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Integrative |
1 School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
2 Department of Integrative Physiology, University of North Texas Health Science Center at Fort Worth, TX 76107, USA
3 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
4 Copenhagen Muscle Research Center, Department of Anaesthesia, Rigshospitalet, University of Copenhagen, DK-2100, Copenhagen, Denmark
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Abstract |
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(Received 6 December 2005;
accepted after revision 28 February 2006;
first published online 2 March 2006)
Corresponding author J. Fisher: School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. Email: j.p.fisher{at}bham.ac.uk
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Introduction |
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25% of the CBR-mediated blood pressure response, suggesting that alterations in vasomotion are the primary means by which the CBR regulates blood pressure at rest in man (Ogoh et al. 2003). During light to moderate dynamic exercise the contribution of cardiac output to the CBR-mediated modulation of blood pressure response is reduced even further (Ogoh et al. 2003), suggesting that the CBR relies solely on alterations in vasomotion for the regulation of blood pressure as exercise intensity increases. This could be explained by progressively decreasing cardiac parasympathetic tone during incremental exercise (Robinson et al. 1966), caused by inhibition of parasympathetic motorneurones due to increasing central command (Mitchell et al. 1989) and muscle mechanoreflex activation (Gladwell & Coote, 2002; Gladwell et al. 2005). Indeed, Ogoh et al. (2005) demonstrated the primary importance of parasympathetic withdrawal on the control of HR and the resetting of the CBR-HR relationship during dynamic exercise, which occurred irrespective of the level of sympathetic activation. Similarly in isometric exercise, cardiac parasympathetic tone will be decreased (Freychuss, 1970; Martin et al. 1974; Maciel et al. 1987) due to the actions of central command (Mitchell et al. 1989) and the muscle mechanoreceptors (Gladwell & Coote, 2002; Gladwell et al. 2005) but the relative contributions of these inhibitory inputs are likely to differ from dynamic exercise.
A fundamental difference between static and dynamic exercise is that during light to moderate dynamic exercise adequate muscle perfusion limits the degree of metabolite accumulation within the muscles whereas during isometric exercise blood flow can be occluded even at low exercise intensities (e.g. 20% of maximal voluntary contraction (MVC)) (Barcroft & Millen, 1939). This is primarily a consequence of the mechanical compression of isometric exercise, which restricts muscle blood flow relative to the metabolic requirements of the exercise causing an accumulation of metabolites within the muscle and activation of the muscle metaboreflex (Mark et al. 1985; Victor et al. 1988; Sinoway et al. 1989). Thus, there are profound increases in vasoconstrictor sympathetic nerve activity during even low intensity isometric exercise (Mark et al. 1985; Victor et al. 1988) leading to increased peripheral resistance and blood pressure (Lind et al. 1964). As such, the ability of the CBR to modulate vasomotor tone might be more difficult during isometric exercise. Thus, it remains unclear whether the same reliance on vasomotor tone occurs during isometric exercise as had been found in dynamic exercise (Ogoh et al. 2003).
The primary aim of this investigation was to determine the importance of cardiac and vasomotor components of the CBR control of blood pressure during low intensity isometric exercise. To achieve this, rapid pulses of neck pressure (NP) and neck suction (NS) were assessed at rest and during isometric exercise. In addition, to separate the role of the cardiac limb of the CBR from that of the vasomotor limb in blood pressure regulation, control experiments were compared with those carried out under pharmacological blockade of the cardiac parasympathetic or sympathetic nervous systems. It was hypothesized that if the carotid-vasomotor response was the predominant mechanism by which blood pressure is regulated during isometric exercise, then these autonomic blockades would have minimal effect on CBR regulation of blood pressure.
