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1 University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA
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Abstract |
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39%) was attenuated during exercise in the exercising leg (15%, P < 0.05). Oral glyburide ingestion partially restored CBR-mediated vasoconstriction in the exercising leg (40% restoration, P < 0.05) compared to control exercise. These findings indicate that KATP channel activity modulates sympathetic vasoconstriction in humans and may prove to be an important mechanism by which functional sympatholysis operates in humans during exercise.
(Received 15 July 2004;
accepted after revision 31 August 2004;
first published online 2 September 2004)
Corresponding author D. M. Keller: Institute for Exercise and Environmental Medicine, 7232 Greenville Ave, Dallas, TX 75231, USA. Email: davidkeller{at}texashealth.org
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Introduction |
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Two prominent mechanisms for causing functional sympatholysis during exercise have been proposed. One involves the endogenous vasodilator nitric oxide (NO), while the other involves the ATP-sensitive potassium (KATP) channel (Hansen et al. 2000b). A body of evidence exists from animal experiments which strongly supports the role of NO as having a role in the phenomenon of functional sympatholysis (Thomas & Victor, 1998; Buckwalter et al. 2004). In contrast, human experiments indicate that NO is not obligatory as the primary mechanism underlying functional sympatholysis (Dinenno & Joyner, 2003). However, it has been shown that KATP channel activity is sensitive to a range of vasodilator metabolites, including NO (Nelson & Quayle, 1995), which may therefore be one of the factors contributing to the activation of the KATP channel in humans during muscle contraction.
Activation of potassium channels, which are widely distributed in vascular smooth muscle (Nelson & Quayle, 1995), generally results in hyperpolarization and relaxation of vascular smooth muscle (Quast et al. 1994). Furthermore, it has been demonstrated that KATP channel activity is sensitive to changes in the concentrations of both intra- and extracellular factors such as ATP, nucleotide diphosphates, molecular oxygen (O2), hydrogen ions (H+), adenosine, prostacyclin and NO (Quayle & Standen, 1994; Nelson & Quayle, 1995). Thomas et al. (1997) investigated the possibility that the activation of KATP channels by some metabolic product of skeletal muscle contraction was a key mechanism by which sympathetic vasoconstriction, especially that mediated by the activation of 
2 adrenoceptors, was attenuated in contracting skeletal muscle. From studies using anaesthetized rats, they reported that pharmacological activation of KATP channels via diazoxide administration attenuated sympathetic vasoconstriction in resting hindlimb in a dose-dependent manner (Thomas et al. 1997). Furthermore, they demonstrated that functional sympatholysis was sensitive to modulation by changes in the activity of the KATP channel and that contraction-induced sympatholysis was moderately prevented by the KATP channel blocker, glibenclamide (Thomas et al. 1997). Thus, contraction-induced activation of KATP channels appears to be a central mechanism underlying functional sympatholysis in the rat. However, the role of KATP channel activity in modulating sympatholysis in humans remains unknown.
Recently, we have identified the effectiveness of functional sympatholysis during disengagement of the carotid baroreflex (CBR) using neck pressure (NP) and the resulting vasoconstrictor response of active skeletal muscle (Keller et al. 2003). Furthermore, in both animals (O'Leary et al. 1991; Collins et al. 2001) and in humans (Ogoh et al. 2003) the importance of baroreflex-mediated control of total vascular conductance in maintaining arterial blood pressure during exercise has been confirmed. However, whether the KATP channel plays a role in the functional sympatholysis observed in the baroreflex-mediated sympathetic vasoconstriction during exercise in humans (Keller et al. 2003) remains to be explored.
Therefore, the current investigation was designed to examine the role of the KATP channel in modulating functional sympatholysis in humans. We hypothesize that KATP channel inhibition will restore CBR-mediated vasoconstriction in a vascular bed supplying exercising skeletal muscle. We addressed this hypothesis in humans performing one-legged knee extension exercise, using quantifiable NP stimulation of the carotid baroreceptors with and without ingestion of oral glyburide with the expectation of partially restoring sympathetically mediated vasoconstriction in the exercising leg.
