Search

Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach—unilateral reduction in renal blood flow to ∼30% of control values until systolic pressure ≥ 140 mmHg and a diastolic pressure ≥ 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients.

We present a combined use of near-infrared spectroscopy and diffuse correlation spectroscopy to noninvasively evaluate the tissue metabolic rate of oxygen in the skeletal muscle for healthcare and sports science applications.

We developed a dual-channel diffuse correlation spectroscopy system, which was validated by simultaneous blood flow measurement of the skeletal muscles of the upper and lower limbs during the head-up-tilt test.

Previous studies showed that conduit artery blood flow rapidly increases after even a brief contraction of muscles within the dependent limb. Whether this rapid hyperemia occurs within contracted skeletal muscle in humans has yet to be confirmed, however. We therefore used diffuse correlation spectroscopy (DCS) to characterize the rapid hyperemia and vasodilatory responses within the muscle microvasculature induced by single muscle contractions in humans. Twenty-five healthy male volunteers performed single 1-s isometric handgrips at 20%, 40%, 60%, and 80% of maximum voluntary contraction. DCS probes were placed on the flexor digitorum superficialis muscle, and a skeletal muscle blood flow index (SMBFI) was derived continuously. At the same time, brachial artery blood flow (BABF) responses were measured using Doppler ultrasound. Single muscle contractions evoked rapid, monophasic increases in both SMBFI and BABF that occurred within 3 s after release of contraction. The initial and peak responses increased with increases in contraction intensity and were greater for BABF than for SMBFI at all intensities. BABF reached its peak within 5 to 8 s after the end of contraction. The SMBFI continued to increase after the BABF passed its peak and was decreasing toward the resting level and peaked about 10 to 15 s after completion of the contraction. We conclude that single muscle contractions induce rapid, intensity-dependent hyperemia within the contracted skeletal muscle microvasculature. Moreover, the characteristics of the rapid hyperemia and vasodilatory responses of skeletal muscle microvessels differ from those simultaneously evaluated in the upstream conduit artery.

Twenty minutes of voluntary hypocapnic hyperventilation prior to exercise reduces the aerobic metabolic rate with a compensatory increase in the anaerobic metabolic rate without affecting exercise ...

We investigated blood flow response for reactive hyperemia test in type1 diabetic and control rats using diffuse correlation spectroscopy (DCS). The baseline blood flow, peak amplitude and time to peak blood flow responses after releasing from ischemia were significantly decreased after induction of hyperglycemic state in diabetic rats. Furthermore, the baseline blood flow and the peak amplitude were significantly decreased from 1st week to 10th week in diabetic rats, suggesting the progress of vascular dysfunction caused by sustained glycemic stress. This research showed a potential of DCS to diagnose vascular function in diabetes that was altered by acute and chronic hyperglycemic stress.

The effect of fatigue on the hemodynamic responses of active skeletal muscle has yet to be fully understood due to the limited evaluation techniques of deep tissues hemodynamics. We adopted diffuse correlation spectroscopy (DCS), a promising optical imaging technique of tissue blood flow velocity, to determine fatigue-related changes in blood flow and vascular conductance of active muscle. Hemodynamic and electrophysiological responses of the flexor digitorum superficialis were continuously monitored by DCS and electromyogram (EMG) from the non-dominant forearm of youngadult participants (n=12). Systemic blood pressure was monitored from the other side of upper arm every minute. Participants performed 2 minutes of dynamic handgrip exercise (with a duty cycle of 2-s contraction and 2-s relaxation) with the load of 10% or 30% of maximal voluntary contraction (MVC) twice. To induce muscle fatigue, static handgrip (40% MVC for 2 minutes) was performed between the two sessions of dynamic handgrip exercise. Induction of fatigue was confirmed by significant decreases of EMG mean frequency in both load conditions. Muscle fatigue induced significant increase of active muscle blood flow and mean blood pressure in both load conditions. Vascular conductance of active muscle showed tendency of (10% MVC) or significant (30% MVC) increase after fatigue induction. These results suggest the enhanced vasodilatation along with fatigue in active muscles, possibly derived by accumulated metabolic and vasodilator substances. Our results demonstrate the possible application of DCS to detect and evaluate the fatigue effect of active skeletal muscle.

The purpose of the present study was to test our hypothesis that unloading the carotid baroreceptors alters the threshold and gain of the muscle metaboreflex in humans. Ten healthy subjects performed a static handgrip exercise at 50% of maximum voluntary contraction. Contraction was sustained for 15, 30, 45, and 60 s and was followed by 3 min of forearm circulatory arrest, during which forearm muscular pH is known to decrease linearly with increasing contraction time. The carotid baroreceptors were unloaded by applying 0.1-Hz sinusoidal neck pressure (oscillating from +15 to +50 mmHg) during ischemia. We estimated the threshold and gain of the muscle metaboreflex by analyzing the relationship between the cardiovascular responses during ischemia and the amount of work done during the exercise. In the condition with unloading of the carotid baroreceptors, the muscle metaboreflex thresholds for mean arterial blood pressure (MAP) and total vascular resistance (TVR) corresponded to significantly lower work levels than the control condition (threshold for MAP: 795 ± 102 vs. 662 ± 208 mmHg and threshold for TVR: 818 ± 213 vs. 572 ± 292 kg·s, P < 0.05), but the gains did not differ between the two conditions (gain for MAP: 4.9 ± 1.7 vs. 4.4 ± 1.6 mmHg·kg·s−1·100 and gain for TVR: 1.3 ± 0.8 vs. 1.3 ± 0.7 mmHg·l−1·min−1·kg·s−1·100). We conclude that the carotid baroreflex modifies the muscle metaboreflex threshold in humans. Our results suggest the carotid baroreflex brakes the muscle metaboreflex, thereby inhibiting muscle metaboreflex-mediated pressor and vasoconstriction responses. NEW & NOTEWORTHY We found that unloading the carotid baroreceptors shifts the pressor threshold of the muscle metaboreflex toward lower metabolic stimulation levels in humans. This finding indicates that, in the normal loading state, the carotid baroreflex inhibits the muscle metaboreflex pressor response by shifting the reflex threshold to higher metabolic stimulation levels.