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Methods |
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Measurements
The exercise modality employed in the present study was isometric calf exercise. The force produced by the calf plantar flexors was measured according to the methods described by Fisher & White (2003). The subjects were seated in a semirecumbent position on a hospital bed that was modified to allow the subject to perform isometric calf exercise. The thigh of the right leg was horizontal whilst the lower limb was in a dependent position with the ankle flexed at 85 deg (1.46 rad). A curved metal plate was clamped proximal to the knee joint preventing heel lift during contraction. The upward force generated by the triceps surae was amplified, interfaced with a personal computer and stored for off-line analysis.
Arterial blood pressure was measured by a catheter (1.1 mm ID, 20 gauge) placed in the brachial artery of the non-dominant arm and connected to a transducer (Baxter, Uden, the Netherlands) positioned at the level of the right atrium in the midaxillary line. A venous catheter (1.2 mm i.d., 18 gauge) was inserted into the subject's median antecubital vein for the administrations of metoprolol and glycopyrrolate. The HR and R-R interval (RRI) were monitored using a lead II electrocardiogram (ECG). The signals were connected to a Dialogue 2000 monitor (IBC-Danica, Copenhagen, Denmark) interfaced with a personal computer equipped with customized data acquisition software for the beat-to-beat recording of variables. Both ECG signal and arterial pressure waveforms were sampled at 200 Hz, and real time beat-to-beat values of HR, systolic blood pressure (SBP), MAP and diastolic blood pressure (DBP) were calculated and stored for off-line analysis. MAP was calculated as the time integral over the pressure pulse. Phase of respiration was monitored using a custom built strain gauge attached to a band and placed around the subject's chest.
Stroke volume was calculated off-line from the blood pressure waveform using a Modelflow software program incorporating the BeatScope version 1.0 software (TNO-TPD, Biomedical Instrumentation, Amsterdam, the Netherlands) (Wesseling et al. 1993). This methodology has been shown to reliably estimate rapid changes in cardiac output during a variety of experimental protocols (Jansen et al. 1990; Gratz et al. 1992; Stok et al. 1993), including those eliciting changes in HR similar to those observed in the present study (Sugawara et al. 2003) and during isometric exercise (Takahashi et al. 2004). Cardiac output (CO) was calculated from the product of SV and HR, and total peripheral resistance (TPR) was the beat-to-beat ratio of MAP to CO (TPR = MAP/CO).
Experimental protocol
On experimental days subjects arrived at the laboratory at least 2 h following a light meal. The subjects were positioned in the leg dynamometer and instrumented for the measurement of blood pressure and HR. The maximum voluntary contraction (MVC) of the calf plantar flexors was assessed by taking the highest force produced in three maximal efforts.
Following a 5-min resting baseline, a cuff (18 cm wide) was then inflated around the thigh of the right leg to 200 mmHg. Sixty seconds later subjects were instructed to contract their calf muscles to elicit a force equivalent to 20% MVC, which was displayed on a computer screen directly in front of them. At rest and during exercise CBR-HR and CBR-MAP function curves were determined using the rapid pulse train method (Potts et al. 1993; Gallagher et al. 2001). Computer controlled pressure stimuli were applied through a cushioned malleable lead collar that was placed around the anterior two-thirds of the neck. Each rapid pulse train was composed of 12 consecutive pulses of 500 ms duration and ranged from +40 to –80 mmHg (in the order of 40, 40, 40, 40, 20, 10, 0, –10, –20, –40, –60, –80). After the delivery of each pressure pulse the neck chamber was vented to atmospheric pressure. Each pulse was delivered 50 ms after the initiation of the R wave of the ECG, such that the artificially generated pressure coincided with the arterial pressure wave at the carotid sinus. The NP and NS pulse train was applied during a 10–15 s end-expiratory breath hold to minimize the effects of respiratory sinus arrhythmia (Eckberg, 1976). Two trials of NP and NS were performed, separated by a period of 30–45 s. After 4 min of exercise subjects were instructed to stop contracting their calf muscles. Fifteen minutes later the protocol was repeated.