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Methods |
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Five men and two women (age, 25 ± 1 years; height, 153 ± 9 cm; weight, 67 ± 1 kg; mean ± S.E.M.) voluntarily participated in the present investigation. Each subject was familiarized with the testing protocols and informed of the potential risks of participating in the current study. Subjects gave written consent to the procedures which were approved by the University of North Texas Health Science Center's Institutional Review Board and performed in accordance with the Declaration of Helsinki. All subjects were healthy, non-smokers, free of known cardiovascular and respiratory disease, and were not using prescription or over-the-counter medications. Subjects were advised not to participate in strenuous physical activity or imbibe alcohol for 24 h prior to the scheduled experiments. In addition, the subjects were asked to refrain from the consumption of caffeinated beverages for 12 h prior to the experiments.
Experimental protocol
Each subject visited the laboratory on two separate days.
Experimental day 1.
Carotid baroreflex control of MAP and LVC was determined in each subject using the variable pressure neck collar technique (Potts et al. 1993) at rest and during exercise trials on experimental day 1. At rest, CBR control of MAP was determined using NP and neck suction (NS) ranging from +40 to –80 Torr as described by Potts et al. (1993). Also at rest, CBR control of LVC was determined in response to NP (+40 Torr) only. After a period of resting data collection (1 h), subjects performed two trials of one-legged knee extension exercise. During exercise, CBR control of MAP and LVC were determined using only NP (+40 Torr). Subjects performed two bouts of 7 W workload exercise at a kicking rate of 30 kicks per minute (kpm) using a modified cycle ergometer (Ergomedic 874 E, Monark) described by Saltin (1985). While kicking, the subjects were provided with an audible cue using a metronome and verbally encouraged when necessary to maintain a consistency of each knee extension. The rate of kicking was set to 30 kpm to allow sufficient time for the exercising leg to relax in order to optimize the integrity of the Doppler ultrasound measures in response to NP during exercise. The effect of contraction rate on leg blood flow has previously been examined (Hoelting et al. 2001, 2002). Osada & Radegran (2002) demonstrated that leg blood flow was linearly matched to total work rate, regardless of contraction frequency. On this experimental day, a resting data collection period of 1 h was completed before the exercise trials. Each exercise trial lasted approximately 25 min. The time of the exercise trials was limited to 25 min in order to eliminate the confounding effects of fatigue, or cardiovascular drift on CBR function. In an effort to minimize changes in skin blood flow, laboratory temperature on experimental days was maintained between 24 and 25°C. Each exercise trial was separated by a recovery period of 30 min to ensure the return of cardiovascular variables to baseline. Two exercise trials at the 7 W workload were performed for the collection of data from an exercising leg (EL) and a non-exercising leg (NEL) during separate trials.
Experimental day 2. After instrumentation, subjects ingested a 5 mg dose of glyburide. On this experimental day, CBR control of MAP was determined at rest after glyburide ingestion to demonstrate any potential direct effects of glyburide ingestion on CBR function. At rest, CBR control of LVC was determined in response to NP (+40 Torr) only. The experimental protocol on experimental day 2 was similar to experimental day 1. During exercise, CBR control of MAP and LVC were determined using only NP (+40 Torr). All data collection (resting and exercise trials) was performed during 3–4 h post glyburide ingestion.
Glyburide administration
All resting and one-legged knee extension exercise trials were performed during hours 3 and 4 post administration of the drug. This time frame has been shown to significantly alter calf blood flow and hyperaemic responses to leg cuff occlusion (Kosmas et al. 1995). Blood glucose for each subject was determined with finger stick blood sampling (Ascensia Elite XL, Bayer) every 3 min during hours 1 and 2 post drug administration. During hours 3 and 4, blood glucose was determined every 2 min. Glyburide administration did not change blood gas variables at rest or during 7 W exercise in three subjects (see Table 2). Meals were provided for each subject at the time of glyburide ingestion and a carbohydrate supplement drink was given to subjects following a decrease in blood glucose below 70 mg dl–1 to prevent the hypoglycaemic response to glyburide.