Objectives Post-occlusive reactive hyperemia (PORH) following arterial occlusion is widely used to assess cutaneous microvascular function, though the underlying mechanisms remain to be fully elucidated. We evaluated the hypothesis that Ca2+ -activated, ATP-sensitive, and voltage-gated K+ channels (KC a , KATP , and KV channels, respectively) contribute to PORH while nitric oxide synthase (NOS) and cyclooxygenase (COX) do not. Methods On separate occasions, cutaneous blood flow (laser Doppler flowmetry) was monitored before and following 5-min arterial occlusion at forearm skin sites treated via microdialysis with the following: Experiment 1 (n = 11): (a) lactated Ringer solution (Control), (b) 10 mM Nω -nitro-L -arginine (NOS inhibitor), (c) 10 mM ketorolac (COX inhibitor), and (d) combined NOS+COX inhibition; Experiment 2 (n = 14): (a) lactated Ringer solution (Control), (b) 50 mM tetraethylammonium (non-selective KC a channel blocker), (c) 5 mM glibenclamide (non-specific KATP channel blocker), and (d) 10 mM 4-aminopyridine (non-selective KV channel blocker). Results Separate and combined NOS and COX inhibition did not influence PORH. Conversely, tetraethylammonium and glibenclamide attenuated, whereas 4-aminopyridine augmented PORH. Conclusions We showed that tetraethylammonium, glibenclamide, and 4-aminopyridine modulate PORH with no roles of NOS and COX in human non-glabrous forearm skin in vivo. Thus, cutaneous PORH changes could reflect altered K+ channel function.

The venoarteriolar reflex is a local mechanism that induces vasoconstriction during venous congestion in various tissues, including skin. This response is thought to play a critical role in minimizing capillary damage or edema resulting from overperfusion, though factors that modulate this response remain largely unknown. Here, we hypothesized that nitric oxide synthase (NOS), cyclooxygenase (COX), and Ca

We examined whether the sustained activation of metaboreceptor in forearm during cycling exercise can modulate sweating and cutaneous vasodilation. On separate days, 12 young participants performed a 1.5-min isometric handgrip exercise at 40% maximal voluntary contraction followed by 1) 9-min forearm ischemia (Occlusion, to activate metaboreceptor) or 2) no ischemia (Control) in thermoneutral conditions (27°C, 50%) with mean skin temperature clamped at 34°C. Thirty seconds after the handgrip exercise, participants cycled for 13.5 min at 40% V̇o2 max. For Occlusion, forearm ischemia was maintained for 9 min followed by no ischemia thereafter. Local sweat rate (SR, ventilated capsule) and cutaneous vascular conductance (CVC, laser-Doppler perfusion units/mean arterial pressure) on the contralateral nonischemic arm as well as esophageal and skin temperatures were measured continuously. The period of ischemia in the early stages of exercise increased SR (+0.03 mg·cm−2·min−1, P < 0.05) but not CVC ( P > 0.05) above Control levels. No differences were measured in the esophageal temperature at which onset of sweating (Control 37.19 ± 0.09 vs. Occlusion 37.07 ± 0.09°C) or CVC (Control 37.21 ± 0.08 vs. Occlusion 37.08 ± 0.10°C) as well as slopes for these responses (all P > 0.05). However, a greater elevation in SR occurred thereafter such that SR was significantly elevated at the end of the ischemic period relative to Control (0.37 ± 0.05 vs. 0.23 ± 0.05 mg·cm−2·min−1, respectively, P < 0.05) despite no differences in esophageal temperature. We conclude that the activation of forearm muscle metaboreceptor can modulate sweating, but not CVC, during cycling exercise without affecting the core temperature-SR relationship.

The venoarteriolar reflex is a local mechanism that induces vasoconstriction during venous congestion in various tissues, including skin. This response is thought to play a critical role in minimizing capillary damage or edema resulting from overperfusion, though factors that modulate this response remain largely unknown. Here, we hypothesized that nitric oxide synthase (NOS), cyclooxygenase (COX), and Ca2+-activated, ATP-sensitive, and voltage-gated K+ channels (KCa, KATP, and KV channels, respectively) modulate the venoarteriolar reflex in human skin. Cutaneous blood flow (laser-Doppler flowmetry) was monitored during a 3-min pre-occlusion baseline and following a 3-min venous occlusion of 45 mmHg, the latter maneuver was used to induce the venoarteriolar reflex. The venoarteriolar reflex was assessed at the following forearm skin sites: Experiment 1 (n = 11): 1) lactated Ringer solution (Control), 2) 10 mM Nω-nitro-L-arginine (NOS inhibitor), 3) 10 mM ketorolac (COX inhibitor), and 4) combined NOS + COX inhibition; Experiment 2 (n = 15): 1) lactated Ringer solution (Control), 2) 50 mM tetraethylammonium (KCa channel blocker), 3) 5 mM glybenclamide (KATP channel blocker), and 4) 10 mM 4-aminopyridine (KV channel blocker). Separate and combined NOS and COX inhibition as well as KATP channel blocker had no effect on venoarteriolar reflex. Conversely, venoarteriolar reflex was attenuated by KCa channel blockade (36–38%) and augmented by KV channel blockade (38–55%). We showed that KCa and KV channels modulate the venoarteriolar reflex with minimum roles of NOS, COX, and KATP channels in human non-glabrous forearm skin in vivo. Thus, cutaneous venoarteriolar reflex changes could reflect altered K+ channel function.