After a rest period (30–40 min), the calf MVC was reassessed before ß1-adrenergic blockade was achieved. Metoprolol was administered in step-wise infusions of 1 mg. An unchanged HR to consecutive 1 mg doses of metoprolol was used to determine full blockade of ß1-receptors (group average dose of 0.15 ± 0.003 mg kg–1). Following ß1 blockade the protocol was conducted twice, with trials separated by a 15 min rest period.
Three to seven days later, subjects came to the laboratory and repeated the protocols with muscarinic cholinergic blockade. On this second visit subjects did not perform the control and ß1-adrenergic blockade protocols. After being instrumented, glycopyrrolate was administered to achieve full cardiac vagal blockade. Glycopyrrolate was infused in 0.2 mg steps until HR was unchanged to consecutive doses of glycopyrrolate (13.6 ± 1.5 µg kg–1). Following complete cardiac vagal blockade the protocol was conducted twice, with trials separated by a 15 min rest period.
Between trials during the ß1-adrenergic blockade and vagal blockade conditions if HR was changed from resting baseline values additional doses of metoprolol (0.013 ± 0.002 mg kg–1) or glycopyrrolate (3.2 ± 0.3 µg kg–1) were administered until no further change in HR occurred. This procedure maintained the initial baseline HR, identified as complete adrenergic or cholinergic blockade. Furthermore, complete parasympathetic blockade was confirmed by the absence of peak changes in HR (within 2–3 s) during NP and NS (Potts & Raven, 1995; Ogoh et al. 2005) in the presence of the highest dose of glycopyrrolate. Although it is possible that administration of glycopyrrolate had peripheral effects on the vasculature, we feel that this is unlikely as there is little evidence for cholinergic innervation of human muscle (Bolme & Fuxe, 1970).
A methodological consideration of the CBR protocol is that the rapid train NP and NS technique cannot be used when the HR exceeds 120 beats min–1. However, even though this HR was approached in the glycopyrrolate condition of the present study it was not exceeded. The alternative approach would be to construct the full baroreflex function curve using 5 s presentations of positive or negative pressure; however, this requires approximately 20 min of steady-state data and therefore is difficult to use during isometric exercise.
CBR function
The CBR-HR and CBR-MAP responses were evaluated by plotting the nine-beat HR and MAP responses that best represented the peak reflex response range, respectively, against estimated carotid sinus pressure (ECSP), which was calculated as MAP minus neck chamber pressure. CBR stimulus–response data were individually fitted for each subject to the logistic model described by Kent et al. (1972). This function incorporates the following equation:
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No correction was made for the transmission of external neck pressure to the carotid sinus tissue as it has been demonstrated that the correction of internal transmission resulted in minimal and non-significant changes in the calculated carotid baroreflex parameters (Querry et al. 2001). Furthermore, the transmission of external neck pressure to the carotid sinus tissue is similar between rest and exercise (Querry et al. 2001).
Several characteristic parameters are derived from the model; firstly the gain of the stimulus–response curve was calculated from the first derivative of the Kent logistic function and the maximal gain (Gmax) was applied as the index of carotid baroreflex responsiveness. In addition, threshold (THR), defined as the point where no further increase in the dependent variable occurred despite reductions in ECSP, and saturation (SAT), defined as the point where no further decrease in the dependent variable occurred despite increases in ECSP, were calculated as the maximum and minimum second derivatives, respectively, of the logistic function curve. For calculation of THR and SAT, we applied equations described by Chen & Chang (1991):
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These calculations of THR and SAT are the carotid sinus pressure at which HR is within 5% of their maximal or minimal responses (Potts et al. 1993). Also, the maximal gain (Gmax) of CBR function curve was calculated as follows:
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Following glycopyrrolate administration, the CBR-HR responses to NP and NS were evaluated by linear regression because the changes were small and did not conform to Kent logistic modelling (Ogoh et al. 2005). Under these conditions, the slope of the linear regression was interpreted as the maximal gain of the CBR-HR stimulus–response relationship.
