AJP - Heart pressure measurements
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 295: H1794-H1801, 2008. First published August 29, 2008; doi:10.1152/ajpheart.131.2008
0363-6135/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
295/4/H1794    most recent
131.2008v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hunt, B. E.
Right arrow Articles by Weiss, J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hunt, B. E.
Right arrow Articles by Weiss, J. W.

Baroreflex responsiveness during ventilatory acclimatization in humans

Brian E. Hunt,1 Renaud Tamisier,2,3 Geoffrey S. Gilmartin,1 Mathew Curley,1 Amit Anand,1 and J. Woodrow Weiss1

1Department of Kinesiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts; 2Pulmonary and Sleep Research Laboratory, Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and 3Laboratoire du Sommeil, Laboratoire HP2 (Hypoxie PathoPhysiologie), Centre Hospitalier Universitaire de Grenoble, Grenoble, France

Submitted 7 February 2008 ; accepted in final form 25 August 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We tested the hypothesis that the decline in muscle sympathetic activity during and after 8 h of poikilocapnic hypoxia (Hx) was associated with a greater sympathetic baroreflex-mediated responsiveness. In 10 healthy men and women (n = 2), we measured beat-to-beat blood pressure (Portapres), carotid artery distension (ultrasonography), heart period, and muscle sympathetic nerve activity (SNA; microneurography) during two baroreflex perturbations using the modified Oxford technique before, during, and after 8 h of hypoxia (84% arterial oxygen saturation). The integrated baroreflex response [change of SNA ({Delta}SNA)/change of diastolic blood pressure ({Delta}DBP)], mechanical ({Delta}diastolic diameter/{Delta}DBP), and neural ({Delta}SNA/{Delta}diastolic diameter) components were estimated at each time point. Sympathetic baroreflex responsiveness declined throughout the hypoxic exposure and further declined upon return to normoxia [pre-Hx, –8.3 ± 1.2; 1-h Hx, –7.2 ± 1.0; 7-h Hx, –4.9 ± 1.0; and post-Hx: –4.1 ± 0.9 arbitrary integrated units (AIU)·min–1·mmHg–1; P < 0.05 vs. previous time point for 1-h, 7-h, and post-Hx values]. This blunting of baroreflex-mediated efferent outflow was not due to a change in the mechanical transduction of arterial pressure into barosensory stretch. Rather, the neural component declined in a similar pattern to that of the integrated reflex response (pre-Hx, –2.70 ± 0.53; 1-h Hx, –2.59 ± 0.53; 7-h Hx, –1.60 ± 0.34; and post-Hx, –1.34 ± 0.27 AIU·min–1·µm–1; P < 0.05 vs. pre-Hx for 7-h and post-Hx values). Thus it does not appear as if enhanced baroreflex function is primarily responsible for the reduced muscle SNA observed during intermediate duration hypoxia. However, the central transduction of baroreceptor afferent neural activity into efferent neural activity appears to be reduced during the initial stages of peripheral chemoreceptor acclimatization.

autonomic

AUTONOMIC RESPONSES TO HYPOXIA vary greatly depending on the intensity, duration, and pattern of the stimulus (31). Transient exposure to hypoxia, as little as 20 min, results in an increase in minute ventilation that returns to prehypoxia levels within several minutes after exposure, whereas vascular sympathetic activity remains elevated for at least an hour after return to normoxia (26, 48). Prolonged exposure to hypoxia (weeks to months) results in an elevated minute ventilation and muscle sympathetic activity, and both are sustained for at least several days after return to normoxia (2, 6, 15). Although much of the work regarding autonomic regulation in humans has focused on the effects of either transient or prolonged hypoxia, little is known about the transitional period between short-term and prolonged hypoxia. The few data available suggest that when the hypoxic exposure is extended to several hours, minute ventilation demonstrates a further increase that persists after a return to normoxia, whereas sympathetic activity returns to preexposure levels (10, 31).

Transient hypoxia elicits a rapid increase in pulmonary ventilation via direct increases in afferent input from peripheral chemoreceptors. This is followed by a modest decline or "roll off" in ventilation over the course of 20–30 min, likely caused by reduced sensitivity of arterial chemoreceptors to PO2 (1, 34). Although the mechanisms underlying the rapid and sustained sympathoexcitation associated with transient hypoxia are not well understood, the baroreflex regulation of vascular sympathetic activity appears well maintained and not a likely candidate (12). Prolonged hypoxia, several hours to days, results in a time-dependent increase in minute ventilation, termed ventilatory acclimatization to hypoxia (VAH), which outlasts the exposure. Previous data suggest that VAH begins by 4 h of hypoxic exposure (43). Increased sensitivity of both the arterial chemoreceptor and the central nervous system to PO2 are thought to underlie this chronic response (31). However, the mechanisms underlying the return of sympathetic activity to prehypoxic levels during the initial stages of VAH are unclear.

