Local metabolite accumulation augments passive muscle stretch-induced modulation of carotid-cardiac but not carotid-vasomotor baroreflex sensitivity in man.

We examined the effects of muscle mechanoreflex stimulation by passive calf muscle stretch, at rest and during concurrent muscle metaboreflex activation, on carotid baroreflex (CBR) sensitivity. Twelve subjects either performed 1.5 min one-legged isometric plantarflexion at 50% maximal voluntary contraction with their right or left calf [two ischaemic exercise (IE) trials, IER and IEL] or rested for 1.5 min [two ischaemic control (IC) trials, ICR and ICL]. Following exercise, blood pressure elevation was partly maintained by local circulatory occlusion (CO). 3.5 min of CO was followed by 3 min of CO with passive stretch (STR-CO) of the right calf in all trials. Carotid baroreflex function was assessed using rapid pulses of neck pressure from +40 to -80 mmHg. In all IC trials, stretch did not alter maximal gain of carotid-cardiac (CBR-HR) and carotid-vasomotor (CBR-MAP) baroreflex function curves. The CBR-HR curve was reset without change in maximal gain during STR-CO in the IEL trial. However, during the IER trial maximal gain of the CBR-HR curve was smaller than in all other trials (-0.34 +/- 0.04 beats min(-1) mmHg(-1) in IER versus -0.76 +/- 0.20, -0.94 +/- 0.14 and -0.66 +/- 0.18 beats min(-1) mmHg(-1) in ICR, IEL and ICL, respectively), and significantly smaller than in IEL (P < 0.05). The CBR-MAP curves were reset from CO values by STR-CO in the IEL and IER trials with no changes in maximal gain. These results suggest that metabolite sensitization of stretch-sensitive muscle mechanoreceptive afferents modulates baroreflex control of heart rate but not blood pressure.     

Reduced α-adrenoceptor responsiveness and enhanced baroreflex sensitivity in Cry-deficient mice lacking a biological clock

To reveal the role of clock genes in generating the circadian rhythm of baroreflexes, we continuously measured mean arterial pressure and baroreflex sensitivity in free-moving normal wild-type mice, and in Cry -deficient mice which lack a circadian rhythm, in constant darkness for 24 h. In wild-type mice the mean arterial pressure was higher at night than during the day, and was accompanied by a significantly enhanced baroreflex sensitivity of −13.6 ± 0.8 at night compared with −9.7 ± 0.7 beats min⁻¹ mmHg⁻¹ during the day ( P < 0.001). On the other hand, diurnal changes in arterial pressure disappeared in Cry -deficient mice with remarkably enhanced baroreflex sensitivity compared with wild-type mice ( P < 0.001): −21.9 ± 1.6 at night and −23.1 ± 2.1 beats min⁻¹ mmHg⁻¹ during the day. Moreover, the mean arterial pressure response to 10 μg kg⁻¹ of phenylephrine, an α₁-adrenoceptor agonist, was severely suppressed in Cry -deficient mice regardless of time, while that for the wild-type mice was 10.1 ± 1.9 mmHg in the night, significantly lower than 22.0 ± 3.5 mmHg in the day ( P < 0.01). These results suggest that CRY genes are involved in generating the circadian rhythm of baroreflex sensitivity, partially by regulating α₁-adrenoceptor-mediated vasoconstriction in peripheral vessels.     

Cardiac and vasomotor components of the carotid baroreflex control of arterial blood pressure during isometric exercise in humans