Statistical analysis
Cardiovascular parameters are reported for the 5 min resting period and the 4th minute of exercise. Statistical comparisons of physiological variables were made using a repeated-measures two-way analyses of variance (ANOVA) test and a Student-Newman-Keuls test was employed post hoc to investigate main effects. The effect of NP and NS on SV was assessed using a three-way ANOVA (drug x experimental phase x beat). Statistical significance was set at P < 0.05. Results are presented as means ± standard error of the mean (S.E.M.). Analyses were conducted using SigmaStat (SPSS Inc., Chicago, IL, USA) for Windows.
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Results |
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Glycopyrrolate increased and metoprolol decreased resting HR (P < 0.001), whilst resting MAP was not affected. Exercise increased HR in all conditions, but this tachycardia was attenuated following glycopyrrolate (Table 1). Drug administration did not affect the increase in MAP produced during exercise (P < 0.05). At rest, metoprolol decreased CO (–12 ± 2%) while glycopyrrolate increased CO (29 ± 7%). However, the CO response to exercise was small (5 ± 3%, P > 0.05) and unaffected by drug administration. Overall resting TPR was higher with metoprolol (15 ± 3%) than under control conditions and lower with glycopyrrolate (–18 ± 6%). However, the increase in TPR produced during exercise was similar in all conditions (17 ± 2, 17 ± 1 and 15 ± 3%, for the control, metoprolol and glycopyrrolate conditions, respectively). Resting SV was not different from control conditions under metoprolol, but decreased under glycopyrrolate conditions (–24 ± 3%). Overall SV was decreased during exercise (P < 0.001), though this decrease was not significant in the glycopyrrolate condition (–15 ± 2, –14 ± 1 and –5 ± 2%, for the control, metoprolol and glycopyrrolate conditions, respectively). Application of NP and NS produced a slight but significant increase in SV (6 ± 1%) over the nine beats used to construct the modelled CBR-HR function curve. However, this change was not altered by drug administration (P > 0.05) and there was no difference between the responses at rest or during exercise (P > 0.05). The changes in CO to NP and NS at rest were 4 ± 2% and –14 ± 2%, respectively, and 3 ± 2% (P > 0.05) and –10 ± 1% (P < 0.05) during exercise, under both the control and metoprolol conditions. More importantly, these minimal changes in CO to NP and NS were completely eliminated by glycopyrrolate administration both at rest (0.7 ± 1% and 0.3 ± 1%; P < 0.05) and during exercise (2 ± 2% and 1 ± 1%; P < 0.05).
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In the control condition isometric exercise produced an upward and rightward shift of the CBR-HR and CBR-MAP function curves, with no change in maximal gain (Tables 2-5 and Figs 1A and 2A).
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Discussion |
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Ogoh et al. (2003) have shown that at rest changes in CO only account for 25% of the CBR-mediated blood pressure response and that during mild to moderate dynamic exercise this contribution is reduced even further. This suggests that alterations in vasomotion are the primary means by which the CBR regulates blood pressure at rest, and that the reliance of the CBR on vasomotion for the regulation of blood pressure increases during dynamic exercise (Ogoh et al. 2003). In the present study, we investigated whether the vasomotor control of blood pressure is compromised during isometric exercise in which marked increases in sympathetic vasoconstrictor drive (Mark et al. 1985; Victor et al. 1988), TPR (Table 1), and blood pressure occur even at low exercise intensities (Lind et al. 1964). Our results demonstrate that blood pressure modulation by the CBR is well maintained during isometric exercise as previously reported (Ebert, 1986; Spaak et al. 1998; Gallagher et al. 2001). More importantly though, when CBR-mediated changes in HR were eliminated with parasympathetic blockade, we demonstrated that CBR control of blood pressure was unaltered at rest and during isometric exercise. We therefore propose that similarly to dynamic exercise blood pressure modulation by the CBR is primarily mediated by alterations in vasomotor tone during isometric exercise.