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All testing was performed with subjects in a semirecumbent 60 deg back-supported seated position, resulting in an 120 deg leg-to-torso angle to optimize one-legged exercise performance, as well as Doppler ultrasound measurements. Cardiovascular variables were monitored beat-to-beat and recorded on a personal computer (PC) equipped with customized software (Necsuc3) that collects and records data on each R-wave, as well as a second PC equipped with an on-line data acquisition program (DI-720, Dataq Instruments, Akron, OH, USA). Heart rate (HR) was monitored with a standard lead II electrocardiogram (ECG). The ECG signal was output to a monitor (model 78342A, Hewlett-Packard, Andover, MA, USA) interfaced with the PC. Arterial blood pressure (ABP) in six subjects, as well as arterial blood sample collection (PO2, PCO2, pH, haematocrit (Hct) and oxygen saturation (SO2)) in three subjects, was measured using a Teflon catheter (18 gauge, 1.35 mm) connected to a pressure transducer (Maxxim Medical, Athens, TX, USA) placed in the femoral artery of the exercising leg. A second Teflon catheter was inserted into the femoral vein of the same three subjects used for arterial blood sampling for whole leg venous blood samples. In one subject, arterial blood pressure was obtained using finger-cuff photoplethysmography (Finapres, Ohmeda 2300) on the middle finger of the right hand and calibrated to match the diastolic blood pressure achieved from brachial auscultation. Subjects were fitted with a malleable lead neck collar for the application of NP/NS. Carotid baroreflex function was assessed at rest and during one-legged knee extension exercise after steady-state haemodynamic conditions had been achieved (5 min) as previously described by Potts et al. (1993).
Leg blood flow
Leg blood flow (LBF) was determined using pulsed Doppler ultrasound velocimetry using the product of the femoral artery mean blood velocity and diameter. Femoral blood velocity (FBV) was obtained using a Doppler unit (model MD6, D. E. Hokanson, Inc., Bellevue, WA, USA) with a bidirectional probe operating at a frequency of 5 MHz and calculated using the formula V
=
fa/(64.9cosØ), were fa is the audio frequency, Ø is the angle of insonation and V is the blood velocity in centimetres per second. The Doppler probe was placed on the skin over the common femoral artery distal to the inguinal ligament. The angle of the transducer crystal relative to the skin was 60 deg. Femoral artery diameter was measured using a 2.5 MHz probe (model RT 6800, GE) at a site matching that at which velocity was measured. Average femoral artery diameters were determined at the beginning and end of the rest period. Furthermore, diameters were measured at the 5th, 15th and 25th minute of the exercise trials in EL and NEL. The application of NP at rest and during exercise, with and without glyburide, did not alter femoral artery diameter. All ultrasound data of femoral arterial diameters were recorded onto VHS tape and further analysed using custom software. The femoral artery radius was determined for each subject at each condition using the formula: radius = diameter/2. All resting FBV and resting femoral artery diameter data were measured from one leg of each of the subjects (i.e. right, or left) before any exercise trials were performed. Femoral artery diameter was not changed in response to 5 s pulses of NP and the following formula was used to calculate LBF:LBF =
x radius2
x FBV. The average LBF was determined as the average prestimulus LBF at rest (NP/NS) and during exercise (NP). The order of the LBF measures for the EL and NEL was randomized between exercise trials.
Carotid baroreflex responsiveness
Carotid baroreflex control of MAP was assessed only at rest by applying single 5 s pulses of NP and NS (NP/NS) ranging from (+40 to –80 Torr) as described by Potts et al. (1993). Under resting conditions, NP/NS was applied during a 10–15 s breath hold at end-expiration, in order to minimize the respiratory modulation of HR and mean arterial pressure (MAP). A minimum of 45 s was allowed to pass between each NP/NS trial to allow physiological variables to return to prestimulus values. Peak responses for MAP were determined as the greatest change over a 4 s period of time that occurred from the application of NP/NS and compared to an average MAP for the 4 s immediately preceding the NP/NS stimulus. The responses for each trial were averaged to provide a mean response for each subject. Changes in FBV were determined during the 4 s at which the peak MAP response occurred. An average FBV over the 4 s interval was used to assess peak FBV changes for each trial compared to an average FBV for the 4 s immediately preceding the NP/NS stimulus. Blood velocity signals were maintained throughout the entire contraction and relaxation phases.
During exercise, only trials of NP of +40 Torr were applied in an effort to maximize the number of trials of NP applied during exercise, and was done so without the presence of a breath hold. Approximately 8–10 trials of NP were applied during each exercise trial. A 4 s interval was chosen in an effort to minimize the effect of kicking frequency, and therefore the contraction relative to the relaxation phase (30 kpm, 2 s kicking cycle). These changes were then averaged to provide a mean response for each NP (+40 Torr) for each subject. LVC was calculated using the following formula: LVC = LBF/MAP. Percentage changes in LVC were determined using the following formula: %LVC = [(LVCpeak – LVCprestim)/LVCprestim] x 100.