We sought to examine the importance of the cardiac component of the carotid baroreflex (CBR) in control of blood pressure during isometric exercise. Nine subjects performed 4 min of ischaemic isometric calf exercise at 20% of maximum voluntary contraction. Trials were repeated with β₁-adrenergic blockade (metoprolol, 0.15 ± 0.003 mg kg⁻¹) or parasympathetic blockade (glycopyrrolate, 13.6 ± 1.5 μg kg⁻¹). CBR function was determined using rapid pulses of neck pressure and neck suction from +40 to −80 mmHg, while heart rate (HR), mean arterial pressure (MAP) and changes in stroke volume (SV, Modelflow method) were measured. Metoprolol decreased and glycopyrrolate increased HR and cardiac output both at rest and during exercise ( P < 0.05), while resting and exercising blood pressure were unchanged. Glycopyrrolate reduced the maximal gain ( G _max) of the CBR-HR function curve (−0.58 ± 0.10 to −0.06 ± 0.01 beats min⁻¹ mmHg⁻¹, P < 0.05), but had no effect on the G _max of the CBR-MAP function curve. During isometric exercise the CBR-HR curve was shifted upward and rightward in the metoprolol and no drug conditions, while the control of HR was significantly attenuated with glycopyrrolate ( P < 0.05). Regardless of drug administration isometric exercise produced an upward and rightward resetting of the CBR control of MAP with no change in G _max. Thus, despite marked reductions in CBR control of HR following parasympathetic blockade, CBR control of blood pressure was well maintained. These data suggest that alterations in vasomotor tone are the primary mechanism by which the CBR modulates blood pressure during low intensity isometric exercise.     

The Rate of Protein Digestion affects Protein Gain Differently during Aging in Humans

Dehydration is known to decrease orthostatic tolerance and cause tachycardia, but little is known about the cardiovascular control mechanisms involved. To test the hypothesis that arterial baroreflex sensitivity increases during exercise-induced dehydration, we assessed arterial baroreflex responsiveness in 13 healthy subjects (protocol 1) at baseline (PRE-EX) and 1 h after (EX-DEH) 90 min of exercise to cause dehydration, and after subsequent intravenous rehydration with saline (EX-REH). Six of these subjects were studied a second time (protocol 2) with intravenous saline during exercise to prevent dehydration. We measured heart rate, central venous pressure and arterial pressure during all trials, and muscle sympathetic nerve activity (MSNA) during the post-exercise trials. Baroreflex responses were assessed using sequential boluses of nitroprusside and phenylephrine (modified Oxford technique). After exercise in protocol 1 (EX-DEH), resting blood pressure was decreased and resting heart rate was increased. Cardiac baroreflex gain, assessed as the responsiveness of heart rate or R-R interval to changes in systolic pressure, was diminished in the EX-DEH condition (9.17 ± 1.06 ms mmHg⁻¹ vs. PRE-EX: 18.68 ± 2.22 ms mmHg⁻¹, P < 0.05). Saline infusion after exercise did not alter the increase in HR post-exercise or the decrease in baroreflex gain (EX-REH: 10.20 ± 1.43 ms mmHg⁻¹; P > 0.10 vs. EX-DEH). Saline infusion during exercise (protocol 2) resulted in less of a post-exercise decrease in blood pressure and a smaller change in cardiac baroreflex sensitivity. Saline infusion caused a decrease in MSNA in protocol 1. We conclude that exercise-induced dehydration causes post-exercise changes in the baroreflex control of blood pressure that may contribute to, rather than offset, orthostatic intolerance.     

Neurovascular responses to mental stress

The effects of mental stress (MS) on muscle sympathetic nerve activity (MSNA) and limb blood flows have been studied independently in the arm and leg, but they have not been studied collectively. Furthermore, the cardiovascular implications of postmental stress responses have not been thoroughly addressed. The purpose of the current investigation was to comprehensively examine concurrent neural and vascular responses during and after mental stress in both limbs. In Study 1, MSNA, blood flow (plethysmography), mean arterial pressure (MAP) and heart rate (HR) were measured in both the arm and leg in 12 healthy subjects during and after MS (5 min of mental arithmetic). MS significantly increased MAP (Δ15 ± 3 mmHg; P < 0.01) and HR (Δ19 ± 3 beats min⁻¹; P < 0.01), but did not change MSNA in the arm (14 ± 3 to 16 ± 3 bursts min⁻¹; n = 6) or leg (14 ± 2 to 15 ± 2 bursts min⁻¹; n = 8). MS decreased forearm vascular resistance (FVR) by −27 ± 7% ( P < 0.01; n = 8), while calf vascular resistance (CVR) did not change (−6 ± 5%; n = 11). FVR returned to baseline during recovery, whereas MSNA significantly increased in the arm (21 ± 3 bursts min⁻¹; P < 0.01) and leg (19 ± 3 bursts min⁻¹; P < 0.03). In Study 2, forearm and calf blood flows were measured in an additional 10 subjects using Doppler ultrasound. MS decreased FVR (−27 ± 10%; P < 0.02), but did not change CVR (5 ± 14%) as in Study 1. These findings demonstrate differential vascular control of the arm and leg during MS that is not associated with muscle sympathetic outflow. Additionally, the robust increase in MSNA during recovery may have acute and chronic cardiovascular implications.     