A point of consideration is that during both dynamic (Robinson et al. 1966) and isometric (Freychuss, 1970; Martin et al. 1974; Maciel et al. 1987) exercise, inhibition of cardiac parasympathetic motorneurones occurs due to activation of both central command (Mitchell et al. 1989) and the muscle mechanoreflex (Gladwell & Coote, 2002; Gladwell et al. 2005). In dynamic exercise, this mechanism may explain the decreased reliance on cardiac output for the CBR regulation of blood pressure (Ogoh et al. 2003). However, it was not known if this explanation was true of isometric exercise as the relative contributions of these inhibitory inputs are likely to differ in isometric and dynamic exercise. This is by virtue of the force–velocity relationship of muscle and the changes in motor unit recruitment thresholds seen during contractions of increasing velocity (Freund, 1983). Therefore, the amount of parasympathetic modulation of HR, and hence blood pressure, might be very different during isometric and dynamic exercise. As such it would be improper to predict CBR-HR modulation of blood pressure during static exercise from studies that have used dynamic exercise.
Previous studies that have observed the effects of parasympathetic blockade on the blood pressure response to hypotensive and hypertensive challenges have produced conflicting results. Thames & Kontos (1970) reported that following atropine administration, the HR response was attenuated to nitroglycerin-induced hypotension and phenylephrine-induced hypertension, whereas the blood pressure response was exaggerated. More recently, Wray et al. (2001) found that the blood pressure response to phenylephrine injection and the hypotensive response to bilateral thigh cuff deflation after circulatory occlusion were augmented following vagal blockade. The reason for the conflict between these results and those of the present study remains unclear but may be a consequence of the protocols employed. Administering vasoactive drugs or generating vasoactive substances in order to provide a baroreceptor challenge may inadvertently impair the ability of the vasculature to respond to haemodynamic challenges. For example, the augmented fall of blood pressure in response to thigh cuff release with parasympathetic blockade could indeed be explained by a failure to increase cardiac output (Wray et al. 2001). However, this failure could be combined with an inability of the vasculature to respond appropriately to increased sympathetic nerve activity because of accumulation of vasoactive substances in the legs from circulatory occlusion. Metabolic inhibition of 
-adrenergic receptors could therefore be an alternative explanation for the exaggerated hypotensive response observed.
Similar to the findings of the present study, Ernsting & Parry (1957), Bjurstedt et al. (1975) and Tyden (1977) reported that following atropine administration, the HR response to NP or NS was attenuated; however, the MAP response was unaffected. Moreover, Eckberg et al. (1972) demonstrated that the decrease in blood pressure elicited by carotid sinus nerve stimulation was not altered significantly by adrenergic or parasympathetic blockade of the heart. Taken together these findings suggest that a cardiac parasympathetic mechanism is not critical to carotid sinus buffering of blood pressure at rest. The findings from the current study are in agreement and extend these findings to include CBR control during isometric exercise.
In the present study isometric calf exercise was performed ischaemically by inflation of a thigh cuff prior to contractions. Although calf exercise at 20% MVC is sufficient to occlude the circulation (Barcroft & Millen, 1939) this may vary with the strength of the subject (Barnes, 1980). Therefore, to remove the possibility for disparities in flow to the exercising muscle between subjects, which would affect the magnitude of the pressor responses elicited (Alam & Smirk, 1937), exercise was performed ischaemically.
We observed a small increase in SV during the rapid train of neck pressures, which seemingly differs from the observations of Ogoh et al. (2002, 2003) and Levine et al. (1990). However we believe this disparity can be explained by the longer duration of HR fall produced by the train of neck pressure changes we used compared to a single 5 s pulse (Ogoh et al. 2002, 2003). The transient HR change produced by a 5-s pulse probably does not allow full expression of the effects of reduced HR on filling time and hence SV. Also, Levine et al. (1990) applied a train of neck pressure changes to subjects who were in the supine position, and thus the transient effects of HR change would have been superimposed upon an already augmented SV, due to optimal conditions for venous return, leaving little opportunity for further increases in SV via the CBR.
