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INTEGRATIVE |
1 The Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark
2 Centre for Sports Medicine and Human Performance, Brunel University, Uxbridge, Middlesex, UK
3 Institute of Exercise and Sports Sciences, University of Copenhagen, Copenhagen, Denmark
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Abstract |
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at rest and during one-legged knee-extensor exercise (19 ± 1 W) in nine healthy subjects with and without intra-arterial infusion of indomethacin (Indo; 621 ± 17 µg min–1), Indo +
NG-monomethyl-L-arginine (L-NMMA; 12.4 ± 0.3 mg min–1) (double blockade) and Indo +
L-NMMA + tetraethylammonium chloride (TEA; 12.4 ± 0.3 mg min–1) (triple blockade). Double and triple blockade lowered leg blood flow (LBF) at rest (P < 0.05), while it remained unchanged with Indo. During exercise, LBF and vascular conductance were 2.54 ± 0.10 l min–1 and 25 ± 1 mmHg, respectively, in control and they were lower with double (33 ± 3 and 36 ± 4%, respectively) and triple (26 ± 4 and 28 ± 3%, respectively) blockade (P < 0.05), while there was no difference with Indo. The lower LBF and vascular conductance with double and triple blockade occurred in parallel with a lower O2 delivery, cardiac output, heart rate and plasma [noradrenaline] (P < 0.05), while blood pressure remained unchanged and O2 extraction and femoral venous plasma [ATP] increased. Despite the increased O2 extraction, leg 
was 13 and 17% (triple and double blockade, respectively) lower than control in parallel to a lower femoral venous temperature and lactate release (P < 0.05). These results suggest that NO and prostaglandins play important roles in skeletal muscle blood flow regulation during moderate intensity exercise and that EDHFs do not compensate for the impaired formation of NO and prostaglandins. Moreover, inhibition of NO and prostaglandin formation is associated with a lower aerobic energy turnover and increased concentration of vasoactive ATP in plasma.
(Received 22 December 2006;
accepted after revision 1 March 2007;
first published online 8 March 2007)
Corresponding author S. P. Mortensen: The Copenhagen Muscle Research Centre, Rigshospitalet, Section 7652, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. Email stefan{at}sport.dk
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Introduction |
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Nitric oxide (NO) and prostaglandins released from contracting myocytes and/or endothelial cells as well as endothelial-derived hyperpolarizing factors (EDHFs) have been proposed to be involved in the regulation of vascular tone during exercise. NO plays an important role in a wide array of physiological processes, including regulation of vascular tone at rest (Rådegran & Saltin, 1999) and cellular respiration (Shen et al. 1995). Inhibition of nitric oxide synthase (NOS) in humans has, however, no effect on blood flow in the exercising leg (Rådegran & Saltin, 1999; Frandsen et al. 2001) and only a limited effect on flow during hand-grip exercise (Schrage et al. 2004). Likewise, single inhibition of cyclooxygenase (COX), which catalyses the conversion of arachidonic acid to prostaglandin H2 from which prostaglandin and prostacyclin are derived, has no or only a transient effect on blood flow during hand-grip exercise in healthy subjects (Shoemaker et al. 1996; Schrage et al. 2004). Nevertheless, when prostaglandin synthesis is inhibited simultaneously with inhibition of NOS, a reduction in arm blood flow during hand-grip exercise has been observed (Schrage et al. 2004; Saunders et al. 2005), as well as a reduction in microvascular blood flow in the quadriceps muscle measured with near infrared spectroscopy (NIRS) during knee extensions (Boushel et al. 2002).
EDHFs are defined as factors that, independently of NO and prostaglandins, can hyperpolarize smooth muscle cells (Busse et al. 2002). Cytochrome P450 2C9 (CYP2C9) has been proposed to be an EDHF in several tissues including cardiac and skeletal muscle (Fisslthaler et al. 1999; Bolz et al. 2000). Previous work from this laboratory has demonstrated that while single blockade of CYP2C9 with sulfaphenazole does not reduce thigh blood flow during one-legged knee extensor exercise, combined inhibition of NOS and CYP2C9 with NG-monomethyl-L-arginine (L-NMMA) and sulfaphenazole, respectively, lowers thigh blood flow by 
16% (Hillig et al. 2003). Collectively, these observations from studies employing single and double blockade of NO, prostaglandins and EDHFs during exercise indicate that there is redundancy, i.e. that when the formation or action of one compound is inhibited, increased formation of other vasodilators can compensate to maintain blood flow and O2 delivery to contracting myocytes. A close interaction of the NOS, COX and EDHF systems has been shown in vitro (Busse et al. 2002), which could explain the observed redundancy, but the effect of combined inhibition of all three systems during exercise has not previously been investigated in humans.