We used diffuse correlation spectroscopy to investigate sympathetic vasoconstriction, local vasodilation, and integration of these two responses in the skeletal muscle microvasculature of 20 healthy volunteers. Diffuse correlation spectroscopy probes were placed on the flexor carpi radialis muscle or vastus lateralis muscle, and a blood flow index was derived continuously. We measured hemodynamic responses during sympathoexcitation induced by forehead cooling, after which the effects of the increased sympathetic tone on vasodilatory responses during postocclusive reactive hyperemia (PORH) were examined. PORH was induced by releasing arterial occlusion (3 min) in an arm or leg. To increase sympathetic tone during PORH, forehead cooling was begun 60 s before the occlusion release and ended 60 s after the release. During forehead cooling, mean arterial pressure rose significantly and was sustained at an elevated level. Significant vasoconstriction and decreases in blood flow index followed by gradual blunting of the vasoconstriction also occurred. The time course of these responses is in good agreement with previous observations in animals. The acute sympathoexcitation diminished the peak vasodilation during PORH only in the vastus lateralis muscle, but it hastened the decline in vasodilation after the peak in both the flexor carpi radialis muscle and vastus lateralis muscle. Consequently, the total vasodilatory response assessed as the area of the vascular conductance during the first minute of PORH was significantly diminished in both regions. We conclude that, in humans, the integrated effects of sympathetic vasoconstriction and local vasodilation have an important role in vascular regulation and control of perfusion in the skeletal muscle microcirculation. NEW & NOTEWORTHY We used diffuse correlation spectroscopy to demonstrate that acute sympathoexcitation constrains local vasodilation in the human skeletal muscle microvasculature during postocclusive reactive hyperemia. This finding indicates that integration of sympathetic vasoconstriction and local vasodilation is importantly involved in vascular regulation and the control of perfusion of the skeletal muscle microcirculation in humans.

Diffuse correlation spectroscopy (DCS) has a potential to noninvasively and quantitatively measure the blood flow in the exercising muscle that could contribute to the fields of sports physiology and medicine. However, the blood flow index (BFI) measured from skin surface by DCS reflects hemodynamic signals from both superficial tissue and muscle layer. Thus, an appropriate calibration technology is required to quantify the absolute blood flow in the muscle layer. We therefore fabricated a realistic two-layer phantom model consisted of a static silicon layer imitating superficial tissue and a dynamic flow layer imitating the muscle blood flow and investigated the relationship between the simulated blood flow rate in the muscle layer and the BFI measured from the surface of the phantom. The absorption coefficient and the reduced scattering coefficient of the forearm were measured from 25 healthy young adults using a time-resolved nearinfrared spectroscopy. The depths of the superficial and muscle layers of forearm were also determined by ultrasound tomography images from 25 healthy young adults. The phantoms were fabricated to satisfy these optical coefficients and anatomical constraints. The simulated blood flow rate were set from 0 mL/ min to 68.7 mL/ min in ten steps, which is considered to cover a physiological range of mean blood flow of the forearm between per 100g of muscle tissue at rest to heavy dynamic handgrip exercise. We found a proportional relationship between the flow rates and BFIs with significant correlation coefficient of R = 0.986. Our results suggest that the absolute exercising muscle blood flow could be estimated by DCS with optimal calibration using phantom models.

We characterized the cardiovascular responses to forearm muscle metaboreflex activation during hypercapnia. Ten healthy males participated under three experimental conditions: 1) hypercapnia (HCA, PetCO2: +10 mmHg, by inhalation of a CO2-enriched gas mixture); 2) muscle metaboreflex activation (MMA, by 5 min of local circulatory occlusion after 1 min of 50% maximum voluntary contraction isometric handgrip under normocapnia); and 3) HCA+MMA. We measured mean arterial pressure (MAP), heart rate (HR), and cardiac output (CO); calculated stroke volume (SV), and total peripheral resistance (TPR); and evaluated myocardial oxygen consumption (MV̇o2) and cardiac work (CW) noninvasively. MAP increased in the three experimental conditions but HCA+MMA led to the highest MAP, CO, and HR. Moreover, HCA+MMA increased SV and was associated with the highest MV̇o2and CW. HCA and MMA exhibited inhibitory interactions with MAP, HR, TPR, MV̇o2, and CW, increases of which were smaller during HCA+MMA than the sum of the increases during HCA and MMA alone (MAP: +28 ± 2 vs. +34 ± 2 mmHg, P < 0.001; HR: +15 ± 2 vs. +22 ± 3 bpm, P < 0.01; TPR: +1.1 ± 1.4 vs. +3.0 ± 1.5 mmHg·l·min−1, P < 0.05; MV̇o2: +50.25 ± 4.74 vs. +59.48 ± 5.37 mmHg·min−1·10−2, P < 0.01; CW: +59.10 ± 7.52 vs. +63.67 ± 7.71 ml mmHg·min−1·10−4, P < 0.05). Oppositely, HCA and MMA interactions were linearly additive for CO (+2.3 ± 0.4 l/min) and SV (+13 ± 4 ml). We showed that muscle metaboreflex and hypercapnia interact in healthy humans, reducing vasoconstriction but enhancing SV.

The present study investigated the role of muscle metaboreceptor activation on human thermoregulation by measuring core temperature thresholds and slopes for sweating and cutaneous vascular responses during passive heating associated with central and peripheral mechanisms. Six male and eight female subjects inserted their lower legs into hot water (43°C) while wearing a water perfusion suit on the upper body (34°C). One minute after immersion, an isometric handgrip exercise—40% of maximum voluntary contraction—was conducted for 1.5 min in both control and experimental conditions, while postexercise occlusion was performed in the experimental condition only for 9 min. The postexercise forearm occlusion during passive heating consistently stimulated muscle metaboreceptors, as implicated by significantly elevated mean arterial blood pressure throughout the experimental period ( P

