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INTEGRATIVE |
1 Penn State Heart and Vascular Institute, Hershey, PA 17033, USA
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Abstract |
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(Received 29 December 2005;
accepted after revision 20 March 2006;
first published online 23 March 2006)
Corresponding author L. I. Sinoway: Penn State Heart & Vascular Institute, Cardiology, H047, 500 University Drive, Hershey, PA 17033, USA. Email: lsinoway{at}psu.edu
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Introduction |
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Static exercise stimulates muscle afferent nerves and activates central command. When these systems are activated, the SNS is activated causing peripheral vasoconstriction and a rise in blood pressure (Mitchell & Schmidt, 1983). A number of prior studies have examined how simultaneous deactivation of baroreflexes and activation of muscle reflexes affect sympathetic activity and vascular resistance to a given circulatory bed. Walker et al. (1980) and Nishiyasu et al. (1993) found that forearm exercise coupled with LBNP raised forearm vascular resistance more than exercise alone. These results suggest a positive interaction exists between the muscle reflex (and/or central command) and the baroreflex. Interestingly, several other reports demonstrated that exercise with and without LBNP led to a similar rise in forearm vascular resistance and/or muscle sympathetic nerve activity (Sanders & Ferguson, 1988; Scherrer et al. 1988; Seals, 1988; Arrowood et al. 1993). These reports suggest that muscle reflex control of the skeletal muscle circulation is not modulated by the baroreflexes.
Handgrip (HG) exercise (Middlekauff et al. 1997; Momen et al. 2003) and LBNP (Gilbert et al. 1966; Tidgren et al. 1990; Miller et al. 1991; Berdeaux et al. 1992; Würzner et al. 2001) both also cause renal vasoconstriction.
In humans, very little is known about the effects of simultaneous exercise and orthostatic stress on the renal circulation. This interaction may be particularly important since the renal circulation contributes to blood pressure and plasma volume regulation. In this report, we tested the hypothesis that the baroreflex does not modulate muscle reflex control of the renal circulation. To test this hypothesis we studied 18 young healthy individuals and evaluated renal blood flow velocity (RBV) responses in a beat-by-beat fashion employing Duplex ultrasound technology during short bouts of static HG and LBNP. Once these studies were completed, we performed additional studies examining whether the baroreflex would modulate muscle mechanoreflex mediated control of the renal circulation. To accomplish this goal, RBV was evaluated during involuntary biceps contractions with and without LBNP. The results of these studies suggest that muscle mechanoreflex mediated renal vasoconstriction is not modulated by baroreflex disengagement.
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Methods |
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Twenty-one healthy volunteers were studied (12 male, 9 female; age 26 ± 1 years, mean body mass index 24 ± 1 kg m–2). Subjects signed an informed written consent approved by the Penn State Hershey Institutional Review Board. A physical examination was performed on all subjects before they were studied. No volunteers were on medications, were smokers or were hypertensive. The study conformed to the Declaration of Helsinki.
Renal blood flow velocity
Duplex ultrasound (HDI 5000, ATL Ultrasound, Bothell, WA, USA) was used to determine renal blood flow dynamics. The renal artery was scanned using the anterior abdominal approach with a curved-array transducer (2–5 MHz) and a 2.5 MHz pulsed Doppler frequency was used. The probe insonation angle to the renal artery was < 60 deg and the focal zone was set at the depth of the renal artery. In order to obtain optimum velocity tracings, the transducer was held in a constant position. Therefore, the data were obtained in the same phase of the respiratory cycle of the respective subject. Care was taken to ensure that the subject did not perform Valsalva's manoeuvres during the HG protocols. Mean RBV was obtained by analysing the cardiac cycle Doppler tracings with HDI 5000 ATL software.
Based on the following considerations, RBV will be used as an index of renal blood flow.
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In addition to continuous recordings of RBV, heart rate (HR; electrocardiogram) and MAP (Finapres; Ohmeda, Madison, WI, USA) were also obtained continuously during each protocol. The MAP values obtained by Finapres were adjusted to baseline MAP values obtained by a Dinamp device (Criticon, Tampa, FL, USA).
Static handgrip
Static HG was performed using an adjustable HG dynamometer (Stoelting, Wood Dove, IL, USA). Maximum contractions were performed three times by each subject. The largest of these was considered the maximal voluntary contraction (MVC).
Lower body negative pressure
The method for LBNP has been previously described (Baily & Sinoway, 1990). Briefly, each subject was placed on a padded table with their lower body (up to the level of the iliac crests and umbilicus) positioned inside a sealed chamber. The upper surface of the LBNP chamber was below the Doppler probe. Suction was applied to the lower body with a vacuum cleaner. The amount of suction was quantified with a pressure gauge.
Involuntary biceps contraction
Involuntary biceps contractions were induced by electrical stimulation of the biceps muscle. Electrical pads (5 cm x 5 cm) were placed 
3 cm apart over the skin of the biceps muscle. The biceps muscle was then electrically stimulated (200 V; phase duration, 0.3 ms; phase interval, 0.1 ms). Electrical biceps contraction evoked contractions with a tension of 20% of MVC that were sustained for 15 s without eliciting pain. Fifteen seconds of involuntary contractions preferentially engages mechanosensitive and not metabosensitive muscle afferent nerves and does not engage central command (Kaufman & Forster, 1996).