Inspiratory muscle training attenuates the human respiratory muscle metaboreflex

We hypothesized that inspiratory muscle training (IMT) would attenuate the sympathetically mediated heart rate (HR) and mean arterial pressure (MAP) increases normally observed during fatiguing inspiratory muscle work. An experimental group (Exp, n = 8) performed IMT 6 days per week for 5 weeks at 50% of maximal inspiratory pressure (MIP), while a control group (Sham, n = 8) performed IMT at 10% MIP. Pre- and post-training, subjects underwent a eucapnic resistive breathing task (RBT) (breathing frequency = 15 breaths min⁻¹, duty cycle = 0.70) while HR and MAP were continuously monitored. Following IMT, MIP increased significantly ( P < 0.05) in the Exp group (−125 ± 10 to −146 ± 12 cmH₂O; mean ± s.e.m. ) but not in the Sham group (−141 ± 11 to −148 ± 11 cmH₂O). Prior to IMT, the RBT resulted in significant increases in HR (Sham: 59 ± 2 to 83 ± 4 beats min⁻¹; Exp: 62 ± 3 to 83 ± 4 beats min⁻¹) and MAP (Sham: 88 ± 2 to 106 ± 3 mmHg; Exp: 84 ± 1 to 99 ± 3 mmHg) in both groups relative to rest. Following IMT, the Sham group observed similar HR and MAP responses to the RBT while the Exp group failed to increase HR and MAP to the same extent as before (HR: 59 ± 3 to 74 ± 2 beats min⁻¹; MAP: 84 ± 1 to 89 ± 2 mmHg). This attenuated cardiovascular response suggests a blunted sympatho-excitation to resistive inspiratory work. We attribute our findings to a reduced activity of chemosensitive afferents within the inspiratory muscles and may provide a mechanism for some of the whole-body exercise endurance improvements associated with IMT.     

Baroreflex-induced sympathetic activation does not alter cerebrovascular CO2 responsiveness in humans

We investigated the effect of baroreflex-induced sympathetic activation, produced by lower body negative pressure (LBNP) at −40 mmHg, on cerebrovascular responsiveness to hyper- and hypocapnia in healthy humans. Transcranial Doppler ultrasound was used to measure blood flow velocity (CFV) in the middle cerebral artery during variations in end-tidal carbon dioxide pressure ( P _ET,CO2) of +10, +5, 0, −5, and −10 mmHg relative to eupnoea. The slopes of the linear relationships between P _ET,CO2 and CFV were computed separately for hyper- and hypocapnia during the LBNP and no-LBNP conditions. LBNP decreased pulse pressure, but did not change mean arterial pressure. LBNP evoked an increase in ventilation that resulted in a 9 ± 2 mmHg decrease in P _ET,CO2, which was corrected by CO₂ supplementation of the inspired air. LBNP did not affect cerebrovascular CO₂ response slopes during steady-state hypercapnia (3.14 ± 0.24 vs. 2.96 ± 0.26 cm s⁻¹ mmHg⁻¹) or hypocapnia (1.31 ± 0.18 vs. 1.32 ± 0.19 cm s⁻¹ mmHg⁻¹), or the CFV responses to voluntary apnoea (+51 ± 19 vs. +50 ± 18 %). Thus, cerebrovascular CO₂ responsiveness was not altered by baroreflex-induced sympathetic activation. Our data challenge the concept that sympathetic activation restrains cerebrovascular responses to alterations in CO₂ pressure.     

Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

An important determinant of [H⁺] in the environment of the central chemoreceptors is cerebral blood flow. Accordingly we hypothesized that a reduction of brain perfusion or a reduced cerebrovascular reactivity to CO₂ would lead to hyperventilation and an increased ventilatory responsiveness to CO₂. We used oral indomethacin to reduce the cerebrovascular reactivity to CO₂ and tested the steady-state hypercapnic ventilatory response to CO₂ in nine normal awake human subjects under normoxia and hyperoxia (50% O₂). Ninety minutes after indomethacin ingestion, cerebral blood flow velocity (CBFV) in the middle cerebral artery decreased to 77 ± 5% of the initial value and the average slope of CBFV response to hypercapnia was reduced to 31% of control in normoxia (1.92 versus 0.59 cm⁻¹ s⁻¹ mmHg⁻¹, P < 0.05) and 37% of control in hyperoxia (1.58 versus 0.59 cm⁻¹ s⁻¹ mmHg⁻¹, P < 0.05). Concomitantly, indomethacin administration also caused 40–60% increases in the slope of the mean ventilatory response to CO₂ in both normoxia (1.27 ± 0.31 versus 1.76 ± 0.37 l min⁻¹ mmHg⁻¹, P < 0.05) and hyperoxia (1.08 ± 0.22 versus 1.79 ± 0.37 l min⁻¹ mmHg⁻¹, P < 0.05). These correlative findings are consistent with the conclusion that cerebrovascular responsiveness to CO₂ is an important determinant of eupnoeic ventilation and of hypercapnic ventilatory responsiveness in humans, primarily via its effects at the level of the central chemoreceptors.     

Baroreflex-Mediated Changes in Cardiac Output and Vascular Conductance in Response to Alterations in Carotid Sinus Pressure during Exercise in Humans

We sought to quantify the contribution of cardiac output ( Q ) and total vascular conductance (TVC) to carotid baroreflex (CBR)-mediated changes in mean arterial pressure (MAP) during mild to heavy exercise. CBR function was determined in eight subjects (25 ± 1 years) at rest and during three cycle exercise trials at heart rates (HRs) of 90, 120 and 150 beats min⁻¹ performed in random order. Acute changes in carotid sinus transmural pressure were evoked using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr (+5.33 to −10.67 kPa). Beat-to-beat changes in HR and MAP were recorded throughout. In addition, stroke volume (SV) was estimated using the Modelflow method, which incorporates a non-linear, three-element model of the aortic input impedance to compute an aortic flow waveform from the arterial pressure wave. The application of NP and NS did not cause any significant changes in SV either at rest or during exercise. Thus, CBR-mediated alterations in Q were solely due to reflex changes in HR. In fact, a decrease in the carotid-HR response range from 26 ± 7 beats min⁻¹ at rest to 7 ± 1 beats min⁻¹ during heavy exercise (   P = 0.001  ) reduced the contribution of Q to the CBR-mediated change in MAP. More importantly, at the time of the peak MAP response, the contribution of TVC to the CBR-mediated change in MAP was increased from 74 ± 14 % at rest to 118 ± 6 % (   P = 0.017  ) during heavy exercise. Collectively, these findings indicate that alterations in vasomotion are the primary means by which the CBR regulates blood pressure during mild to heavy exercise.     

Limb neurovascular control during altered otolithic input in humans

Head-down rotation (HDR), which activates the vestibulosympathetic reflex, increases leg muscle sympathetic nerve activity (MSNA) and produces calf vasoconstriction with no change in either cardiac output or arterial blood pressure. Based on animal studies, it was hypothesized that differential control of arm and leg MSNA explains why HDR does not alter arterial blood pressure. Fifteen healthy subjects were studied. Heart rate, arterial blood pressure, forearm and calf blood flow, and leg MSNA responses were measured during HDR in these subjects. Simultaneous recordings of arm and leg MSNA were obtained from five of the subjects. Forearm and calf blood flow, vascular conductances, and vascular resistances were similar before HDR, as were arm and leg MSNA. HDR elicited similar significant increases in leg (Δ6 ± 1 bursts min⁻¹; 59 ± 16 % from baseline) and arm MSNA (Δ5 ± 1 bursts min⁻¹; 80 ± 28 % from baseline). HDR significantly decreased calf (−19 ± 2 %) and forearm vascular conductance (−12 ± 2 %) and significantly increased calf (25 ± 4 %) and forearm vascular resistance (15 ± 2 %), with ∼60 % greater vasoconstriction in the calf than in the forearm. Arterial blood pressure and heart rate were not altered by HDR. These results indicate that there is no differential control of MSNA in the arm and leg during altered feedback from the otolith organs in humans, but that greater vasoconstriction occurs in the calf than in the forearm. These findings indicate that vasodilatation occurs in other vascular bed(s) to account for the lack of increase in arterial blood pressure during HDR.     