Voluntary apnea during dynamic exercise evokes marked bradycardia, peripheral vasoconstriction, and pressor responses. However, the mechanism(s) underlying the cardiovascular responses seen during apnea in exercising humans is unknown. We therefore tested the hypothesis that the muscle metaboreflex contributes to the apnea-induced pressor response during dynamic exercise. Thirteen healthy subjects participated in apnea and control trials. In both trials, subjects performed a two-legged dynamic knee extension exercise at a workload that elicited heart rates at ~100 beats/min. In the apnea trial, after reaching a steady state, subjects began voluntary apnea. Immediately after cessation of the apnea, arterial occlusion was initiated at both thighs and the subjects stopped exercising. The occlusion was sustained for 3 min in the postexercise period. In the control trial, the occlusion was started without subjects performing the apnea. The apnea induced marked bradycardia, pressor responses, and decreases in arterial O

We studied blood flow dynamics of active skeletal muscle using diffuse correlation spectroscopy (DCS), an emerging optical modality that is suitable for noninvasive quantification of microcirculation level in deep tissue. Seven healthy subjects conducted 0.5 Hz dynamic handgrip exercise for 3 minutes at intensities of 10, 20, 30, and 50 % of maximal voluntary contraction (MVC). DCS could detect the time-dependent increase of the blood flow response of the forearm muscle for continuous exercises, and the increase ratios of the mean blood flow through the exercise periods showed good correlation with the exercise intensities. We also compared blood flow responses detected from DCS with two different photon sampling rates and found that an appropriate photon sampling rates should be selected to follow the wide-ranged increase in the muscle blood flow with dynamic exercise. Our results demonstrate the possibility for utilizing DCS in a field of sports medicine to noninvasively evaluate the dynamics of blood flow in the active muscles.

The cardiopulmonary baroreflex responds to an increase in central venous pressure (CVP) by decreasing total peripheral resistance and increasing heart rate (HR) in dogs. However, the direction of ventricular contractility change is not well understood. The aim was to elucidate the cardiopulmonary baroreflex control of ventricular contractility during normal physiological conditions via a mathematical analysis. Spontaneous beat-to-beat fluctuations in maximal ventricular elastance ( Emax), which is perhaps the best available index of ventricular contractility, CVP, arterial blood pressure (ABP), and HR were measured from awake dogs at rest before and after β-adrenergic receptor blockade. An autoregressive exogenous input model was employed to jointly identify the three causal transfer functions relating beat-to-beat fluctuations in CVP to Emax (CVP → Emax), which characterizes the cardiopulmonary baroreflex control of ventricular contractility, ABP to Emax, which characterizes the arterial baroreflex control of ventricular contractility, and HR to Emax, which characterizes the force-frequency relation. The CVP → Emax transfer function showed a static gain of 0.037 ± 0.010 ml−1 (different from zero; P < 0.05) and an overall time constant of 3.2 ± 1.2 s. Hence, Emax would increase and reach steady state in ∼16 s in response to a step increase in CVP, without any change to ABP or HR, due to the cardiopulmonary baroreflex. Following β-adrenergic receptor blockade, the CVP → Emax transfer function showed a static gain of 0.0007 ± 0.0113 ml−1 (different from control; P < 0.10). Hence, Emax would change little in steady state in response to a step increase in CVP. Stimulation of the cardiopulmonary baroreflex increases ventricular contractility through β-adrenergic receptor system mediation.

Activation of muscle metaboreceptors and mechanoreceptors has been shown to independently influence the sweating response, while their integrative control effects remain unclear. We examined the sweating response when the two muscle receptors are concurrently activated in different limbs, as well as the blood pressure response. In total, 27 young males performed passive calf muscle stretches (muscle mechanoreceptor activation) for 30 s in a semisupine position with and without postisometric handgrip exercise muscle ischemia (PEMI, muscle metaboreceptor activation) at exercise intensities of 35 and 50% of maximum voluntary contraction (MVC) under hot conditions (ambient temperature, 35°C, relative humidity, 50%). Passive calf muscle stretching alone increased the mean sweating rate significantly on the forehead, chest, and thigh (SRmean) and mean arterial blood pressure (MAP), but not the heart rate (HR), from prestretching levels by 0.04 ± 0.01 mg·cm2·min−1, 4.0 ± 1.3 mmHg ( P < 0.05), and −1.0 ± 0.5 beats/min ( P > 0.05), respectively. The SRmean and MAP during PEMI were significantly higher than those at rest. The passive calf muscle stretch during PEMI increased MAP significantly by 3.4 ± 1.0 and 2.0 ± 0.7 mmHg for 35 and 50% of MVC, respectively ( P < 0.05), but not that of SRmean or HR at either exercise intensity. These results suggest that sweating and blood pressure responses to concurrent activation of the two muscle receptors in different limbs differ and that the influence of calf muscle mechanoreceptor activation alone on the sweating response disappears during forearm muscle metaboreceptor activation.

論文

We tested the hypotheses that, in humans, changes in cardiac output (CO) and total peripheral vascular resistance (TPR) occurring in response to isometric handgrip exercise vary considerably among individuals and that those individual differences are related to differences in muscle metaboreflex and arterial baroreflex function. Thirty-nine healthy subjects performed a 1-min isometric handgrip exercise at 50% of maximal voluntary contraction. This was followed by a 4-min postexercise muscle ischemia (PEMI) period to selectively maintain activation of the muscle metaboreflex. All subjects showed increases in arterial pressure during exercise. Interindividual coefficients of variation (CVs) for the changes in CO and TPR between rest and exercise periods (CO: 95.1% and TPR: 87.8%) were more than twofold greater than CVs for changes in mean arterial pressure (39.7%). There was a negative correlation between CO and TPR responses during exercise ( r = −0.751, P < 0.01), but these CO and TPR responses correlated positively with the corresponding responses during PEMI ( r = 0.568 and 0.512, respectively, P < 0.01). The CO response during exercise did not correlate with PEMI-induced changes in an index of cardiac parasympathetic tone and cardiac baroreflex sensitivity. These findings demonstrate that the changes in CO and TPR that occur in response to isometric handgrip exercise vary considerably among individuals and that the two responses have an inverse relationship. They also suggest that individual differences in components of the pressor response are attributable in part to variations in muscle metaboreflex-mediated cardioaccelerator and vasoconstrictor responses.

