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.     

Cytochrome P450 2C9 plays an important role in the regulation of exercise-induced skeletal muscle blood flow and oxygen uptake in humans

Previous studies show that exercise-induced hyperaemia is unaffected by systemic inhibition of nitric oxide synthase (NOS) and it has been proposed that this may be due to compensation by other vasodilators. We studied the involvement of cytochrome P450 2C9 (CYP 2C9) in the regulation of skeletal muscle blood flow in humans and the interaction between CYP 2C9 and NOS. Seven males performed knee extensor exercise. Blood flow was measured by thermodilution and blood samples were drawn frequently from the femoral artery and vein at rest, during exercise and in recovery. The protocol was repeated three times on the same day. The first and the third protocols were controls, and in the second protocol either the CYP 2C9 inhibitor sulfaphenazole alone, or sulfaphenazole in combination with the NOS inhibitor N ^ω-monomethyl- l -arginine ( l -NMMA) were infused. Compared with control there was no difference in blood flow at any time with sulfaphenazole infusion (   P > 0.05  ) whereas with infusion of sulfaphenazole and l -NMMA, blood flow during exercise was 16 ± 4 % lower than in control (9 min: 3.67 ± 0.31 vs. 4.29 ± 0.20 l min⁻¹;   P < 0.05  ). Oxygen uptake during exercise was 12 ± 3 % lower (9 min: 525 ± 46 vs. 594 ± 24 ml min⁻¹;   P < 0.05  ) with co-infusion of sulfaphenazole and l -NMMA, whereas oxygen uptake during sulfaphenazole infusion alone was not different from that of control (   P > 0.05  ). The results demonstrate that CYP 2C9 plays an important role in the regulation of hyperaemia and oxygen uptake during exercise. Since inhibition of neither NOS nor CYP 2C9 alone affect skeletal muscle blood flow, an interaction between CYP 2C9 and NOS appears to exist so that a CYP-dependent vasodilator mechanism takes over when NO production is compromised.     

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.     

Does nitric oxide allow endothelial cells to sense hypoxia and mediate hypoxic vasodilatation?in vivo and in vitro studies

Hypoxia-evoked vasodilatation is a fundamental regulatory mechanism that is often attributed to adenosine. The identity of the O₂ sensor is unknown. Nitric oxide (NO) inhibits endothelial mitochondrial respiration and ATP generation by competing with O₂ for its binding site on cytochrome oxidase. We proposed that in vivo this interaction allows endothelial cells to release adenosine when O₂ tension falls or NO concentration increases. Using anaesthetised rats, we confirmed that the increase in femoral vascular conductance (FVC, hindlimb vasodilatation) evoked by systemic hypoxia is attenuated by NO synthesis blockade with l -NAME, but restored when baseline FVC is restored by infusion of NO donor. This 'restored' hypoxic response, like the control hypoxic response, is inhibited by the adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. Similarly, the FVC increase evoked by adenosine infusion was attenuated by l -NAME but restored by infusion of NO donor. However, when baseline FVC was restored after l -NAME with 8-bromo-cGMP, the FVC increase evoked by adenosine infusion was restored, but not in response to systemic hypoxia, suggesting that adenosine was no longer released by hypoxia. Infusion of NO donor at a given rate after treatment with l -NAME evoked a greater FVC increase during systemic hypoxia than during normoxia, both responses being reduced by 8-cyclopentyl-1,3-dipropylxanthine. Finally, both bradykinin and NO donor released adenosine from superfused endothelial cells in vitro ; l -NAME attenuated only the former response. We propose that in vivo , shear-released NO increases the apparent K _m of endothelial cytochrome oxidase for O₂, allowing the endothelium to act as an O₂ sensor, releasing adenosine in response to moderate falls in O₂.     