Recent models of blood flow control propose that apart from the downstream signalling systems involving NO, prostaglandins and/or EDHFs, signals released from the circulating erythrocytes contribute to the regulation of oxygen supply (Ellsworth et al. 1995; Stamler et al. 1997; Gonzalez-Alonso et al. 2002; Gonzalez-Alonso et al. 2006) The idea that the erythrocytes, the major oxygen supplier to tissue, play a role in regulating blood flow by matching O2 delivery to the metabolic demand is supported by in vitro and in vivo reports demonstrating that (1) erythrocytes release ATP and S-nitrosohaemoglobin in association with the offloading of O2 from the haemoglobin molecule (Ellsworth et al. 1995; Stamler et al. 1997), (2) plasma [ATP] is tightly correlated to alterations in haemoglobin saturation with hypoxia, hyperoxia and carbon monoxide (Gonzalez-Alonso et al. 2002), and (3) ATP is a potent vasodilator when infused in the femoral artery (Gonzalez-Alonso et al. 2002; Rosenmeier et al. 2004). ATP can induce vasodilatation by binding to P2y-purinergic receptors located on the vascular endothelial cells whereby the vasoactive actions of the subsequent release of NO, prostanglandins and/or EDHFs initiate a conducted vasomotor response which increases blood flow to tissue (Ellsworth et al. 1995; McCullough et al. 1997; Collins et al. 1998). Plasma [ATP] could be increased in conditions with reduced blood flow and O2 delivery, where O2 extraction is expected to be high and venous O2 content low. However, it is likely that blockade of NO, prostaglandins and EDHFs interferes with the vasodilatory effects of ATP.
In the investigation of the regulation of skeletal muscle blood flow with pharmacological inhibitors, an essential factor to be monitored is O2 delivery and O2 uptake (
). In theory, the infused pharmacological compounds could directly alter O2 utilization and, secondary to this, O2 delivery and blood flow. Indeed, in vitro experiments suggest that treatment of mitochondria with either NOS blockade (Shen et al. 1995) or COX inhibitors (Krause et al. 2003) can alter mitochondrial respiration, and we have previously found that leg 
is reduced when NOS and CYP2C9 are inhibited (Hillig et al. 2003). Despite this fact, only a few studies on the role of various vasodilators for exercise hyperaemia in humans have determined the effect of the used inhibitors on 
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Therefore, the aim of this study was to investigate the role of prostanglandins, NO and EDHFs alone and in combination in the regulation of blood flow and 
during leg exercise and the effect of reduced vasodilator formation on plasma [ATP]. We hypothesized that combined NOS and COX inhibition would lower the exercise hyperaemia and that adding an EDHF blocker would lower the hyperaemia further. In addition, we hypothesized that the reduced blood flow would be paralleled by an increase in plasma [ATP], reflecting an increased oxygen extraction to maintain leg 
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Methods |
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On the two first visits to the laboratory, the subjects completed two training sessions to become accustomed to the knee-extensor model and on the third visit they performed incremental exercise until exhaustion to determine maximal aerobic power output in the knee-extensor model. On the day of the experiment, the subjects arrived at the laboratory 1 h prior to the experiment after a light breakfast. Catheters were placed into the femoral artery and vein of the experimental leg and femoral artery of the non-experimental leg under local anaesthesia. Following 30 min of rest, the subjects performed 5 min of one-legged knee-extensor exercise (19 ± 1 W corresponding to 20% of the 92 ± 2 W achieved during the incremental test) under the following conditions: (1) control, (2) indomethacin (Indo) single blockade, (3) L-NMMA + Indo (double blockade), and (4) L-NMMA + Indo + tetraethylammonium chloride (TEA) (triple blockade)(Fig. 1). Each experimental condition was separated by 30 min of rest and the orders of the single, double and triple blockade trials were counterbalanced across subjects, whereas control was always performed first due to the long-term effect of Indo. To test the effect of time on LBF, we repeated five control trials separated by 30 min of rest in two subjects and found no difference in leg blood flow (LBF) between trials. In all four trials, saline (control), Indo (50 µg min–1 (kg leg mass)–1; Confortid, Alphapharma, Denmark), L-NMMA (1.0 mg min–1 (kg leg mass)–1; Clinalfa, Laufelfingen, Switzerland) and/or TEA (1.0 mg min–1 (kg leg mass)–1; Clinalfa) to inhibit COX, NOS and/or block EDHFs, respectively, were infused alone or in combination into the femoral artery of the experimental leg for 5 min prior to start of exercise and during the 5 min exercise period. The subjects quadriceps femoris muscle mass was 3.1 ± 0.1 kg and total leg mass was 12.4 ± 0.3 kg. The infused concentrations were therefore 621 ± 17 µg min–1 for Indo and 12.4 ± 0.3 mg min–1 for L-NMMA and TEA. Blood samples (1–5 ml) were drawn simultaneously from the femoral artery of the non-experimental leg and femoral vein at rest, during the resting infusion period (4 min) and during exercise (1.5 and 4 min).