Data analyses
Stimulus–response curves for CBR control of MAP were fitted for individual subjects to a four-parameter logistic function described by Kent et al. (1972), using the following equation: MAP = A1{1 + exp[A2(ECSP – A3]} – 1 + A4. A1 is the MAP response range (maximum – minimum), A2 is the gain coefficient, A3 is the centring point (estimated carotid sinus pressure (ECSP) required to elicit equal pressor and depressor responses) and A4 is the minimum MAP response. The individual data were fitted to this model by non-linear least-squares regression which minimized the sum-of-squares error to predict a curve of ‘best fit’ for each data set. The gain of the CBR–MAP stimulus–response curve was derived from the first derivative of the logistic function of Kent et al. (1972), and the maximal gain (Gmax) was calculated as the gain at the centring point (A3). The threshold (i.e. point where no further increase in MAP occurred, despite reductions in ECSP), as well as the saturation (i.e. point where no further decrease in MAP occurred, despite increases in ECSP) were also determined. All parameters were averaged and presented as group means. We chose not to use the logistic model of Kent et al. (1972) to generate function curves for CBR control of LVC due to the limitations observed with muscle sympathetic nerve activity (Fadel et al. 2001).
Statistical analyses
Comparisons of physiological variables, CBR–MAP stimulus–response parameters and CBR–LVC reflex sensitivity between rest and exercise were made using paired t tests. Based on our power calculation from pilot data, we a priori expected a significant effect of glyburide administration on baroreflex-induced percentage changes in LVC of the exercising leg with an n
4. This a priori expectation was tested using paired t tests with significance set at P < 0.05 following a two-way analysis of variance used to determine significant differences in CBR–%LVC values between rest, non-exercising leg and exercising leg, with and without glyburide. Statistical significance was set at P < 0.05. Values are means ±
S.E.M.
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Results |
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Glyburide administration did not alter resting HR, MAP, LBF or LVC (Table 1). Furthermore, oral glyburide administration did not alter HR, LBF or LVC during one-legged knee extension exercise at 7 W (Table 1). MAP at rest was not different after glyburide administration, while MAP during control exercise was similar to rest (P > 0.05). MAP during exercise after glyburide ingestion appeared to be increased (P = 0.053).
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The calculated parameters of the CBR–MAP reflex function curve at rest are presented in Table 3. At rest, CBR stimulus–response curves for MAP were unaffected by glyburide administration (Fig. 1), except for a significant decrease in the centering point pressure (90 ± 6 mmHg) compared to a control value of 95 ± 5 mmHg, P < 0.05). Furthermore, the MAP response to NP (+40 Torr) during exercise was no different with glyburide (8 ± 1 mmHg) compared to control exercise (8 ± 1 mmHg), P > 0.05.
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The CBR-mediated changes in LVC expressed as a percentage change from baseline are presented in Fig. 2. At rest, the application of +40 Torr NP resulted in a decrease in LVC (39 ± 3%). During one-legged knee extension exercise, the application of +40 Torr NP decreased LVC in both the exercising leg (15 ± 2%) and non-exercising leg (40 ± 6%). The decrease in percentage LVC in the exercising leg (15%) was significantly less than at rest (39%, P < 0.05). Furthermore, the percentage decrease in LVC in the exercising leg after glyburide (25 ± 4%) was significantly greater than control exercise (15 ± 2%, P < 0.05) and represented a 40% reinstatement of vasoconstriction.
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Discussion |
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Thomas et al. (1997), using lumbar sympathetic stimulation, demonstrated the importance of KATP channel activity in causing functional sympatholysis in rats. To our knowledge, the data of the present investigation is the first to demonstrate a role of KATP channel activity in modulating functional sympatholysis in humans. Similar to Thomas et al. (1997), and using lumbar sympathetic stimulation, the findings of the current investigation using CBR-mediated increases in muscle sympathetic nerve activity (MSNA), demonstrated an attenuation of sympathetic vasoconstriction in the vasculature supplying exercising skeletal muscle. Data from the present investigation identified a clear attenuation of CBR-mediated decreases in LVC (% change) at very low exercise workloads (7 W). Recently, it has been demonstrated in both dogs (Buckwalter et al. 2001) and humans (Wray et al. 2004b), that functional sympatholysis occurs at low workloads and that 2-adrenergic receptors were susceptible to sympatholysis at lower workloads than 1-adrenergic receptors. This may be especially important when considering baroreflex control of vascular tone in that, presumably, there may be a shift in the relative contribution of -adrenergic receptor subtypes to changes in vasomotor tone between rest and exercise at increasing exercise intensities. While there is a clear diminution of vascular responsiveness, as indicated by a percentage change in LVC in the exercising leg compared to rest, CBR control of the leg vasculature remains functional (Keller et al. 2004; Wray et al. 2004a). This attenuation in CBR control of the vasculature supplying exercising skeletal muscle occurs despite obvious preservation of arterial blood pressure control during exercise. Ogoh et al. (2003) demonstrated the importance of CBR-mediated changes in total vascular conductance as the sole contributor to changes in arterial blood pressure during cycling at an exercise intensity equivalent to a heart rate of 90 beats min–1. Furthermore, Collins et al. (2001) demonstrated an increased contribution of changes in hindlimb vascular conductance to baroreflex-mediated (bilateral carotid occlusion) changes in total vascular conductance. Collectively, these findings demonstrate a delicate balance between the effects of functional sympatholysis and baroreflex control of the vasculature in regulating arterial blood pressure.