H1 receptor-mediated vasodilatation contributes to postexercise hypotension

In normally active individuals, postexercise hypotension after a single bout of aerobic exercise is due to an unexplained peripheral vasodilatation. Histamine has been shown to be released during exercise and could contribute to postexercise vasodilatation via H₁ receptors in the peripheral vasculature. The purpose of this study was to determine the potential contribution of an H₁ receptor-mediated vasodilatation to postexercise hypotension. We studied 14 healthy normotensive men and women (ages 21.9 ± 2.1 years) before and through to 90 min after a 60 min bout of cycling at 60%     on randomized control and H₁ receptor antagonist days (540 mg oral fexofenadine hydrochloride; Allegra). Arterial blood pressure (automated auscultation) and femoral blood flow (Doppler ultrasound) were measured in the supine position. Femoral vascular conductance was calculated as flow/pressure. Fexofenadine had no effect on pre-exercise femoral vascular conductance or mean arterial pressure ( P > 0.5). At 30 min postexercise on the control day, femoral vascular conductance was increased (Δ+33.7 ± 7.8%; P < 0.05 versus pre-exercise) while mean arterial pressure was reduced (Δ−6.5 ± 1.6 mmHg; P < 0.05 versus pre-exercise). In contrast, at 30 min postexercise on the fexofenadine day, femoral vascular conductance was not elevated (Δ+10.7 ± 9.8%; P = 0.7 versus pre-exercise) and mean arterial pressure was not reduced (Δ−1.7 ± 1.2 mmHg; P = 0.2 versus pre-exercise). Thus, ingestion of an H₁ receptor antagonist markedly reduces vasodilatation after exercise and blunts postexercise hypotension. These data suggest H₁ receptor-mediated vasodilatation contributes to postexercise hypotension.     

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.     

Ischemic exercise hyperemia in the human forearm: reproducibility and roles of adenosine and nitric oxide

The roles of local metabolites in reactive and exercise hyperemia remain incompletely understood. A maximum metabolic stimulus caused by ischemic exercise (IE) could potentially fully activate all vasodilator pathways and limit potential redundancy amongst vasoactive substances. We tested the hypotheses that IE elicits a reproducible hyperemic response in the forearm and that adenosine (ADO) and nitric oxide (NO) contribute to this response. In separate protocols, forearm blood flow (FBF) was measured with venous occlusion plethysmography following IE trials consisting of 5 min of ischemia and rhythmic forearm handgrip exercise (performed during last 2 min of ischemia). In protocol 1 (n = 8), FBF was measured after three trials of IE. In protocol 2 (n = 9), subjects performed IE during control (saline), aminophylline (APH; adenosine receptor antagonist), and combined APH/N (G)-monomethyl-L-arginine (L-NMMA; NOS inhibition) infusions. In protocol 1, coefficients of variation for total (area under the curve) ΔFBF and ΔFVC (forearm vascular conductance) following IE were 10.4 ± 1.0% and 14.9 ± 1.0%, respectively. In protocol 2, peak ΔFBF was similar for saline and APH trials. Peak ΔFBF for the APH+L: -NMMA trial was greater than that of the APH trial (P = 0.03), and peak ΔFVC was marginally non-significant (P = 0.053). Total ΔFBF (54.8 ± 3.9, 55.2 ± 5.4, and 60.4 ± 4.8 ml 100 ml(-1); P = 0.43) and ΔFVC (51.4 ± 3.5, 52.1 ± 5.5, and 56.5 ± 5.0 ml 100 ml(-1) 100 mmHg(-1); P = 0.52) were similar for saline, APH, and APH+L: -NMMA, respectively. Our data suggest that (1) the hyperemic response to IE is reproducible and (2) inhibition of ADO alone or combined ADO and NO does not blunt the hyperemic response following IE.     