Long-term effects of streptozotocin-induced diabetes on the electrocardiogram, physical activity and body temperature in rats

In vivo biotelemetry studies have demonstrated that short-term streptozotocin (STZ)-induced diabetes is associated with a reduction in heart rate (HR) and heart rate variability (HRV) and prolongation of QT and QRS intervals. This study investigates the long-term effects of STZ-induced diabetes on the electrocardiogram (ECG), physical activity and body temperature. Transmitter devices were surgically implanted in the peritoneal cavity of young adult male Wistar rats. Electrodes from the transmitter were arranged in Einthoven bipolar lead II configuration. ECG, physical activity and body temperature data were continuously recorded with a telemetry system before and following the administration of STZ (60 mg kg⁻¹) for a period of 22 weeks. HR, physical activity and body temperature declined rapidly 3–5 days after the administration of STZ. The effects became conspicuous with time reaching a new steady state approximately 1–2 weeks after STZ treatment. HR at 4 weeks was 268 ± 5 beats min⁻¹ in diabetic rats compared to 347 ± 12 beats min⁻¹ in age-matched controls. HRV at 4 weeks was also significantly reduced after STZ treatment (18 ± 3 beats min⁻¹) compared to controls (33 ± 3 beats min⁻¹). HR and HRV were not additionally altered in either diabetic rats (266 ± 5 and 20 ± 4 beats min⁻¹) or age-matched controls (316 ± 6 and 25 ± 4 beats min⁻¹) at 22 weeks. Reduced physical activity and/or body temperature may partly underlie the reductions in HR and HRV. In addition, the increased power spectral low frequency/high frequency ratio from 4 weeks after STZ treatment may indicate an accompanying disturbance in sympathovagal balance.     

Fluid replacement and heat stress during exercise alter post-exercise cardiac haemodynamics in endurance exercise-trained men

It has been reported that endurance exercise-trained men have decreases in cardiac output with no change in systemic vascular conductance during post-exercise hypotension, which differs from sedentary and normally active populations. As inadequate hydration may explain these differences, we tested the hypothesis that fluid replacement prevents this post-exercise fall in cardiac output, and further, exercise in a warm environment would cause greater decreases in cardiac output. We studied 14 trained men (     4.66 ± 0.62 l min⁻¹) before and to 90 min after cycling at 60%     for 60 min under three conditions: Control (no water was consumed during exercise in a thermoneutral environment), Fluid (water was consumed to match sweat loss during exercise in a thermoneutral environment) and Warm (no water was consumed during exercise in a warm environment). Arterial pressure and cardiac output were measured pre- and post-exercise in a thermoneutral environment. The fall in mean arterial pressure following exercise was not different between conditions ( P = 0.453). Higher post-exercise cardiac output (Δ 0.41 ± 0.17 l min⁻¹; P = 0.027), systemic vascular conductance (Δ 6.0 ± 2.2 ml min⁻¹ mmHg⁻¹ ; P = 0.001) and stroke volume (Δ 9.1 ± 2.1 ml beat⁻¹; P < 0.001) were seen in Fluid compared to Control, but there was no difference between Fluid and Warm (all P > 0.05). These data suggest that fluid replacement mitigates the post-exercise decrease in cardiac output in endurance-exercise trained men. Surprisingly, exercise in a warm environment also mitigates the post-exercise fall in cardiac output.     