We investigated the integration of sympathetic vasoconstriction and local vasodilation in the skeletal muscle and skin microvasculature of humans. In 39 healthy volunteers, we simultaneously measured the blood flow index in the flexor carpi radialis muscle using diffuse correlation spectroscopy and the skin using laser‐Doppler flowmetry. We examined the effects of acute sympathoexcitation induced by forehead cooling on relatively weak and robust vasodilatory responses during postocclusive reactive hyperemia (PORH) induced by 70‐sec and 10‐min arterial occlusion in the upper arm. To increase sympathetic tone during PORH, forehead cooling was begun 60 sec before the occlusion release and ended 60 sec after the release. In the 70‐sec occlusion trials, acute sympathoexcitation reduced the peak and duration of vasodilation in both skeletal muscle and skin. The inhibition of vasodilation by sympathoexcitation was blunted in both tissues by the robust vasodilatory stimulation produced by the 10‐min occlusion, and the degree of blunting was greater in skeletal muscle than in skin, especially the initial and peak responses. Sympathoexcitation reduced the peak vasodilation only in skin, while it accelerated the initial vasodilation only in skeletal muscle. However, the decline in vasodilation after the peak was significantly hastened in skeletal muscle, shortening the duration of the vasodilation. We conclude that, in humans, the integration of sympathetic vasoconstriction and local vasodilation has different effects in skeletal muscle and skin and is likely an important contributor to the selective control of perfusion in the microcirculations of different tissues.

During high-intensity dynamic exercise, O2 delivery to active skeletal muscles is enhanced through marked increases in both cardiac output and skeletal muscle blood flow. When the musculature is vigorously engaged in exercise, the human heart lacks the pumping capacity to meet the blood flow demands of both the skeletal muscles and other organs such as the brain. Vasoconstriction must therefore be induced through activation of sympathetic nervous activity to maintain blood flow to the brain and to produce the added driving pressure needed to increase flow to the skeletal muscles. In this review, we first briefly summarize the local vascular and neural control mechanisms operating during high-intensity exercise. This is followed by a review of the major neural mechanisms regulating blood pressure during high-intensity exercise, focusing mainly on the integrated activities of the arterial baroreflex and muscle metaboreflex. In high cardiac output situations, such as during high-intensity dynamic exercise, small changes in total peripheral resistance can induce large changes in blood pressure, which means that rapid and fine regulation is necessary to avoid unacceptable drops in blood pressure. To accomplish this rapid regulation, arterial baroreflex function may be modulated in various ways through activation of the muscle metaboreflex and/or other neural mechanisms. Moreover, this modulation of the arterial baroreflex may change over the time course of an exercise bout, or to accommodate changes in exercise intensity. Within this model, integration of arterial baroreflex modulation with other neural mechanisms plays an important role in cardiovascular control during high-intensity exercise.

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after α1-adrenergic blockade (prazosin 20–50 μg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after α1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility.

Static and dynamic exercise is accompanied by increases in arterial blood pressure, heart rate and sympathetic nerve activity. It has been hypothesized that these cardiovascular responses are mediated by central command as well as by feedback mechanisms operating via afferent nerves (group III and IV fibers) that arise from skeletal muscles, are sensitive to mechanical (the so-called muscle mechanoreflex) and metabolic changes (the so-called muscle metaboreflex), and are modulated by arterial and cardiopulmonary baroreflexes. In this review, discussion is focused on the roles of the arterial baroreflex and muscle metaboreflex in cardiovascular regulation during exercise. In the first part of the review, brief discussion is made of the functions of these two reflexes during exercise; in the second part, their interactions are looked at in more detail. It is thought that during heavy exercise, the arterial baroreflex and the muscle metaboreflex are both activated, and interact in ways that lead to modulation of the primary cardiovascular reflex responses. Two types of interaction have been demonstrated. In the first, the arterial baroreflex acts to oppose pressor responses induced via the muscle metaboreflex. The second type of interaction involves the modulation of arterial baroreflex function during muscle metaboreflex activation. The authors offer commentary on these two types of interaction, including recent knowledge.

Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Our aim was to determine the muscle metaboreflex threshold and gain in humans by creating an open-loop relationship between active muscle blood flow and hemodynamic responses during a rhythmic handgrip exercise. Eleven healthy subjects performed the exercise at 5 or 15% of maximal voluntary contraction (MVC) in random order. During the exercise, forearm blood flow (FBF), which was continuously measured using Doppler ultrasound, was reduced in five steps by manipulating the inner pressure of an occlusion cuff on the upper arm. The FBF at each level was maintained for 3 min. The initial reductions in FBF elicited no hemodynamic changes, but once FBF fell below a threshold, mean arterial blood pressure (MAP) and heart rate (HR) increased and total vascular conductance (TVC) decreased in a linear manner. The threshold FBF during the 15% MVC trial was significantly higher than during the 5% MVC trial. The gain was then estimated as the slope of the relationship between the hemodynamic responses and FBFs below the threshold. The gains for the MAP and TVC responses did not differ between workloads, but the gain for the HR response was greater in the 15% MVC trial. Our findings thus indicate that increasing the workload shifts the threshold for the muscle metaboreflex to higher blood flows without changing the gain of the reflex for the MAP and TVC responses, whereas it enhances the gain for the HR response.