Adenosine transporter antagonism in humans augments vasodilator responsiveness to adenosine, but not exercise, in both adenosine responders and non-responders

We previously demonstrated a bimodal distribution of forearm vasodilator responsiveness to adenosine (ADO) infusion in the brachial arteries of human subjects. We also demonstrated that ADO receptor antagonism blunted exercise hyperaemia during heavy rhythmic handgripping, but vasodilator responses to exogenous ADO were only blunted in ADO responders. In this study, we continued investigating the contribution of ADO to exercise hyperaemia and possible differences between responders and non-responders. We hypothesized that ADO transporter antagonism would increase vasodilatation in response to exogenous ADO in responders only, but not effect exercise-mediated vasodilation. To test this hypothesis, we compared forearm vascular conductance (FVC) during infusion of ADO to FVC during handgripping before and after infusion of dipyridamole (DIP) in 20 subjects. In ADO responders, change in FVC above baseline (ml min⁻¹ (100 mmHg)⁻¹) for low, medium and high doses of ADO, respectively, was 58 ± 8, 121 ± 22 and 184 ± 38, and after DIP was 192 ± 32, 238 ± 50 and 310 ± 79. For non-responders, these values were 23 ± 2, 43 ± 5 and 66 ± 9, respectively, before DIP ( P < 0.01 versus responders). Contrary to our hypothesis, these values were increased by DIP in non-responders ( P < 0.001) and therefore not different from responders ( P > 0.20). We found that ADO transporter blockade had no effect on exercise hyperaemia in either subgroup. We conclude that there may be increased ADO transporter activity in non-responders resulting in reduced ADO-mediated vasodilatation. The failure of DIP to augment exercise hyperemia under these conditions suggests that ADO concentrations may not rise enough during rhythmic handgripping to have a major impact on these responses.     

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.     

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.     

Blunted Sympathetic Vasoconstriction in Contracting Skeletal Muscle of Healthy Humans: is Nitric Oxide Obligatory?

We tested the hypothesis that nitric oxide (NO) is responsible for blunting sympathetic α-adrenergic vasoconstriction in the active muscles of humans (functional sympatholysis). We measured forearm blood flow (Doppler ultrasound) and calculated the reductions in forearm vascular conductance (FVC) in response to α-adrenergic receptor stimulation during rhythmic handgrip exercise and during a control non-exercise vasodilator condition (intra-arterial adenosine), before and after local NO synthase (NOS) inhibition in healthy men. The forearm vasoconstrictor responses to endogenous noradrenaline release (intra-arterial tyramine) were significantly blunted during moderate exercise compared with adenosine, and these vasoconstrictor responses were not restored by NOS inhibition with N ^G-monomethyl- l -arginine ( l -NMMA;   n = 6  ) or N ^G-nitro- l -arginine methyl ester ( l -NAME;   n = 8  ). Similarly, l -NAME did not restore the vasoconstrictor responses to tyramine in contracting muscle during heavy rhythmic handgrip exercise (   n = 4  ). In four additional subjects, we also found that the vasoconstrictor responses evoked by tyramine during exercise or adenosine were repeatable in the absence of NOS inhibition (i.e. time control). Finally, in five subjects the forearm vasoconstrictor responses to direct α₁-adrenergic (phenylephrine) and α₂-adrenergic (clonidine) receptor stimulation were blunted during moderate exercise compared with adenosine; these responses were also unaffected by l -NAME. Taken together, our results demonstrate that NO is not obligatory for functional sympatholysis in contracting skeletal muscles of healthy men.     

Flow-mediated dilatation in the superficial femoral artery is nitric oxide mediated in humans