Dynamic changes in the direction of blood flow through the ductus arteriosus at birth

Major cardiovascular changes occur at birth, including increased pulmonary blood flow (PBF) and closure of the ductus arteriosus (DA), which acts as a low resistance shunt between the fetal pulmonary and systemic circulations. Although the pressure gradient between these circulations reverses after birth, little is known about DA blood flow changes and whether reverse DA flow contributes to PBF after birth. Our aim was to describe the changes in PBF and DA flow before, during and after the onset of pulmonary ventilation at birth. Flow probes were implanted on the left pulmonary artery (LPA) and DA in preterm fetal sheep ( n = 8) ∼3 days before they were delivered and ventilated. Blood flow was measured in the LPA and DA, before and after umbilical cord occlusion (UCO) and for 2 h after ventilation onset. Following UCO, DA flow decreased from 534 ± 57 ml min⁻¹ to 237 ± 29 ml min⁻¹ which reflected a similar reduction in right ventricular output. Within 5 min of ventilation onset, PBF increased from 11 ± 6 ml min⁻¹ to 230 ± 13 ml min⁻¹ whereas DA flow decreased to −172 ± 54 ml min⁻¹; negative values indicate reverse DA flow (left-to-right shunting). Reverse flow through the DA contributed up to 50% of total PBF at 30 min and a decrease in this contribution accounted for 71 ± 13% of the time-related decrease in PBF after birth. DA blood flow is very dynamic after birth and depends upon the pressure gradient between the pulmonary and systemic circulations. Following ventilation, reverse DA flow provided a significant contribution to total PBF after birth.     

A respiratory response to the activation of the muscle metaboreflex during concurrent hypercapnia in man

In this study, we aimed to assess the ventilatory and cardiovascular responses to the combined activation of the muscle metaboreflex and the ventilatory chemoreflex, achieved by postexercise circulatory occlusion (PECO) and euoxic hypercapnia (end-tidal partial pressure of CO₂ 7 mmHg above normal), respectively. Eleven healthy subjects (4 women and 7 men; 29 ± 4.4 years old; mean ± s.d. ) undertook the following four trials, in random order: 2 min of isometric handgrip exercise followed by 2 min of PECO with hypercapnia; 2 min of isometric handgrip exercise followed by 2 min of PECO while breathing room air; 4 min of rest with hypercapnia; and 4 min of rest while breathing room air. Ventilation was significantly increased during exercise in both the hypercapnic (+3.17 ± 0.82 l min⁻¹) and the room air breathing trials (+2.90 ± 0.26 l min⁻¹; all P < 0.05). During PECO, ventilation returned to pre-exercise levels when breathing room air (+0.52 ± 0.37 l min⁻¹; P > 0.05), but it remained elevated during hypercapnia (+3.77 ± 0.23 l min⁻¹; P < 0.05). The results indicate that the muscle metaboreflex stimulates ventilation with concurrent chemoreflex activation. These findings have implications for disease states where effort intolerance and breathlessness are linked.     

Heart rate at the onset of muscle contraction and during passive muscle stretch in humans: a role for mechanoreceptors

Previous evidence suggests that the heart rate (HR) increase observed with isometric exercise is dependent on different afferent mechanisms to those eliciting the increase in blood pressure (BP). Central command and muscle metaboreceptors have been shown to contribute to this differential effect. However, in experimental animals passive stretch of the hindlimb increases HR suggesting that small fibre mechanoreceptors could also have a role. This has not been previously shown in humans and was investigated in this study. Healthy human volunteers were instrumented to record BP, ECG, respiration, EMG of rectus femoris and gastrocnemius and contraction force of triceps surae. Voluntary isometric contraction of triceps surae elicited a significant HR change in the first three respiratory cycles at 40 % of maximum voluntary contraction whereas BP did not change significantly until after 30 s. This suggests that different mechanisms are involved in the initiation of the cardiovascular changes. Sustained passive stretch of triceps surae for 1 min, by dorsiflexion of the foot, caused a significant (   P < 0.05  ) increase in HR (5 ± 2.6 beats min⁻¹) with no significant change in BP. A time domain measure of cardiac vagal activity was reduced significantly during passive stretch from 69.7 ± 12.9 to 49.6 ± 8.9 ms. Rapid rhythmic passive stretch (0.5 Hz for 1 min) was without significant effect suggesting that large muscle proprioreceptors are not involved. We conclude that in man small fibre muscle mechanoreceptors responding to stretch, inhibit cardiac vagal activity and thus increase HR. These afferents could contribute to the initial cardiac acceleration in response to muscle contraction.     

Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise

The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow was quantified by near infrared spectroscopy and indocyanine green in six healthy humans during dynamic knee extension exercise with and without combined pharmacological inhibition of NO synthase (NOS) and PG by l -NAME and indomethacin, respectively. Microdialysis was applied to determine interstitial release of PG. Compared to control, combined blockade resulted in a 5- to 10-fold lower muscle interstitial PG level. During control incremental knee extension exercise, mean blood flow in the quadriceps muscles rose from 10 ± 0.8 ml (100 ml tissue)⁻¹ min⁻¹ at rest to 124 ± 19, 245 ± 24, 329 ± 24 and 312 ± 25 ml (100 ml tissue)⁻¹ min⁻¹ at 15, 30, 45 and 60 W, respectively. During inhibition of NOS and PG, blood flow was reduced to 8 ± 0.5 ml (100 ml tissue)⁻¹ min⁻¹ at rest, and 100 ± 13, 163 ± 21, 217 ± 23 and 256 ± 28 ml (100 ml tissue)⁻¹ min⁻¹ at 15, 30, 45 and 60 W, respectively ( P < 0.05 vs. control). In conclusion, combined inhibition of NOS and PG reduced muscle blood flow during dynamic exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction.     

Arm Blood Flow and Oxygenation on the Transition from Arm to Combined Arm and Leg Exercise in Humans

The cardiovascular response to exercise with several groups of skeletal muscle implies that work with the legs may reduce arm blood flow. This study followed arm blood flow ( _arm) and oxygenation on the transition from arm cranking (A) to combined arm and leg exercise (A+L). Seven healthy male subjects performed A at ∼80 % of maximum work rate ( W _max) and A at ∼80 % W _max combined with L at ∼60 % W _max. A transition trial to volitional exhaustion was performed where L was added after 2 min of A. The _arm was determined by constant infusion thermodilution in the axillary vein and changes in biceps muscle oxygenation were measured with near-infrared spectroscopy. During A+L _arm was lowered by 0.38 ± 0.06 l min⁻¹ (10.4 ± 3.3 %,   P < 0.05  ) from 2.96 ± 1.54 l min⁻¹ during A. Total (HbT) and oxygenated haemoglobin (HbO₂) concentrations were also lower. During the transition from A to A+L _arm decreased by 0.22 ± 0.03 l min⁻¹ (7.9 ± 1.8 %,   P < 0.05  ) within 9.6 ± 0.2 s, while HbT and HbO₂ decreased similarly within 30 ± 2 s. At the same time mean arterial pressure and arm vascular conductance also decreased. The data demonstrate reduction in blood flow to active skeletal muscle during maximal whole body exercise to a degree that arm oxygen uptake and muscle tissue oxygenation are compromised.     

Rapid Report

Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscles. We sought to determine whether this blunted vasoconstriction is specific for post-junctional α₁- or α₂-adrenergic receptors. We measured forearm blood flow (Doppler ultrasound) and calculated the vascular conductance (FVC) responses to brachial artery infusions of tyramine (which evokes endogenous noradrenaline release), phenylephrine (an α₁ agonist) and clonidine (an α₂ agonist) in 10 healthy men during rhythmic handgrip exercise (10-15 % of maximum) and during a control non-exercise vasodilator condition (intra-arterial adenosine). Steady-state FVC during exercise and adenosine was similar in all trials (range: 243-272 and 234-263 ml min⁻¹ (100 mmHg)⁻¹, respectively; P > 0.5). During exercise the percentage reductions in FVC in response to tyramine (−24 ± 7 vs. −55 ± 6 %), phenylephrine (−12 ± 8 vs. −37 ± 8 %) and clonidine (−17 ± 6 vs. −49 ± 4 %) were significantly less compared with adenosine (all P < 0.05). The magnitude of the blunted vasoconstrictor responses was similar for both receptor subtypes. These findings are in contrast to those from studies in animals demonstrating that α₂-adrenergic receptor-mediated vasoconstrictor responses are much more sensitive to contraction-induced inhibition than α₁-mediated responses. We conclude that vasoconstrictor responses mediated via both post-junctional α₁- and α₂-adrenergic receptors are blunted in contracting human skeletal muscles.     