We examined the degree to which ventilatory sensitivity to rising body temperature (the slope of the regression line relating ventilation and body temperature) is altered by restoration of arterial Pco2 to the eucapnic level during prolonged exercise in the heat. Thirteen subjects exercised for ∼60 min on a cycle ergometer at 50% of peak O2 uptake with and without inhalation of CO2-enriched air. Subjects began breathing CO2-enriched air at the point that end-tidal Pco2 started to decline. Esophageal temperature (Tes), minute ventilation (V̇e), tidal volume (VT), respiratory frequency ( fR), respiratory gases, middle cerebral artery blood velocity, and arterial blood pressure were recorded continuously. When V̇e, VT, fR, and ventilatory equivalents for O2 uptake (V̇e/V̇o2) and CO2 output (V̇e/V̇co2) were plotted against changes in Tes from the start of the CO2-enriched air inhalation (ΔTes), the slopes of the regression lines relating V̇e, VT, V̇e/V̇o2, and V̇e/V̇co2 to ΔTes (ventilatory sensitivity to rising body temperature) were significantly greater when subjects breathed CO2-enriched air than when they breathed room air (V̇e: 19.8 ± 10.3 vs. 8.9 ± 6.7 l·min−1·°C−1, VT: 18 ± 120 vs. −81 ± 92 ml/°C; V̇e/V̇o2: 7.4 ± 5.5 vs. 2.6 ± 2.3 units/°C, and V̇e/V̇co2: 7.6 ± 6.6 vs. 3.4 ± 2.8 units/°C). The increase in V̇e was accompanied by increases in VT and fR. These results suggest that restoration of arterial Pco2 to nearly eucapnic levels increases ventilatory sensitivity to rising body temperature by around threefold.

We propose a novel application of diffuse correlation spectroscopy to evaluate microvascular malfunctions of muscle tissue affected by hyperglycemia and determine their correlation with the severity of diabetic neuropathy at a later stage. Microvascular responses of the thigh muscle and the mechanical pain threshold of the hind paw of streptozotocin-induced type I diabetic rats were continuously monitored once per week for 70 days. Significantly decreased baseline blood flow and reactive hyperemia responses were observed as early as 1 week after hyperglycemia induction. The reactive hyperemia response at 2 weeks of hyperglycemia waths highly correlated with the mechanical pain threshold at 8 weeks, at which time a decreased pain threshold was statistically confirmed in hyperglycemic rats relative to controls.

Ischemia of active skeletal muscle elicits a pressor response termed the muscle metaboreflex. We tested the hypothesis that in normal dogs during dynamic exercise, graded muscle metaboreflex activation (MMA) would progressively attenuate spontaneous heart rate baroreflex sensitivity (SBRS). The animals were chronically instrumented to measure heart rate (HR), cardiac output (CO), mean and systolic arterial pressure (MAP and SAP), and left ventricular systolic pressures (LVSP) at rest and during mild or moderate treadmill exercise before and during progressive MMA [via graded reductions of hindlimb blood flow (HLBF)]. SBRS [slopes of the linear relationships (LRs) between HR and LVSP or SAP during spontaneous sequences of ≥3 consecutive beats when HR changed inversely vs. pressure] decreased during mild exercise from the resting values (−5.56 ± 0.86 vs. −2.67 ± 0.50 beats·min−1·mmHg−1, P −1·mmHg−1, P

We tested the hypotheses that arterial baroreflex (ABR) control over muscle sympathetic nerve activity (MSNA) in humans does not remain constant throughout a bout of leg cycling ranging in intensity from very mild to exhausting. ABR control over MSNA (burst incidence, burst strength and total MSNA) was evaluated by analysing the relationship between beat-to-beat spontaneous variations in diastolic arterial pressure (DAP) and MSNA in 15 healthy subjects at rest and during leg cycling in a seated position at five workloads: very mild (10 W), mild (82 ± 5.0 W), moderate (126 ± 10.2 W), heavy (156 ± 14.3 W), and exhausting (190 ± 21.2 W). The workload was incremented every 6 min. The linear relationships between DAP and MSNA variables were significantly shifted downward during very mild exercise, but then shifted progressively upward as exercise intensity increased. During heavy and exhausting exercise, moreover, the DAP–MSNA relationships were also significantly shifted rightward from the resting relationship. The sensitivity of ABR control over burst incidence and total MSNA was significantly lower during very mild exercise than during rest, and the sensitivity of the burst incidence control remained lower than the resting level at all higher exercise intensities. By contrast, the sensitivity of the total MSNA control recovered to the resting level during mild and moderate exercise, and was significantly increased during heavy and exhausting exercise (versus rest). We conclude that, in humans, ABR control over MSNA is not uniform throughout a leg cycling exercise protocol in which intensity was varied from very mild to exhausting. We suggest that this non-uniformity of ABR function is one of the mechanisms by which sympathetic and cardiovascular responses are matched to the exercise intensity.

We have previously shown that spontaneous baroreflex-induced changes in heart rate (HR) do not always translate into changes in cardiac output (CO) at rest. We have also shown that heart failure (HF) decreases this linkage between changes in HR and CO. Whether dynamic exercise and muscle metaboreflex activation (via imposed reductions in hindlimb blood flow) further alter this translation in normal and HF conditions is unknown. We examined these questions using conscious, chronically instrumented dogs before and after pacing-induced HF during mild and moderate dynamic exercise with and without muscle metaboreflex activation. We measured left ventricular systolic pressure (LVSP), CO, and HR and analyzed the spontaneous HR-LVSP and CO-LVSP relationships. In normal animals, mild exercise significantly decreased HR-LVSP (−3.08 ± 0.5 vs. −5.14 ± 0.6 beats·min−1·mmHg−1; P < 0.05) and CO-LVSP (−134.74 ± 24.5 vs. −208.6 ± 22.2 ml·min−1·mmHg−1; P < 0.05). Moderate exercise further decreased both and, in addition, significantly reduced HR-CO translation (25.9 ± 2.8% vs. 52.3 ± 4.2%; P < 0.05). Muscle metaboreflex activation at both workloads decreased HR-LVSP, whereas it had no significant effect on CO-LVSP and the HR-CO translation. HF significantly decreased HR-LVSP, CO-LVSP, and the HR-CO translation in all situations. We conclude that spontaneous baroreflex HR responses do not always cause changes in CO during exercise. Moreover, muscle metaboreflex activation during mild and moderate dynamic exercise reduces this coupling. In addition, in HF the HR-CO translation also significantly decreases during both workloads and decreases even further with muscle metaboreflex activation.

