, and left ventricular dP/dtmax Myocardial perfusion was unchanged in subendocardial midmyocardial, and subepicardial regions by the administration of either dose of desflurane. No redistribution of intramyocardial blood flow (endo/epi ratio) was observed during desflurane anaesthesia. Although regional myocardial perfusion was reduced (P < 0.05) in a dose-related fashion by halothane and by isoflurane at high concentrations, redistribution of intramyocardial blood flow was not observed during halothane or isoflurane anaesthesia. All three volatile anaesthetics reduced blood flow to the renal cortex, but only desflurane produced a decrease in renal cortical vascular resistance. Hepatic blood flow decreased in response to halothane but not desflurane or isoflurane. Concomitant decreases in hepatic resistance were observed during administration of desflurane and isoflurane. Dose-related decreases in intestinal and skeletal muscle blood flow were observed during halothane and isoflurane but not desflurane anaesthesia. The results suggest that desflurane maintains myocardial, hepatic, intestinal, and skeletal muscle blood flow while halothane and isoflurane decrease regional tissue perfusion in these vascular beds to varying degrees during systemic hypotension in the chronically instrumented dog.
Read more77Inhaled alternatives to nitric oxide.
should decrease pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), without affecting systemic arterial pressure (SAP), and potentially improve oxygenation by redistributing pulmonary blood flow to ventilated areas of lung. INO (INO Therapeutics Inc., Clinton NJ) possesses these properties and has gained approval from the Food and Drug Administration (FDA) for the care of neonates with acute lung injury and pulmonary hypertension (PH), and widespread clinical acceptance (but not FDA approval) for adults with PH with or without lung injury. Delivered as a gas, INO is preferentially distributed to the ventilated areas of the lung, where it produces relaxation of pulmonary vascular smooth muscle via activation of guanylate cyclase and the conversion of guanosine-5-triphosphate to cyclic guanosine monophosphate. 1 Absorbed INO is rapidly inactivated by hemoglobin, thereby preventing systemic effects and confining its vasodilator properties to the pulmonary circulation. 1 The search for inhaled selective pulmonary vasodilators was an active area of research, particularly in Europe and Australia, before the widespread publicity and testing of INO in the early 1990s. However, research on this subject appears to have declined inversely with the growing acceptance and use of INO. Until FDA approval had been granted, INO had been supplied free of charge in the United States on an investigational-drug basis. However, after FDA approval, the cost of treatment with INO became very expensive. This prompted a search at our institution for alternative agents to INO. The purpose of this article is to review the published experience concerning alternative inhaled vasodilators and, when possible, compare their reported efficacy with that of INO.
Read more12A phosphodiesterase 3 inhibitor, K-134, improves hindlimb skeletal muscle circulation in rat models of peripheral arterial disease
A phosphodiesterase 3 inhibitor, K-134, improves hindlimb skeletal muscle circulation in rat models of peripheral arterial disease
Read moreThe root of the matter: nitrate-rich beetroot juice reduces skeletal muscle O2 uptake during exercise.
The root of the matter: nitrate-rich beetroot juice reduces skeletal muscle O2 uptake during exercise.
28Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow
Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising skeletal muscle. Skeletal muscle blood flow was measured in seven healthy young men using near-infrared spectroscopy and indocyanine green and muscle glucose uptake using positron emission tomography and 2-fluoro-2-deoxy-D-[(18)F]glucose without and with local blockade of NO and PG at rest and during one-legged dynamic knee-extension exercise. Local blockade was produced by infusing nitro-L-arginine methyl ester and indomethacin directly in the muscle via a microdialysis catheter. Blood flow and glucose uptake were measured in the region of blockade and in two additional regions of vastus lateralis muscle 1 and 4 cm away from the infusion of blockers. Local blockade during exercise at 25 and 40 watts significantly decreased blood flow in the infusion region and in the region 1 cm away from the site of infusion but not in the region 4 cm away. During exercise, muscle glucose uptake did not show any regional differences in response to blockade. These results show that NO and PG synergistically contribute to the local regulation of blood flow in skeletal muscle independently of muscle glucose uptake in healthy young men. Thus these vasodilators can play a role in regulating microvascular blood flow in localized regions of vastus lateralis muscle but do not influence regional glucose uptake. The findings suggest that local substrate uptake in skeletal muscle can be regulated independently of regional changes in blood flow.