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was measured online (Quark b2 system, Cosmed, Italy). Heart rate was obtained from an electrocardiogram, while arterial pressure was monitored with transducers positioned at the level of the heart (Pressure Monitoring Kit, Baxter, Deerfield, IL, USA). Cardiac output was calculated by multiplying heart rate by stroke volume (SV). Stroke volume was calculated using the Modelflow method (BeatScope version 1.1; Finapress Medical Systems BV, Amsterdam, the Netherlands) (Gonzalez-Alonso et al. 2006). For leg O2 delivery, LBF was multiplied by the arterial O2 content; leg O2 extraction was the ratio between the leg a-vO2 difference and the arterial O2 content; and leg lactate release was the lactate a-v difference multiplied by LBF. Blood gases, haemoglobin, glucose and lactate concentrations were measured using an ABL725 analyser (Radiometer, Copenhagen, Denmark) and were corrected for temperature obtained in the femoral vein. Leg mass was calculated from whole-body dual-energy X-ray absorptiometry scanning (Prodigy, General Electric Medical Systems, WI, USA) and quadriceps femoris muscle mass was calculated using the antropometric method (Andersen & Saltin, 1985). Plasma ATP was determined with the luciferin–luciferase technique, using a luminometer with two automatic injectors (Orion Microplate Luminometer, Berthold Detection System GmbH, Pforzheim, Germany). Blood samples (2.0 ml) were drawn into a stop solution (2.7 ml) containing S-(4-nitrobenzyl)-6-thioinosine (NBTI; 5 nM), 3-isobutyl-1-methylxanthine (IBMX; 100 µM), forskolin (10 µM), EDTA (4.15 mM), NaCl (118 mM), KCl (5 mM), and Tricine buffer (40 mM) (Gorman et al. 2003). Immediately thereafter, the samples were centrifuged for 3 min at 4000 g in plastic tubes containing a gel for plasma separation (BD Biosciences, Franklin Lakes, NJ, USA) and measured in duplicates at room temperature (20–22°C) using an ATP kit (ATP Kit SL; BioTherma AB, Dalarö, Sweden) with an internal ATP standard procedure. As an indicator of haemolysis, plasma haemoglobin was measured spectrophotometrically and samples with haemoglobin > 1 mg dl–1 were excluded. Plasma adrenaline and noradrenaline concentration were determined with a radioimmunoassay (LDN, Nordhorn, Germany).
Statistical analysis
A two-way repeated measures ANOVA was performed to test significance within and between trials. Following a significant F-test, pair-wise differences were identified using Tukey's honestly significant difference (HSD) post hoc procedure. The significance level was set at P < 0.05 and data are given as means ± S.E.M. unless otherwise indicated.
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Results |
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There was no difference in LBF, O2 delivery and leg vascular conductance between Indo and control either at rest or during exercise. At rest, LBF was 0.32 ± 0.03 l min–1 and was lower with double (0.22 ± 0.03 l min–1) and triple (0.22 ± 0.02 l min–1) blockade (P < 0.05). During exercise with double blockade, LBF was 33 ± 2% lower at 1.5 min (2.55 ± 0.08 versus 1.66 ± 0.05 l min–1, respectively, P < 0.05) and 33 ± 3% lower at 4 min (2.54 ± 0.10 versus 1.62 ± 0.08 l min–1, respectively, P < 0.05) compared to control (Fig. 2). Similarly, during exercise with triple blockade, LBF was 25 ± 4% lower at 1.5 min (1.91 ± 0.11 l min–1) and 26 ± 4% lower at 4 min (1.84 ± 0.09 l min–1) (P < 0.05). The lower LBF during the combined infusions was paralleled by a lower leg vascular conductance at rest (2.4 ± 0.3 and 2.4 ± 0.2 versus 3.4 ± 0.3 ml min–1 mmHg–1, in double and triple versus control, respectively, P < 0.05) and during exercise (16 ± 1 and 19 ± 1 versus 25 ± 1 ml min–1 mmHg–1, respectively, at 4 min, P < 0.05), while blood pressures remained unchanged. There was no difference in LBF and leg vascular conductance between double and triple blockade. Arterial O2 content was similar in all trials and leg O2 delivery was therefore lower during exercise with double and triple blockade compared to control (P < 0.05).