Dynamic cardiac baroreflex responses are frequently investigated by analyzing the spontaneous reciprocal changes in arterial pressure and heart rate (HR). However, whether the spontaneous baroreflex-induced changes in HR translate into changes in cardiac output (CO) is unknown. In addition, this linkage between changes in HR and changes in CO may be different in subjects with heart failure (HF). We examined these questions using conscious dogs before and after pacing-induced HF. Spontaneous baroreflex sensitivity in the control of HR and CO was evaluated as the slopes of the linear relationships between HR or CO and left ventricular systolic pressure (LVSP) during spontaneous sequences of greater or equal to three consecutive beats when HR or CO changed inversely versus pressure. Furthermore, the translation of baroreflex HR responses into CO responses (HR-CO translation) was examined by computing the overlap between HR and CO sequences. In normal resting conditions, 44.0 ± 4.4% of HR sequences overlapped with CO sequences, suggesting that only around half of the baroreflex HR responses cause CO responses. In HF, HR-LVSP, CO-LVSP, and the HR-CO translation significantly decreased compared with the normal condition (−2.29 ± 0.5 vs. −5.78 ± 0.7 beats·min−1·mmHg−1; −70.95 ± 11.8 vs. −229.89 ± 29.6 ml·min−1·mmHg−1; and 19.66 ± 4.9 vs. 44.0 ± 4.4%, respectively). We conclude that spontaneous baroreflex HR responses do not always cause changes in CO. In addition, HF significantly decreases HR-LVSP, CO-LVSP, and HR-CO translation.

In heart failure (HF), there is a reduced baroreflex sensitivity at rest, and during dynamic exercise there is enhanced muscle metaboreflex activation (MRA). However, how the arterial baroreflex modulates HR during exercise is unknown. We tested the hypothesis that spontaneous baroreflex sensitivity (SBRS) is attenuated during exercise in HF and that MRA further depresses SBRS. In seven conscious dogs we measured heart rate (HR), cardiac output, and left ventricular systolic pressure at rest and during mild and moderate dynamic exercise, before and during MRA (via imposed reductions of hindlimb blood flow), and before and after induction of HF (by rapid ventricular pacing). SBRS was assessed by the sequences method. In control, SBRS was reduced from rest with a progressive resetting of the baroreflex stimulus-response relationship in proportion to exercise intensity and magnitude of MRA. In HF, SBRS was significantly depressed in all settings; however, the changes with exercise and MRA occurred with a pattern similar to the control state. As in control, the baroreflex stimulus-response relationship showed an intensity- and muscle metaboreflex (MMR)-dependent rightward and upward shift. The results of this study indicate that HF induces an impairment in baroreflex control of HR at rest and during exercise, although the effects of exercise and MRA on SBRS occur with a similar pattern as in control, indicating the persistence of some vagal activity.

Continuous measurement of leg blood flow (LBF) using Doppler ultrasound with simultaneous noninvasive mean arterial blood pressure (MAP) measurement permits beat-to-beat estimates of leg vascular resistance (LVR) in humans. We tested the hypothesis that the beat-to-beat fluctuations in LVR and the dynamic relationship between MAP and LVR are modulated by the activation of muscle metaboreflex. Twelve healthy subjects performed a 1-min isometric handgrip exercise at 50% maximal voluntary contraction, which was followed by a period of imposed postexercise muscle ischemia (PEMI). We then employed transfer function analysis to examine the dynamic relationships between MAP and LBF and between MAP and LVR, both at rest (control) and during PEMI. We found the following. 1) The spectral power for LBF and LVR in low-frequency ( approximately 0.03-0.15 Hz) range significantly increased from control during PEMI without a significant change in the high-frequency ( approximately 0.15-0.35 Hz) power. 2) During PEMI, the transfer function gains for MAP-LBF and MAP-LVR relationships in the low-frequency ( approximately 0.05-0.15 Hz) range were significantly increased during PEMI (vs. control) but were unchanged in the high-frequency ( approximately 0.2-0.3 Hz) range. 3) The phases for MAP-LBF and MAP-LVR relationships were not different during control and PEMI. The phase for MAP-LVR relationship revealed that changes in MAP were followed by directionally similar changes in LVR, which is consistent with the characteristics of intrinsic vascular regulatory mechanisms such as the myogenic response of the resistance arteries. We suggest that, in humans, modulation of the dynamic MAP-LVR relationship during activation of the muscle metaboreflex reflects complex interactions between intrinsic vascular regulatory mechanisms and sympathetic vascular regulation.

We tested the hypothesis that peripheral vascular responses (in the lower and upper limbs) to application of lower body positive pressure (LBPP) are dependent on the posture of the subjects. We measured heart rate, stroke volume, mean arterial pressure, leg and forearm blood flow (using the Doppler ultrasound technique), and leg (LVC) and forearm (FVC) vascular conductance in 11 subjects (9 men, 2 women) without and with LBPP (25 and 50 mmHg) in supine and upright postures. Mean arterial pressure increased in proportion to increases in LBPP and was greater in supine than in upright subjects. Heart rate was unchanged when LBPP was applied to supine subjects but was reduced in upright ones. Leg blood flow and LVC were both reduced by LBPP in supine subjects [LVC: 4.8 (SD 4.0), 3.6 (SD 3.5), and 1.4 (SD 1.8) ml·min−1·mmHg−1 before LBPP and during 25 and 50 mmHg LBPP, respectively; P < 0.05] but were increased in upright ones [LVC: 2.0 (SD 1.2), 3.4 (SD 3.4), and 3.0 (SD 2.0) ml·min−1·mmHg−1, respectively; P < 0.05]. Forearm blood flow and FVC both declined when LBPP was applied to supine subjects [FVC: 1.3 (SD 0.6), 1.0 (SD 0.4), and 0.9 (SD 0.6) ml· min−1·mmHg−1, respectively; P < 0.05] but remained unchanged in upright ones [FVC: 0.7 (SD 0.4), 0.7 (SD 0.4), and 0.6 (SD 0.5) ml·min−1·mmHg−1, respectively]. Together, these findings indicate that the leg vascular response to application of LBPP is posture dependent and that the response differs in the lower and upper limbs when subjects assume an upright posture.