Flow-mediated dilatation (FMD) of the brachial and radial arteries is an important research tool for assessment of endothelial function in vivo , and is nitric oxide (NO) dependent. The leg skeletal muscle vascular bed is an important territory for studies in exercise physiology. However, the role of endothelial NO in the FMD response of lower limb arteries has never been investigated. The purpose of this study was to examine the contribution of NO to FMD in the superficial femoral artery in healthy subjects. Since physical inactivity may affect endothelial function, and therefore NO availability, spinal cord-injured (SCI) individuals were included as a model of extreme deconditioning. In eight healthy men (34 ± 13 years) and six SCI individuals (37 ± 10 years), the 5 min FMD response in the superficial femoral artery was assessed by echo-Doppler, both during infusion of saline and during infusion of the NO synthase blocker N ^G-monomethyl- l -arginine ( l -NMMA). In a subset of the controls ( n = 6), the 10 min FMD response was also examined using the same procedure. The 5 min FMD response in controls (4.2 ± 0.3%) was significantly diminished during l -NMMA infusion (1.0 ± 0.2%, P < 0.001). In SCI, l -NMMA also significantly decreased the FMD response (from 8.2 ± 0.4% during saline to 2.4 ± 0.5% during l -NMMA infusion). The hyperaemic flow response during the first 45 s after cuff deflation was lower in both groups during infusion of l -NMMA, but the effect of l -NMMA on FMD persisted in both groups after correction for the shear stress stimulus. The 10 min FMD was not affected by l -NMMA (saline: 5.4 ± 1.6%, l -NMMA: 5.6 ± 1.5%). Superficial femoral artery FMD in response to distal arterial occlusion for a period of 5 min is predominantly mediated by NO in healthy men and in the extremely deconditioned legs of SCI individuals.     

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.     

Nitric oxide (NO) does not contribute to the generation or action of adenosine during exercise hyperaemia in rat hindlimb

Exercise hyperaemia is partly mediated by adenosine A_2A-receptors. Adenosine can evoke nitric oxide (NO) release via endothelial A_2A-receptors, but the role for NO in exercise hyperaemia is controversial. We have investigated the contribution of NO to hyperaemia evoked by isometric twitch contractions in its own right and in interaction with adenosine. In three groups of anaesthetized rats the effect of A_2A-receptor inhibition with ZM241385 on femoral vascular conductance (FVC) and hindlimb O₂ consumption     at rest and during isometric twitch contractions (4 Hz) was tested (i) after NO synthase inhibition with l- NAME, and when FVC had been restored by infusion of (ii) an NO donor (SNAP) or (iii) cell-permeant cGMP. Exercise hyperaemia was significantly reduced (32%) by l- NAME and further significantly attenuated by ZM241385 (60% from control). After restoring FVC with SNAP or 8-bromo-cGMP, l- NAME did not affect exercise hyperaemia, but ZM241385 still significantly reduced the hyperaemia by 25%. There was no evidence that NO limited muscle     during contraction. These results indicate that NO is not required for adenosine release during contraction and that adenosine released during contraction does not depend on new synthesis of NO to produce vasodilatation. They also substantiate our general hypothesis that the mechanisms by which adenosine contributes to muscle vasodilatation during systemic hypoxia and exercise are different: we propose that, during muscle contraction, adenosine is released from skeletal muscle fibres independently of NO and acts directly on A_2A-receptors on the vascular smooth muscle to cause vasodilatation.     

Onset exercise hyperaemia in humans: partitioning the contributors

Using a step-wise, reductionist approach we characterized the time course and degree to which mechanical, vasodilatory and cardiac mechanisms contribute to the increase in leg blood flow (LBF) at the onset of dynamic knee-extensor exercise. Heart rate (HR) and LBF (ultrasound Doppler) were evaluated during (1) voluntary and (2) passive exercise in the seated position, (3) passive exercise in the supine position with the leg above the heart, and (4) passive exercise with measurements made in the non-moving leg. In trials 2 and 3, the degree of change and time course of peak ΔHR (8.7 ± 2 bpm, seated; 10 ± 1 bpm, supine) and peak ΔLBF (518 ± 135 ml min⁻¹, seated; 448 ± 179 ml min⁻¹, supine) were similar, supporting the concept that the skeletal muscle pump was minimized. Even with the reduction of skeletal muscle pump and metabolic influences (trials 2, 3 and 4) a significant cardio-acceleration and hyperaemia was seen. In the first 5 s of seated passive exercise, the retrograde component of the blood velocity profile was significantly greater than rest or the 5–20 s interval, which may suggest an arterial inflow that initially exceeded leg vasodilatation. Steady-state LBF (minutes 2 and 3) remained elevated during voluntary exercise, but returned to near baseline during passive movement. Taken together, these data suggest that cardio-acceleration (i.e. tachycardia) and mechanical forces other than the skeletal muscle pump play a role in reducing vascular resistance and ultimately increasing LBF at the onset of exercise, followed by steady-state LBF which matches muscle metabolic demand.     

