Muscle metaboreflex activation during hypercapnia modifies nonlinear heart rhythm dynamics, increasing the complexity of the sinus node autonomic regulation in humans.

Muscle metaboreflex activation during hypercapnia leads to enhanced pressive effects that are poorly understood while autonomic responses including baroreflex function are not documented. Thus, we assessed heart rate variability (HRV) that is partly due to autonomic influences on sinus node with linear tools (spectral analysis of instantaneous heart period), baroreflex set point and sensitivity with the heart period-arterial pressure transfer function and sequences methods, and system coupling through the complexity of RR interval dynamics with nonlinear tools (Poincaré plots and approximate entropy (ApEn)). We studied ten healthy young men at rest and then during muscle metaboreflex activation (MMA, postexercise muscle ischemia) and hypercapnia (HCA, PetCO2 = + 10 mmHg from baseline) separately and combined (MMA + HCA). The strongest pressive responses were observed during MMA + HCA, while baroreflex sensitivity was similarly lowered in the three experimental conditions. HRV was significantly different in MMA + HCA compared to MMA and HCA separately, with the lowest total power spectrum (p < 0.05), including very low frequency (p < 0.05), low frequency (p < 0.05), and high frequency (tendency) power spectra decreases, and the lowest Poincaré plot short-term variability index (SD1): SD1 = 36.2 ms (MMA + HCA) vs. SD1 = 43.1 ms (MMA, p < 0.05) and SD1 = 46.1 ms (HCA, p < 0.05). Moreover, RR interval dynamic complexity was significantly increased only in the MMA + HCA condition (ApEn increased from 1.04 ± 0.04, 1.07 ± 0.02, and 1.05 ± 0.03 to 1.10 ± 0.03, 1.13 ± 0.04, and 1.17 ± 0.03 in MMA, HCA, and MMA + HCA conditions, respectively; p < 0.01). These results suggest that in healthy young men, muscle metaboreflex activation during hypercapnia leads to interactions that reduce parasympathetic influence on the sinus node activity but complexify its dynamics.

Hypertension depresses arterial baroreflex control of both heart rate and cardiac output during rest, exercise, and metaboreflex activation.

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.

Rapid vasodilation within contracted skeletal muscle in humans: new insight from concurrent use of diffuse correlation spectroscopy and Doppler ultrasound.

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.NEW & NOTEWORTHY Through the concurrent use of diffuse correlation spectroscopy and Doppler ultrasound, we provide the first evidence in humans that a single brief muscle contraction evokes rapid, intensity-dependent hyperemia within the contracted skeletal muscle microvasculature and the upstream conduit artery. We also show that the magnitude and time course of the contraction-induced rapid hyperemia and vasodilatory responses within skeletal muscle microvessels significantly differ from those in the conduit artery.

Tetraethylammonium, glibenclamide, and 4-aminopyridine modulate post-occlusive reactive hyperemia in non-glabrous human skin with no roles of NOS and COX.

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 (KCa , 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 KCa 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.

Sympathoexcitation constrains vasodilation in the human skeletal muscle microvasculature during postocclusive reactive hyperemia.

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.

Voluntary apnea during dynamic exercise activates the muscle metaboreflex in humans.

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 O2 saturation, cardiac output, and total vascular conductance. In addition, arterial blood pressure was significantly higher and total vascular conductance was significantly lower in the apnea trials than the control trials throughout the occlusion period. In separate sessions, we measured apnea-induced changes in exercising leg blood flow in the same subjects. Leg blood flow was significantly reduced by apnea and reached the resting level at the peak of the apnea response. We conclude that the muscle metaboreflex is activated by the decrease in O2 delivery to the working muscle during apnea in exercising humans and contributes to the large pressor response. NEW & NOTEWORTHY We demonstrated that apnea during dynamic exercise activates the muscle metaboreflex in humans. This result indicates that a reduction in O2 delivery to working muscle triggers the muscle metaboreflex during apnea. Activation of the muscle metaboreflex is one of the mechanisms underlying the marked apnea-induced pressor response.