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at rest to be maintained (21 ± 3, 25 ± 1, 22 ± 3 and 19 ± 2 ml min–1 in control, Indo, double and triple, respectively), but during exercise, leg 
was lower during double and triple blockade at 1.5 min (251 ± 8 and 277 ± 17 versus 298 ± 13 ml min–1 in double and triple versus control, respectively) and at 4 min (245 ± 11 and 267 ± 13 versus 306 ± 14 ml min–1, respectively) (P < 0.05). Lactate release was lower during double and triple blockade (Fig. 3) (P < 0.05).
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, [noradrenaline] and temperatures were lower during double and triple blockade than during control (Table 1).
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In agreement with the responses at the level of the leg, neither Indo, nor double nor triple blockade affected systemic 
, cardiac output, heart rate or SV at rest, but cardiac output and heart rate were lower during exercise with double and triple blockade compared to control (P < 0.05)(Fig. 5). Compared to control, systemic 
was lower during double blockade (546 ± 29 versus 451 ± 27 ml min–1, respectively, P < 0.05), tended to be lower during triple blockade (486 ± 29 ml min–1, P = 0.067), but was similar with Indo (536 ± 21 ml min–1).
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Discussion |
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, despite of an increase in O2 extraction and a lower lactate release. Together, these findings indicate that NO and prostaglandins play important roles in the regulation of skeletal muscle blood flow during moderate intensity exercise and that EDHFs do not compensate for their impaired formation. Moreover, the results suggest that combined infusion of NOS and COX inhibitors lowers aerobic energy turnover and support a function of circulating ATP as a signalling pathway to increase blood flow during conditions with low O2 availability. The difficulties in identifying crucial vasodilators have been attributed to the concept of redundancy and the complex nature of the regulatory system, which ensures the vital delivery of O2 to contracting myocytes. Here we employed a model which allowed us to study the role of prostaglandins alone and in combination with NOS inhibition as well as to identify the role of EDHFs by adding TEA to the combined inhibition of NOS and COX. Inhibition of NO and prostaglandin formation resulted in a lower LBF and vascular conductance during knee-extensor exercise, but in contrast to our hypothesis adding TEA to block the action of EDHFs did not result in a further reduction in LBF or vascular conductance. Although the exact nature of EDHFs is still unknown, they induce vasodilatation independently of NO and prostaglandins by hyperpolarizing endothelial cells and their mechanism of action has been linked to Ca2+-sensitive K+ channels (KCa) (Busse et al. 2002). The finding that blocking the action of EDHFs with TEA did not lower LBF is in contrast to a previous report from our laboratory showing that combined inhibition of NOS with L-NMMA and the EDHF synthase, CYP2C9, with sulfaphenazole lowered thigh blood flow during knee-extensor exercise (Hillig et al. 2003). In this previous study, single blockade of CYP2C9 did not lower blood flow, and in agreement with this we found no effect on LBF when we tested single infusion of TEA in two subjects. One possibility for the lack of effect of TEA during triple blockade is that we may not have blocked all EDHFs. We administered TEA at an infusion rate of 1.0 mg min–1 (kg leg mass)–1, which would result in an estimated local plasma concentration of 0.5 mmol l–1. TEA selectively blocks KCa channels in smooth muscle cells at concentrations < 1 mmol l–1 (Nelson & Quayle, 1995) and a similar concentration of TEA has been shown to inhibit vasodilatation in the human forearm induced by bradykinin, which acts via EDHFs (Honing et al. 2000), as well vasodilatation induced by CNP (Honing et al. 2001) and acetazolamide (Pickkers et al. 2001), both openers of KCa channels. Alternatively, TEA may be less efficient in causing a general block of the KCa channels than sulfaphenazole is at specifically blocking the enzyme CYP2C9, but when we replaced TEA with sulfaphenazole in one subject, we also observed no difference in LBF between the double and triple blockade. Collectively, these results demonstrate that when NOS and COX are inhibited, EDHFs are not able to compensate for the impaired formation of NO and prostaglandins.