Plasma catecholamines and plasma renin activity measurements
Venous blood samples were obtained at rest and during LBNP of –30 mmHg. Plasma noradrenaline (NA) and adrenaline (Adr) were measured by high performance liquid chromatography. Plasma renin activity was measured by radioimmunoassay technique.
Study protocols
Protocol 1. Static HG (n = 18). Baseline ECG, RBV and MAP data were recorded over 5 min. Each subject performed 15 s static HG exercise at 30% MVC. This voluntary contraction protocol was utilized to raise sympathetic outflow by preferentially engaging central command and/or the muscle mechanoreflex without engaging the metaboreflex.
Protocol 2. Graded LBNP with static HG (n = 18). After a 15 min rest period, 5 min of baseline ECG, RBV, and MAP data were recorded. LBNP was applied in a graded fashion. It was started at –10 mmHg and was increased by 20 mmHg every 5 min to –50 mmHg. LBNP was discontinued if: (1) hypotensive symptoms developed (nausea, diaphoresis, etc.); or (2) a sustained fall of > 10 mmHg in MAP was noted.
All 18 subjects tolerated –10 mmHg LBNP. Sixteen subjects tolerated –30 mmHg, and 12 tolerated –50 mmHg of LBNP. Subjects performed 15 s HG (30% MVC) at the end (5 min) of –10 and –30 mmHg LBNP.
Protocol 3. Involuntary biceps contraction with and without LBNP (n = 6).
Protocol 3 was performed on a separate day from protocols 1 and 2. After determining MVC for voluntary biceps contractions, involuntary biceps contractions were performed at 20% MVC for 15 s.
After a 15 min rest period, baseline data were recorded (5 min) and –10 mmHg LBNP was applied. Involuntary biceps contraction was then performed at the end of 5 min of LBNP.
Data analysis and statistics
Variables obtained during baseline and LBNP are presented as the mean values during each 5 min period of baseline and LBNP.
Repeated measures one-way ANOVA was applied to variables during the graded LBNP protocol. Student's paired t test was used to compare responses from baseline in the different protocols. Responses during handgrip/involuntary biceps contraction and during combined LBNP with HG/involuntary contraction were analysed using paired t tests. Data are presented as means ± S.E.M. P < 0.05 was considered significant.
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Results |
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Graded LBNP led to progressive increases in RVR (P < 0.001; Fig. 1), decreases in RBV (P < 0.01), and increases in HR (P < 0.001; Table 1). MAP did not change during LBNP. Plasma NA rose with LBNP (baseline: 1.54 ± 0.19 nmol l–1 versus LBNP: 2.37 ± 0.19 nmol l–1; P < 0.0001). Plasma Adr and PRA did not rise with LBNP (Adr baseline: 0.23 ± 0.04 nmol l–1 versus LBNP: 0.30 ± 0.11 nmol l–1; not significant (NS); PRA baseline: 0.91 ± 0.14 ng ml–1 h–1 versus LBNP: 0.89 ± 0.18 ng ml–1 h–1; NS).
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Both static HG and LBNP –10 mmHG and –30 mmHg LBNP raised RVR (12 ± 6%; P < 0.02 during HG; 9 ± 3%; P < 0.005 during LBNP –10 mmHg; 18 ± 5%; P < 0.005 during LBNP –30 mmHg). MAP and HR rose during HG, whereas RBV did not rise with HG (Table 2). RVR rose when HG was performed during LBNP at –10 mmHg (17 ± 6%; P < 0.005) and at –30 mmHg (25 ± 8%; P < 0.005). RVR responses during HG were not statistically different from RVR responses during combined HG and LBNP (Fig. 2A and B). Changes in MAP, HR and RBV values during HG and HG + LBNP are shown in Table 2. Of note, increases in HR during HG were less than increases in HR seen with HG + LBNP.
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RVR responses during involuntary contraction alone are not significantly different from RVR responses during involuntary contractions + LBNP (Fig. 3). Changes in MAP, HR and RBV during involuntary contraction alone were also not different from changes in the corresponding values during involuntary contraction + LBNP. To exclude the possibility of a ceiling effect for RVR responses during involuntary biceps contraction, additional studies were performed in four subjects. In these studies, a similar protocol was followed to protocol 3 except that biceps muscle contraction was evoked with less electrical stimulation (10% of maximum voluntary contraction). One subject did not show any vasoconstrictor responses during e-stim nor during e-stim + LBNP. However, three other subjects showed small increases in renal vasoconstriction. The average magnitude of the vasoconstriction observed during e-stim alone was similar to the response during e-stim + LBNP (9 ± 4%
versus 10 ± 9%, respectively; NS). These data suggest that a ceiling effect was not involved in the observed RVR responses during the involuntary muscle contraction protocol.