Ischemia of active skeletal muscle evokes a powerful blood pressure-raising reflex termed the muscle metaboreflex (MMR). MMR activation increases cardiac sympathetic nerve activity, which increases heart rate, ventricular contractility, and cardiac output (CO). However, despite the marked increase in ventricular work, no coronary vasodilation occurs. Using conscious, chronically instrumented dogs, we observed MMR-induced changes in arterial pressure, CO, left circumflex coronary blood flow (CBF), and coronary vascular conductance (CVC) before and after α1-receptor blockade (prazosin, 100 μg/kg iv). MMR was activated during mild treadmill exercise by partially reducing hindlimb blood flow. In control experiments, MMR activation caused a substantial pressor response-mediated via increases in CO. Although CBF increased (+28.1 ± 3.7 ml/min; P < 0.05), CVC did not change (0.45 ± 0.05 vs. 0.47 ± 0.06 ml·min−1·mmHg−1, exercise vs. exercise with MMR activation, respectively; P > 0.05). Thus all of the increase in CBF was due to the increase in arterial pressure. In contrast, after prazosin, MMR activation caused a greater increase in CBF (+55.9 ± 17.1 ml/min; P < 0.05 vs. control) and CVC rose significantly (0.59 ± 0.08 vs. 0.81 ± 0.17 ml·min−1·mmHg−1, exercise vs. exercise with MMR activation, respectively; P < 0.05). A greater increase in CO also occurred (+2.01 ± 0.1 vs. +3.27 ± 1.1 l/min, control vs. prazosin, respectively; P < 0.05). We conclude that the MMR-induced increases in sympathetic activity to the heart functionally restrain coronary vasodilation, which may limit increases in ventricular function.

Reducing blood flow to working muscles during dynamic exercise causes metabolites to accumulate within the active muscles and evokes systemic pressor responses. Whether a similar cardiovascular response is elicited with normal blood flow to exercising muscles during dynamic exercise remains unknown, however. To address that issue, we tested whether cardiovascular responses are affected by increases in blood flow to active muscles. Thirteen healthy subjects performed dynamic plantarflexion exercise for 12 min at 20%, 40%, and 60% of peak workload (EX20, EX40, and EX60) with their lower thigh enclosed in a negative pressure box. Under control conditions, the box pressure was the same as the ambient air pressure. Under negative pressure conditions, beginning 3 min after the start of the exercise, the box pressure was decreased by 20, 45, and then 70 mmHg in stepwise fashion with 3-min step durations. During EX20, the negative pressure had no effect on blood flow or the cardiovascular responses measured. However, application of negative pressure increased blood flow to the exercising leg during EX40 and EX60. This increase in blood flow had no significant effect on systemic cardiovascular responses during EX40, but it markedly attenuated the pressor responses otherwise seen during EX60. These results demonstrate that during mild exercise, normal blood flow to exercising muscle is not a factor eliciting cardiovascular responses, whereas it elicits an important pressor effect during moderate exercise. This suggests blood flow to exercising muscle is a major determinant of cardiovascular responses during dynamic exercise at higher than moderate intensity.

We tested the hypothesis that arterial baroreflex (ABR)-mediated beat-to-beat control over muscle sympathetic nerve activity (MSNA) is progressively modulated as orthostatic stress increases in humans, but that this control becomes impaired just before the onset of orthostatic syncope. In 17 healthy subjects, the ABR control over MSNA (burst incidence, burst strength and total MSNA) was evaluated by analysing the relationship between beat-to-beat spontaneous variations in diastolic blood pressure (DAP) and MSNA during supine rest (control) and during progressive, stepwise increases in lower body negative pressure (LBNP) that were incremented by -10 mmHg every 5 min until presyncope (nine subjects) or -60 mmHg was reached. (1) The linear relationships between DAP and burst strength and between DAP and total MSNA were shifted progressively upward as LBNP increased until the level at which syncope occurred. The relationship between DAP and burst incidence, however, gradually shifted upward from control only to LBNP = -30 mmHg; there was no further upward shift at higher LBNPs. (2) Although the slope of the relationship between DAP and burst strength and between DAP and total MSNA remained constant at all LBNPs tested, except at the level where syncope occurred, the slope of the relationship between DAP and burst incidence was reduced at LBNPs of -40 mmHg and higher (versus control). (3) In syncopal subjects, the slopes of the relationships between DAP and burst incidence, burst strength, and total MSNA were all substantially reduced during the 1-2 min period prior to the onset of syncope. Taken together, these results suggest baroreflex control over MSNA is progressively modulated as orthostatic stress increases, so that its sensitivity is substantially reduced during the period immediately preceding the severe hypotension associated with orthostatic syncope.

The purpose of this study was to determine whether the metabolic response and running performance during intermittent graded sprint running were affected by moderate hypobaric hypoxia (H; 2,500 m above sea level) in competitive middle-distance runners. Nine male runners performed intermittent graded sprint running until exhaustion, to evaluate the metabolic response and running performance in H and normobaric normoxia (N). The test constructed of incremental (25 m min−1) 20 s running bouts (4° inclination) interspaced with 100 s recovery periods. Maximal running speed was not different between conditions [453 (7) m min−1 vs. 458 (4) m min−1 in N vs. H]. $$V_{{\text{O}}_{2}}$$ at each speed was lower in H than N (ANOVA; P