The carotid baroreflex modifies the pressor threshold of the muscle metaboreflex in humans.

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.

Influence of forearm muscle metaboreceptor activation on sweating and cutaneous vascular responses during dynamic exercise.

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.

Increasing blood flow to exercising muscle attenuates systemic cardiovascular responses during dynamic exercise in humans.

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.

Cardiovascular responses to forearm muscle metaboreflex activation during hypercapnia in humans.

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 MV̇o2 and 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.

Modulation of muscle metaboreceptor activation upon sweating and cutaneous vascular responses to rising core temperature in humans.

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 <0.05). Stimulation of the forearm muscle metaboreceptors increased sweating and cutaneous vascular responses during passive heating, and was associated with significant reductions in esophageal temperature threshold of sweating and cutaneous vasodilation (Δ threshold, sweating: 0.33 ± 0.05 and 0.16 ± 0.04°C, cutaneous vascular conductance: 0.38 ± 0.08 and 0.16 ± 0.05°C for control and experimental groups, respectively, P < 0.05). The slopes of these responses were not different between the conditions. These results suggest that muscle metaboreceptor activation in the forearm accelerates sweating and cutaneous vasodilation during passive heating associated with a reduction in core temperature thresholds and may be related to central mechanisms controlling heat loss responses.

Individual differences in cardiac and vascular components of the pressor response to isometric handgrip exercise in humans.

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.

Sweating response to passive stretch of the calf muscle during activation of forearm muscle metaboreceptors in heated humans.

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·cm(2)·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.

Stimulation of the cardiopulmonary baroreflex enhances ventricular contractility in awake dogs: a mathematical analysis study.

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 ß-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 ß-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 ß-adrenergic receptor system mediation.

Blood pressure regulation II: what happens when one system must serve two masters--oxygen delivery and pressure regulation?

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.

Differential changes in blood flow and oxygen utilization in active muscles between voluntary exercise and electrical muscle stimulation in young adults.

The physiological effects on blood flow and oxygen utilization in active muscles during and after involuntary contraction triggered by electrical muscle stimulation (EMS) remain unclear, particularly compared with those elicited by voluntary (VOL) contractions. Therefore, we used diffuse correlation and near-infrared spectroscopy (DCS-NIRS) to compare changes in local muscle blood flow and oxygen consumption during and after these two types of muscle contractions in humans. Overall, 24 healthy young adults participated in the study, and data were successfully obtained from 17 of them. Intermittent (2-s contraction, 2-s relaxation) isometric ankle dorsiflexion with a target tension of 20% of maximal VOL contraction was performed by EMS or VOL for 2 min, followed by a 6-min recovery period. DCS-NIRS probes were placed on the tibialis anterior muscle, and relative changes in local tissue blood flow index (rBFI), oxygen extraction fraction (rOEF), and metabolic rate of oxygen (rMRO2) were continuously derived. EMS induced more significant increases in rOEF and rMRO2 than VOL exercise but a comparable increase in rBFI. After EMS, rBFI and rMRO2 decreased more slowly than after VOL and remained significantly higher until the end of the recovery period. We concluded that EMS augments oxygen consumption in contracting muscles by enhancing oxygen extraction while increasing oxygen delivery at a rate similar to the VOL exercise. Under the conditions examined in this study, EMS demonstrated a more pronounced and/or prolonged enhancement in local muscle perfusion and aerobic metabolism compared with VOL exercise in healthy participants.NEW & NOTEWORTHY This is the first study to visualize continuous changes in blood flow and oxygen utilization within contracted muscles during and after electrical muscle stimulation (EMS) using combined diffuse correlation and near-infrared spectroscopy. We found that initiating EMS increases blood flow at a rate comparable to that during voluntary (VOL) exercise but enhances oxygen extraction, resulting in higher oxygen consumption. Furthermore, EMS increased postexercise muscle perfusion and oxygen consumption compared with that after VOL exercise.

Correlation of diabetic renal hypoperfusion with microvascular responses of the skeletal muscle: a rat model study using diffuse correlation spectroscopy.