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Discussion |
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Importantly, the observed non-algebraic summation of renal vasoconstrictor responses observed in this report was not due to a ceiling effect since: (1) the RVR responses seen were less than RVR values previously reported for greater levels of HG (Momen et al. 2003); and (2) the RVR values seen at –10 and –30 mmHg LBNP were less than values seen during –50 mmHG (Fig. 1). Thus, the most likely explanation for our results is that the ‘occlusion’ occurred between some neural circuit engaged during HG exercise and the baroreflex. The occlusion phenomenon takes place when two different redundant neural mechanisms are simultaneously activated to modulate the cardiovascular system, and one system simply gets turned off (Goodwin et al. 1972; McRitchie et al. 1976; Rybicki et al. 1989). In the present report, isometric muscle contraction stimulated central command and/or the exercise pressor refex to increase SNS. Similarly, LBNP caused SNS activation by disengaging baroreflexes. Therefore, during combined static exercise and LBNP, two different mechanisms were activated for neurovascular control to the kidney. Under these circumstances, SNS activation and the resultant rise in RVR during combined HG and LBNP would be less than the algebraic sum of HG and LBNP alone.
Renal vasoconstriction during 15 s of HG is primarily due to muscle mechanoreflex and/or the central command mechanism (Krogh & Lindhard, 1913; Kaufman & Forster, 1996; Herr et al. 1999). Thus based on the HG and HG + LBNP data from this report, it is not possible to identify whether neural occlusion occurred between central command and the baroreflex or between the muscle mechanoreflex and the baroreflex. To address this issue, we examined renal blood flow responses during 15 s of involuntary contraction of biceps muscle with and without LBNP at –10 mmHg. Involuntary contraction eliminates any influences of central command on RVR responses (Goodwin et al. 1972). Since the RVR responses seen during involuntary contraction were not different from RVR during involuntary contractions coupled with LBNP, we suggest that occlusion occurred between the muscle mechanoreflex and the baroreflex.
Our findings do not support the data reported by Matsukawa et al. (1991). In this prior report, conscious cats performed static exercise while resting arterial pressure was raised by injecting noradrenaline. The investigators observed less of an increase in renal sympathetic nerve activity suggesting an inhibitory influence due to baroreflex engagement during exercise. The reason for the variances between this prior report and our current findings is not exactly known. However, fundamental differences in study design and/or species differences might play a role.
Interestingly, unlike RVR, increases in HR were greater during HG + LBNP than during HG alone. On the other hand, HR during involuntary biceps contraction was similar with and without LBNP. The exact explanation for these findings is unclear. However, we believe the most likely explanation is that increase in HR during HG is mediated predominantly by central command (Goodwin et al. 1972) and that occlusion does not occur between central command and the baroreflex.
LBNP disengages the afferent nerve activity of the baroreflex system and causes activation of the SNS. Renal vasoconstriction (as well as increased sodium and water reabsorption) has been previously seen during LBNP (Gilbert et al. 1966; Tidgren et al. 1990; Miller et al. 1991; Berdeaux et al. 1992; Würzner et al. 2001). However, unlike our findings, some of the previous reports did not observe increases in RVR at low (–10 or –15 mmHg) levels of LBNP (Miller et al. 1991; Berdeaux et al. 1992; Würzner et al. 2001). The exact reason for these differences is not clear although differences in study design as well as differences in the methods used to measure renal blood flow between prior reports and ours are likely to be important issues.
Finally, we observed increases in plasma NA but not PRA during the LBNP procedure. This suggests that the rise in RVR response during LBNP was due to sympathetic activation (Würzner et al. 2001) and not to a hormone related process.
In conclusion, our findings suggest that muscle mechanoreflex mediated renal vasoconstrictor responses are not influenced by baroreflex disengagement in healthy humans during short bouts of exercise.
Renal circulation importantly contributes to blood pressure as well as fluid volume regulation. During both static exercise and orthostatic stress, activation of SNS plays an important role in evoking renal vasoconstriction and this helps in maintaining blood pressure. During the activities of daily living (ADL), different physical activities involve short bouts of isometric muscle contraction (e.g. holding, gripping, lifting, etc.). These ADL often occur in the upright posture. Since exercise has a profound impact on the renal circulation, we believe that understanding renal circulatory control mechanisms during exercise combined with orthostatic stress is of major clinical relevance. Our findings indicate that renal vasoconstrictor responses seen during short bouts of exercise are not modulated by orthostatic stress induced baroreflex disengagement. However, it should be noted that in our study design the simulated orthostatic stress was non-hypotensive (up to –30 mmHg LBNP level). Therefore, our current data may not be reflective of the situation seen during exercise in the presence of moderate to severe hypovolumia (e.g. severe haemorrhage) or in disease processes associated with altered sympathetic function (e.g. hypertension, heart failure). Abnormalities in neural mechanisms in these conditions cause abnormal neurovascular control to the kidney. Accordingly, in these clinical settings, compensatory exaggerated renal vasoconstriction may occur to maintain blood pressure and extracellular body fluid volumes. Therefore, an important question raised by these studies is whether occlusion is seen to the same degree in conditions associated with heightened renal constriction such as hypertension and heart failure.
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