Carotid chemoreceptor modulation of sympathetic vasoconstrictor outflow during exercise in healthy humans

Recently, we have shown that specific, transient carotid chemoreceptor (CC) inhibition in exercising dogs causes vasodilatation in limb muscle. The purpose of the present investigation was to determine if CC suppression reduces muscle sympathetic nerve activity (MSNA) in exercising humans. Healthy subjects ( N = 7) breathed hyperoxic gas ( F _IO2∼1.0) for 60 s at rest and during rhythmic handgrip exercise (50% maximal voluntary contraction, 20 r.p.m.). Microneurography was used to record MSNA in the peroneal nerve. End-tidal P _CO2 was maintained at resting eupnoeic levels throughout and breathing rate was voluntarily fixed. Exercise increased heart rate (67 versus 77 beats min⁻¹), mean blood pressure (81 versus 97 mmHg), MSNA burst frequency (28 versus 37 bursts min⁻¹) and MSNA total minute activity (5.7 versus 9.3 units), but did not change blood lactate (0.7 versus 0.7 m m ). Transient hyperoxia had no significant effect on MSNA at rest. In contrast, during exercise both MSNA burst frequency and total minute activity were significantly reduced with hyperoxia. MSNA burst frequency was reduced within 9–23 s of end-tidal P _O2 exceeding 250 mmHg. The average nadir in MSNA burst frequency and total minute activity was −28 ± 2% and −39 ± 7%, respectively, below steady state normoxic values. Blood pressure was unchanged with hyperoxia at rest or during exercise. CC stimulation with transient hypoxia increased MSNA with a similar time delay to that obtained with CC inhibition via hyperoxia. Consistent with previous animal work, these data indicate that the CC contributes to exercise-induced increases in sympathetic vasoconstrictor outflow.     

An acute decrease in TCA cycle intermediates does not affect aerobic energy delivery in contracting rat skeletal muscle

We tested the hypothesis that an acute decrease in muscle TCA cycle intermediates during contraction would compromise aerobic energy delivery. Male Wistar rats were anaesthetized and the gastrocnemius–plantaris–soleus (GPS) muscle complex from one leg was isolated and perfused with a red cell medium containing either saline (Con) or cycloserine (Cyclo; 0.05 mg g⁻¹), an inhibitor of alanine aminotransferase (AAT). After 1 h of perfusion, the GPS muscle was either snap frozen (Con-Rest, n = 11; Cyclo-Rest, n = 9) or stimulated to contract for 10 min (1 Hz, 0.3 ms, 2 V) with blood flow fixed at 30 ml min⁻¹ (100 g)⁻¹ and then snap frozen (Con-Stim, n = 10; Cyclo-Stim, n = 10). Maximal AAT activity was > 80% lower ( P < 0.001) in both Cyclo-treated groups (Rest: 0.61 ± 0.02; Stim: 0.63 ± 0.01 mmol (kg wet wt)⁻¹ min⁻¹; mean ± s.e.m. ) compared to Con (Rest: 3.56 ± 0.16; Stim: 3.92 ± 0.29). The sum of five measured TCAI (ΣTCAI) was reduced by 23% in Cyclo-Rest versus Con-Rest but this was not different ( P = 0.08). However, after 10 min of contraction, the ΣTCAI was 25% lower ( P = 0.006) in Cyclo-Stim compared to Con-Stim (1.88 ± 0.15 versus 2.48 ± 0.11 mmol (kg dry wt)⁻¹). Despite the acute decrease in TCAI after Cyclo treatment, the contraction-induced changes in markers of non-oxidative energy provision (phosphocreatine, ATP and lactate) and the decline in tension after 10 min of stimulation were similar compared to Con. These data do not support the hypothesis that the total muscle concentration of TCAI is causally linked to the rate of mitochondrial respiration during contraction.