The effect of KATP channel inhibition on reactive hyperaemic responses in the forearm has produced variable findings. Banitt et al. (1996) demonstrated a reduction in the total hyperaemic volume in the forearm with cuff occlusion release after local infusion of tolbutamide (KATP channel inhibitor) into the brachial artery. In contrast, Farouque & Meredith (2003) demonstrated that KATP channel inhibition with glibenclamide lyophilisate did not alter hyperaemia during recovery from wrist flexion/extension exercise. However, the comparison of findings between the arm and the leg, as well as vascular responses to hyperaemia or sympathetic activation must be made with caution. In the current investigation, an oral dose of glyburide (5 mg) enhanced baroreflex-mediated vasoconstriction in EL as indicated by a 40% increase in the leg vasoconstrictor response to 5 s pulses of NP (hypotensive stimuli) compared to control exercise. There are several possible explanations for the remaining 60% effect of sympatholysis. First, and possibly the major factor, is that the oral dose used in the current investigation (5 mg) did not completely inhibit all vascular smooth muscle KATP channel activity. Therefore, the effect of KATP activation on functional sympatholysis was only partially prevented, while the remaining KATP channel activation prevented complete expression of baroreflex vasoconstriction observed at rest. However, as the population studied in this investigation were young, healthy adults, increases in the oral dosage may have further complicated experimental side-effects by exaggerating the insulin response to the drug and resulting in clinically significant hypoglycaemia. A second possible explanation for the remaining 60% attenuation is that the pathways involved in functional sympatholysis are not limited to the KATP channel. While the data from this investigation, similar to the work by Thomas et al. (1997) indicate an important role of KATP activation in contributing to functional sympatholysis, the vasoconstictor response was not completely restored in either investigation. It is therefore possible that other mechanisms, along with KATP channel activation, result in attenuated -adrenergic vasoconstriction during muscle contraction. Rosenmeier et al. (2004) recently demonstrated that vasodilatation induced by femoral artery infusion of ATP increased resting leg blood flow, as well as eliminating the vasoconstrictor response to tyramine infusion. While the findings of Rosenmeier et al. do not directly support the role of the KATP channel addressed in the current investigation, they do indicate a potentially interesting role for ATP in modulating skeletal muscle blood flow during exercise. A third, less likely explanation, is that increased flow in and of itself is partially responsible for the attenuated vasoconstrictor response during muscle contraction. Although Tschakovsky et al. (2002) convincingly demonstrated that dilatation with both adenosine and sodium nitroprusside at rest resulted in no sympatholysis, it is possible that the mechanical and physical consequences of skeletal muscle contraction in conjunction with increased flow results in altered vascular responsiveness.
In the current investigation, baroreflex control of NEL was also determined and indicates that CBR control of the vasculature supplying NEL was unchanged by both the exercise and glyburide administration. It has been suggested that KATP channel inhibition at rest does not effectively augment sympathetically mediated vasoconstriction, due to the low probability of KATP channel activation in vascular smooth muscle supplying resting skeletal muscle (Thomas et al. 1997). Although KATP channel activity is likely enhanced during muscle contraction, it remains possible that KATP channel activity in the vasculature supplying skeletal muscle at rest and in the NEL varies across species and within a given population.