Combined inhibition of NOS and COX with intra-arterial infusion of L-NMMA and Indo lowered LBF and vascular conductance by 33 and 36%, respectively, during exercise. The similar reduction in vascular conductance indicates that the lower blood flow was due to vasoconstriction, rather than altered perfusion pressure. Enhanced sympathetic vasoconstrictor activity was unlikely to be the reason for the lower LBF because plasma [noradrenaline] was lower during the combined blockades than in the control situation. These observations suggest that the lower LBF during double and triple blockade resulted from a reduction in the effective vasodilator signalling achieved by pharmacological inhibition of NOS and COX. We have previously demonstrated that single inhibition of NOS, with a similar dose of L-NMMA and in the same exercise model does not lower LBF (Radegran & Saltin, 1999). With the present finding that Indo alone did not alter LBF, the lower blood flow must have been the result of the combined inhibition. The lower LBF with combined blockades was paralleled by a 21–26% lower cardiac output, which was associated with a lower heart rate. While the signalling mechanisms for the lower cardiac output remain unclear, a probable explanation is the lower LBF and/or a baroreceptor-mediated sympathetic withdrawal as indicated by the lower plasma catacholamines (Sheriff et al. 2000). This is the first time LBF has been measured in the human leg during combined NOS and COX inhibition, but the lower blood flow and cardiac output is compatible with findings in microvascular quadriceps blood flow measured with NIRS (Boushel et al. 2002) and in the human forearm (Schrage et al. 2004). Notably, these two studies used NG-nitro-L-arginine methyl ester (L-NAME) to inhibit NOS which is associated with increases in blood pressure and may have affected the findings (Sander et al. 1999).
An interesting finding was that femoral venous plasma [ATP] increased during exercise with the combined blockades and was significantly higher than in the femoral artery. The erythrocytes could contribute to the regulation of blood flow by releasing ATP depending on the number of unoccupied O2 binding sites in the haemoglobin molecule. The potent vasodilatory and sympatholytic effects of ATP in the leg makes it an attractive candidate to contribute in the regulation of microvascular blood flow (Gonzalez-Alonso et al. 2002; Rosenmeier et al. 2004). The [ATP] was strongly correlated with femoral venous O2 saturation (r2 = 0.97) and our results support the hypothesis that in conditions with reduced O2 availability, such as during the combined blockades, ATP released from erythrocytes functions as a pathway to increase muscle blood flow to restore O2 delivery to contracting myocytes. However, the vasodilatory actions of ATP during the combined blockades were likely to have been blunted because of a reduced formation of the mediators of ATP-induced vasodilatation.
Despite the same mechanical work performed, leg 
was 13–17% lower during double and triple blockade, in parallel to a lower systemic 
, lactate release and femoral venous temperature. The presence of eNOS in the vascular endothelium has been shown to affect muscle mitochondrial respiration and consequently 
(Shen et al. 1995). Two recent studies in isolated muscle have reported a similar reduced O2 cost of force development with NOS inhibition (King-VanVlack et al. 2002; Baker et al. 2006). In contrast, NO has been demonstrated to inhibit mitochondrial respiration in animals and isolated cells by binding to the O2-binding site at cytochrome c oxidase in the electron transport chain (Shen et al. 1994; Brown, 2000). However, single inhibition of NOS and prostaglandins does not alter leg 
during leg exercise (Radegran & Saltin, 1999; Frandsen et al. 2001) and 
was not altered at rest, suggesting that a high energy turnover and multiple inhibitors are required for 
to be altered. An elevated P/O ratio is unlikely to completely explain the lower LBF, as the reduction in LBF was greater (> 26%) than the reduction in leg 
(< 17%), because of an increased O2 extraction. Alternatively, the reduced leg 
during exercise was directly related to the 29–36% lower O2 delivery and consequently lower O2 availability in the mitochondria, but in this setting a higher and not lower lactate release would be expected. Future studies are required to determine the exact mechanisms behind the lower energy turnover, but our observations add to the complexity in identifying vasoactive compounds of importance for the regulation of skeletal muscle blood flow.
In conclusion, these results demonstrate that NO and prostaglandins play important roles in skeletal muscle blood flow regulation during moderate intensity exercise, but also suggest that EDHFs may not be important as they are not able to compensate for the impaired formation of NO and prostaglandins. Moreover, the results suggest that combined infusion of NOS and COX inhibitors lowers aerobic energy turnover and support a function of circulating ATP as a signalling pathway to increase blood flow during conditions with low O2 availability.
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Femoral venous significantly different from arterial (P < 0.05).