The small changes in cardiac output seen in response to NP and NS during control and metoprolol were eliminated when the HR response to NP and NS were markedly attenuated by glycopyrrolate administration. However, despite this complete elimination of any changes in CO to NP and NS with parasympathetic blockade, the CBR-mediated BP responses were unaffected. We reasoned that if CO were contributing significantly to the CBR-mediated MAP response, one would expect that removal of this response with parasympathetic blockade would alter the CBR-mediated change in MAP. Since this did not happen these data strongly suggest that the regulation of blood pressure by the CBR depends critically on the ability to alter total vascular resistance both at rest and during isometric exercise, thus supporting previous findings at rest (Ogoh et al. 2002) and during dynamic exercise (Ogoh et al. 2003). However, caution should be taken in extrapolating these findings to higher intensities of isometric exercise.
We assessed carotid baroreflex function using HR rather than R-R interval as the non-linear relationship between these variables would mean that when the heart rate is elevated (e.g. during exercise or parasympathetic blockade), the chronotropic responses to NP and NS will be less in comparison to rest when expressed as R-R interval (O'Leary, 1996; Fadel et al. 2003). As such, use of R-R interval can lead to overestimations in calculations of the change in baroreflex sensitivity, especially from rest to mild exercise (Ogoh et al. 2005). Therefore, it has been recommended that carotid-cardiac responses should be assessed in terms of HR when comparing conditions with different basal heart rates (Fadel et al. 2003).
It is important to consider the limitations of our study design. First, because of the limited ability of subjects to sustain the isometric contraction we had to use the rapid pulse train method to assess CBR control rather than using multiple 5 s pulses of neck pressure and neck suction. Thus, the calculation of vascular resistance and cardiac output are based on the assumption that Ohm's law holds true under these non-steady state conditions. While not ideal, this approach was necessary given the inherent limitations in the design of such human studies. More importantly, our conclusions in regards to CBR control of CO and TPR using the rapid pulse trains at rest are similar to other studies using the more optimal 5 s pulses of neck pressure and neck suction (Ogoh et al. 2002, 2003).
Another consideration is the underlying autonomic mechanisms mediating the CBR chronotropic responses (Coleman, 1980). While the parasympathetic nervous system predominates in the chronotropic response to rapid perturbations in blood pressure, the sympathetic nervous system has a slightly longer response latency (Warner & Cox, 1962). Therefore, with a longer-term change in carotid sinus transmural pressure a greater role for the sympathetic nervous system in the CBR-mediated HR response might be elucidated. This may also be true for the adrenergic control of vascular resistance by the CBR.
Finally, we recognize that our conclusion that blood pressure regulation is dependent on the ability to alter total vascular resistance both at rest and during isometric exercise is indirect as no blockade of vasomotor control was used. However, the combination of our findings with previous studies performed at rest and during dynamic exercise (Ogoh et al. 2002, 2003) strongly indicates that alterations in vasomotion are the primary means by which the CBR controls blood pressure. Nevertheless, it is plausible that changes in cardiac output may take on greater importance if the ability of the CBR to alter vascular resistance is blocked. This would not be unexpected given the potential for redundant control mechanisms (Freychuss, 1970; Martin et al. 1974; Maciel et al. 1987). Further experiments are necessary to investigate this possibility.
The results of this study demonstrate that despite marked reductions in CBR control of HR following parasympathetic blockade, the CBR control of blood pressure was well maintained. We therefore suggest that the primary mechanism by which the CBR modulates blood pressure during low intensity isometric exercise is an alteration of vasomotor tone.
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Author's present address
J. Fisher: Department of Medical Pharmacology and Physiology, One Hospital Drive MA415, University of Missouri – Columbia, MO 65212, USA.
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