Using diffuse correlation spectroscopy, we assessed the renal blood flow and thigh muscle microvascular responses in a rat model of type 2 diabetes. The blood flow index at the renal surface decreased significantly with arterial clamping, cardiac extirpation, and the progression of diabetic endothelial dysfunction. Renal blood flow measured in diabetic and nondiabetic rats also showed a significant correlation with the reactive hyperemic response of the thigh muscle. These results suggest shared microcirculatory dysfunction in the kidney and skeletal muscle and support endothelial responses in the skeletal muscle as a potential noninvasive biomarker of renal hypoperfusion.

Muscle metaboreflex activation speeds the recovery of arterial blood pressure following acute hypotension in humans.

It has been suggested that the arterial baroreflex and muscle metaboreflex are both activated during heavy exercise and that they interact to modulate primary cardiovascular reflex responses. This proposed interaction and its consequences are not fully understood, however. The purpose of present study was to test our hypothesis that dynamic arterial baroreflex-mediated cardiovascular responses to acute systemic hypotension in humans are augmented when the muscle metaboreflex is active and that this results in a faster recovery of arterial blood pressure. Acute hypotension was induced nonpharmacologically in 12 healthy subjects by releasing bilateral thigh cuffs after 9 min of suprasystolic resting ischemia, with and without muscle metaboreflex activation via postexercise muscle ischemia (PEMI) after 1 min of isometric handgrip exercise at 50% maximum voluntary contraction. The thigh-cuff release evoked rapid reductions in mean arterial pressure (MAP) and increases in heart rate, cardiac output (Doppler), and total vascular conductance (TVC) under control conditions and during PEMI. The reductions in MAP from baseline were greater and the increases in TVC were smaller during PEMI than control. In addition, arterial baroreflex-mediated peripheral vasoconstriction was augmented during PEMI, as evidenced by a near doubling of the rate of recovery of MAP and TVC. These results show that when the muscle metaboreflex is activated in humans, arterial baroreflex-mediated peripheral vasoconstriction elicited in response to acute hypotension is augmented, which halves the time needed for MAP recovery. Such modulation of baroreflex function would be advantageous for maintaining an elevated arterial blood pressure during activation of the muscle metaboreflex.

Muscle metaboreflex-induced coronary vasoconstriction limits ventricular contractility during dynamic exercise in heart failure.

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.

Changes in arterial blood pressure elicited by severe passive heating at rest is associated with hyperthermia-induced hyperventilation in humans.

The arterial blood pressure and ventilatory responses to severe passive heating at rest varies greatly among individuals. We tested the hypothesis that the increase in ventilation seen during severe passive heating of resting humans is associated with a decrease in arterial blood pressure. Passive heating was performed on 18 healthy males using hot water immersion to the level of the iliac crest and a water-perfused suit. We then divided the subjects into two groups: MAP(NOTINC) (n = 8), whose mean arterial blood pressure (MAP) at the end of heating had increased by ≤3 mmHg, and MAP(INC) (n = 10), whose MAP increased by >3 mmHg. Increases in esophageal temperature (T (es)) elicited by the heating were similar in the two groups (+2.3 ± 0.3 vs. +2.4 ± 0.4 °C). Early during heating (increase in T (es) was <1.5 °C), MAP, minute ventilation ([Formula: see text]), and end-tidal CO(2) pressure ([Formula: see text]) were similar between the groups. However, during the latter part of heating (increase in T (es) was ≥1.5 °C), the increase in [Formula: see text] and decrease in [Formula: see text] were significantly greater or tended to be greater, while the increase in MAP was significantly smaller in MAP(NOTINC) than MAP(INC). Among all subjects, heating-induced changes in [Formula: see text] significantly and negatively correlated with heating-induced changes in MAP during the latter part of heating (r = -0.52 to -0.74, P < 0.05). These results suggest that, in resting humans, 25-50 % of the variation in the magnitude of the arterial blood pressure response to severe passive heating can be explained by the magnitude of hyperthermia-induced hyperventilation.