Exercise hyperaemia: magnitude and aspects on regulation in humans

The primary function of the cardiovascular system is to supply oxygen to tissues and organs in the body. When muscles contract the aerobic demands are met by an increase in oxygen delivery both at the systemic and the regional levels, a match that is very close and holds at submaximal exercise and when small muscle group contract also at vigorous intensities. The level of muscle perfusion reached is 250 ml min⁻¹ (100 g)⁻¹ in muscle of sedentary subjects and in endurance-trained athletes 400 ml min⁻¹ (100 g)⁻¹ has been reported. These levels of peak exercise hyperaemia equal what has been observed in other species. One consequence of these high muscle blood flows is that the human heart cannot support an optimal blood flow in whole body exercise (arms and legs combined) and sympathetically mediated vasoconstriction, also in arterioles feeding active limb muscles, contributes to matching peripheral resistance in order to maintain blood pressure. Respiratory muscles appear to have a higher priority for a blood flow than limb and torso muscles. There is no consensus in regard to which locally produced substances elicit the vasodilatation when muscle contracts. In addition to NO, data are presented for various metabolites of arachidonic acid and also on ATP, possibly released from the red cells. Using blockers of nitric oxide synthase ( l -NMMA or l -NAME) and the enzymes producing epoxyeicosatrienoic acid (EET) (sulpaphenozole or tetraetylammonium chloride) or prostaglandins (indomethacin), muscle blood flow may be reduced by up to 25–40%. Evaluating the exact role of ATP has to await further studies in humans and especially the use of specific ATP receptor blockers.     

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.     

The carbonic anhydrase inhibitors methazolamide and acetazolamide have different effects on the hypoxic ventilatory response in the anaesthetized cat

We compared the effects of the carbonic anhydrase inhibitors methazolamide and acetazolamide (3 mg kg⁻¹, i.v .) on the steady-state hypoxic ventilatory response in 10 anaesthetized cats. In five additional animals, we studied the effect of 3 and 33 mg kg⁻¹ methazolamide. The steady-state hypoxic ventilatory response was described by the exponential function: where     is the inspired ventilation_, G is hypoxic sensitivity, D is the shape factor and A is hyperoxic ventilation. In the first group of 10 animals, methazolamide did not change parameters G and D , while A increased from 0.86 ± 0.33 to 1.30 ± 0.40 l min⁻¹ (mean ± s.d. , P = 0.003). However, the subsequent administration of acetazolamide reduced G by 44% (control, 1.93 ± 1.32; acetazolamide, 1.09 ± 0.92 l min⁻¹, P = 0.003), while A did not show a further change. Acetazolamide tended to reduce D (control, 0.20 ± 0.07; acetazolamide, 0.14 ± 0.06 kPa⁻¹, P = 0.023). In the second group of five animals, neither low- nor high-dose methazolamide changed parameters G , D and A . The observation that even high-dose methazolamide, causing full inhibition of carbonic anhydrase in all body tissues, did not reduce the hypoxic ventilatory response is reminiscent of previous findings by others showing no change in magnitude of the hypoxic response of the in vitro carotid body by this agent. This suggests that normal carbonic anhydrase activity is not necessary for a normal hypoxic ventilatory response to occur. The mechanism by which acetazolamide reduces the hypoxic ventilatory response needs further study.     

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.     

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.