Read more29Methods for the determination of skeletal muscle blood flow: development, strengths and limitations
Since the first measurements of limb blood flow at rest and during nerve stimulation were conducted in the late 1800s, a number of methods have been developed for the determination of limb and skeletal muscle blood flow in humans. The methods, which have been applied in the study of aspects such as blood flow regulation, oxygen uptake and metabolism, differ in terms of strengths and degree of limitations but most have advantages for specific settings. The purpose of this review is to describe the origin and the basic principles of the methods, important aspects and requirements of the procedures. One of the earliest methods, venous occlusion plethysmography, is a noninvasive method which still is extensively used and which provides similar values as other more direct blood flow methods such as ultrasound Doppler. The constant infusion thermodilution method remains the most appropriate for the determination of blood flow during maximal exercise. For resting blood flow and light-to-moderate exercise, the non-invasive ultrasound Doppler methodology, if handled by a skilled operator, is recommendable. Positron emission tomography with radiolabeled water is an advanced method which requires highly sophisticated equipment and allows for the determination of muscle-specific blood flow, regional blood flows and estimate of blood flow heterogeneity within a muscle. Finally, the contrast-enhanced ultrasound method holds promise for assessment of muscle-specific blood flow, but the interpretation of the data obtained remains uncertain. Currently lacking is high-resolution methods for continuous visualization and monitoring of the skeletal muscle microcirculation in humans.
Read moreProtection against skeletal muscle hypoperfusion by adenosine and nitric oxide: together alone?
regulation of vasomotor tone in the microcirculation is essential to ensure adequate tissue oxygenation, particularly when oxygen demand is high, i.e., in skeletal or cardiac muscle during exercise and/or when supply is compromised, i.e., during hypoxia or in the presence of a flow-limiting stenosis
Read moreInvolvement of α- and β-Adrenergic Receptors in Skeletal Muscle Blood Flow Changes During Hyper-/Hypocapnia in Anesthetized Rabbits.
This study investigated the involvement of α1- and β2-adrenergic receptors in skeletal muscle blood flow changes during variations in ETCO2. Forty Japanese White rabbits anesthetized with isoflurane were randomly allocated to 1 of 5 groups: phentolamine, metaproterenol, phenylephrine, butoxamine, and atropine. Heart rate (HR), systolic blood pressure (SBP), common carotid artery blood flow (CCBF), masseter muscle tissue blood flow (MBF), and quadriceps muscle tissue blood flow (QBF) were recorded and analyzed at 3 periods: (1) baseline, (2) during hypercapnia (phentolamine and metaproterenol groups) or hypocapnia (phenylephrine, butoxamine, and atropine groups), and (3) during or after receiving vasoactive agents. MBF and QBF decreased during hypercapnia. The decrease in MBF was smaller than that in QBF. SBP and CCBF increased, while HR decreased. Both MBF and QBF recovered to their baseline levels after phentolamine administration. MBF became greater than its baseline level, while QBF did not fully recover after metaproterenol administration. MBF and QBF increased during hypocapnia. The increase rate in MBF was larger than that in QBF. HR, SBP, and CCBF did not change. Both MBF and QBF decreased to ∼90% to 95% of their baseline levels after phenylephrine or butoxamine administration. Atropine showed no effects on MBF and QBF. These results suggest the skeletal muscle blood flow changes observed during hypercapnia and hypocapnia may mainly involve α1-adrenergic but not β2-adrenergic receptor activity.
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