Unique to the one-legged knee extension exercise model is the ability to determine steady-state haemodynamics, as well as baroreflex control of the vasculature supplying the NEL. This determination potentially allows for more unique interpretation of the data in the current investigation regarding CBR control of arterial blood pressure in humans. Keller et al. (2003) had previously suggested that with functional sympatholysis, the vascular responses in the NEL may serve as a more appropriate control compared to rest in that the comparison of the EL to the NEL accounts for potential non-specific effects of the exercise on functional sympatholysis that are not related to muscle contraction (i.e. hormonal, temperature-related, etc.). In this study, there was no significant increase in LVC in the NEL during 7 W exercise. Green et al. (2002) demonstrated that brachial artery blood flow of an inactive forearm was reduced during low workload leg cycling and reported an increase in the retrograde flow in the brachial artery during exercise with little to no change in anterograde flow. These findings suggested that the decrease in total flow was the result of either increased downstream resistance, or of a ‘stealing’ phenomenon during exercise (Green et al. 2002). However, based upon the flow recordings observed in the present investigation, we suggest that the lack of an increase in flow in the NEL during exercise is the result of increased retrograde flow during diastole. Nonetheless, the CBR control of LVC was not altered during exercise compared to rest (see Figs 2 and 3).
Potential limitations
The primary limitation of the current investigation pertains to the use of oral glyburide as the KATP channel inhibitor. As with many orally ingested drugs, the actual delivery of the drug to the site of interest (i.e. the EL's vascular smooth muscle) is subject to a number of influences (i.e. digestion, blood volume, etc.). Furthermore, we did not challenge the effect of KATP channel inhibition of the vascular smooth muscle in this investigation with a KATP channel agonist, such as diazoxide, and therefore, have no direct indication of the degree of channel inhibition. However, the 5 mg dosage used in this investigation resulted in clear reproducible decreases in blood glucose within subjects. While the relationship between KATP channel inhibition at the pancreas and peripheral smooth muscle have not been examined, ensuing hypoglycaemia, as well as modulated CBR-mediated vasoconstriction in the EL, indicate that some significant inhibition had occurred at this dosage.
Another limitation with regard to the usage of oral glyburide is the possible confounding effects of insulin on vascular responsiveness. It is possible that elevated blood insulin, resulting from KATP channel inhibition at the pancreas from the drug, or in response to the food given to the subjects during the study, may modulate the vascular response to sympathetically mediated vasoconstriction. Although data collection on experimental day 2 (glyburide) was performed 2–4 h after ingestion of the drug and a meal, it remains possible that the consumption of the meal alone, and the resulting changes in insulin, may alter the cardiovascular responses investigated. However, a body of evidence exists suggesting that insulin blunts sympathetic vasoconstriction (Lembo et al. 1994; Clark et al. 2003). Nonetheless, if insulin is contributing to an attenuated vasoconstriction after glyburide administration, the effect of KATP channel inhibition on restoring sympathetically mediated vasoconstriction in the EL was apparent. However, it is unlikely that insulin confounded the findings of the present investigation in that there was no difference in the vasoconstriction at rest or in the NEL before and after glyburide administration.
One methodological limitation involves the lack of our ability, using Doppler ultrasound measures of leg blood flow, to distinguish the supply of other tissue in the leg (i.e. skin, bone, inactive skeletal muscle, etc.). It is unclear how changes in vascular responsiveness of the skin during exercise contributes, if at all, to the measured effects of functional sympatholysis. It has been previously demonstrated that the skin vasoconstrictor response to noradrenaline (norepinephrine) is reduced with whole body heating (Wilson et al. 2002). However, the roles that skin blood flow and whole body or limb temperature play in the effect of functional sympatholysis in this experimental protocol remain unknown. We suggest that the modulation of CBR-mediated changes in LVC during exercise originates in the active skeletal muscle due to a lack of evidence for CBR control of skin sympathetic nerve activity (Wilson et al. 2001).
In summary, the findings of the current investigation demonstrate that KATP channel activity is important in modulating baroreflex-mediated vasoconstriction in the vasculature supplying exercising skeletal muscle in humans. The data suggest that KATP channel activation is an underlying mechanisms by which functional sympatholysis occurs in humans during exercise and partial blockade of the KATP channel results in a moderate restoration of the sympathetically mediated vasoconstriction in the exercising leg. Furthermore, KATP channel inhibition with glyburide did not alter CBR control of MAP at rest. These findings are important in the understanding of skeletal muscle blood flow control during exercise in healthy individuals, and potentially provide a clinically relevant baseline response by which the treatment of Type II diabetic patients can be evaluated.
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Author's present address
D. M. Keller: Institute for Exercise and Environmental Medicine at Presbyterian Hospital of Dallas, 7232 Greenville Ave, Dallas, TX 75231, USA.
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Significantly different from control, P < 0.05.