As chemoreceptors are sympathoexcitatory, the dissociation between augmented peripheral chemoreceptor sensitivity and reduced sympathetic neural outflow during VAH argues against a direct chemoreceptor-mediated response. However, given the close proximity of carotid chemoreceptor and sympathoinhibitory baroreceptor afferent projections into the medulla, it is plausible that the increased medullary activity associated with VAH may augment baroreflex restraint of muscle sympathetic activity during this period. Therefore, we tested the hypothesis that sympathetic baroreflex-mediated responsiveness would be augmented during and after 8 h of poikilocapnic hypoxia.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Study Sample

Twelve healthy, nonsmoking, normotensive volunteers, free of vasoactive medications, completed the study (women = 3). Adequate sympathetic neurograms were obtained in 10 volunteers. All study volunteers underwent a routine medical history and physical examination to exclude overt cardiopulmonary or neurological disease before giving written informed consent. To eliminate possible confounding hormonal effects on cardiovascular function, the women were studied during the week following menses and all tested negative for pregnancy via human chorionic gonadotropin test. This protocol conformed to the provisions of the Declaration of Helsinki and was thus approved by the Institutional Review Board at the Beth Israel Deaconess Medical Center.

Experimental Protocol

All studies were conducted between 9:00 AM and 7:00 PM after study volunteers had fasted overnight. After instrumentation, the volunteers rested in the supine position for 15–30 min until all parameters were stable for at least 5 min. During the following 45 min, continuous baseline recordings were made of sympathetic activity, arterial pressure, and electrocardiogram (ECG) while the subjects breathed room air. In addition, two consecutive baroreflex perturbations using the modified Oxford technique were performed (8). We then exposed the volunteers to continuous poikilocapnic hypoxia (Hx). The volunteers breathed through a leak-free face mask (8940 Series; Hans Rudolph, Kansas City, MO) fitted with a Hans Rudolph 2600 series two-way valve. A three-way valve on the inspiratory tubing allows rapid switching between the 30-liter respiratory bag and room air. The respiratory bag was filled with a gas mixture containing 9% oxygen balanced with nitrogen. Nitrogen or room air was added to the inspired gas as necessary to maintain arterial oxygen saturation (SaO2) near 85%. During the exposure, the measurements of blood pressure, ECG, and two baroreflex perturbations were performed after 1 and 7 h. During the hypoxic exposure study, the volunteers were allowed to drink water ad libitum and were continuously infused with 5% glucose at a rate of 100 ml/h. After 8 h, the volunteers were returned to room-air breathing and all measurements were repeated after SaO2 returned to baseline, with baroreflex testing beginning at 30 min of posthypoxia.

Measurements

Cardiovascular and pulmonary variables. Heart rate was derived from the ECG. Clinical arterial pressure was measured in the right arm using an automated arm-cuff sphygmomanometer (Dinamap model, Critikon, Tampa, FL). Continuous beat-by-beat blood pressure measurements by photoplethysmography (Portapres TNO-Institute of Applied Physics Biomedical Instrumentation, Amsterdam, The Netherlands) were used in the calculation of baroreflex responsiveness. SaO2 was monitored with a pulse oximeter (Biox model 3740; Ohmeda, Louisville, CO), and CO2 fraction was measured continuously using an infrared gas analyzer connected to the mask (model 17630; Vacumed, Ventura, CA). End-tidal CO2 (ETCO2) was calculated as the product of the Fe CO2 value at the end of the expiratory plateau and barometric pressure. Data from previous subjects exposed to the same 8 h of poikilocapnic hypoxia (10) demonstrated that ETCO2, fraction of inspired oxygen (FIO2), and SaO2 were not different between the 1- and 7-h time points, suggesting the SaO2 is an adequate index of the hypoxic stress in our healthy study volunteers. The change in ETCO2 across time points within an individual was used as a gross index of peripheral chemoreflex drive.

Muscle sympathetic nerve activity. We obtained nerve recordings using standard tungsten microelectrodes inserted into the peroneal nerve posterior in the popliteal area after localization by surface stimulation. The signals were filtered, amplified, and full-wave rectified. The rectified signal was integrated for display on an oscilloscope and for recording (Nerve Traffic Analyzer, Model 662c-3, Bioengineering Dept., University of Iowa, Iowa City, IA). The electrode position in the muscle fibers was confirmed by pulse synchronous bursts of activity occurring 1.2–1.4 s after the QRS complex, reproducible activation during the second phase of the Valsalva maneuver, elicitation of afferent nerve activity by mild muscle stretching, and the absence of response to startle. We recorded the sympathetic neurogram before hypoxia and continued the recordings for 1 h after hypoxia was begun. The electrodes were then removed. The microelectrodes were replaced, and the sympathetic neurogram was recorded after 7 h of hypoxia and continued recording for 1 h after volunteers returned to breathing room air. Sympathetic bursts were identified by the Hamner-Taylor detection algorithm (14) using Matlab software (Mathworks, Natick, MA). Burst amplitude was normalized by assigning a value of 1,000 arbitrary units to the largest burst identified during stable baseline activity before each measurement; this was expressed as both frequency (in bursts/min) and rate (in bursts/100 heart beats). Both metrics are stable and reproducible indexes and thus are used to compare sympathetic activity between time points. The total burst activity was then estimated by calculating the area under each sympathetic burst; this was expressed as arbitrary integrated units (AIU) and used to express the change in sympathetic activity during baroreflex perturbations. Since the Hamner-Taylor algorithm has not been independently validated, we compared the sympathetic burst frequency as determined by the semiautomated Hamner-Taylor algorithm to manual burst detection in 14 neurograms (7 steady-state normoxia and 7 steady-state hypoxia). The burst frequency determined by both methods was highly correlated (r2 = 0.79) with the automated detection having a fixed bias of –1.5 bursts/min.

Baroreflex engagement. We used the modified Oxford technique, which involves a bolus injection of 100 µg of sodium nitroprusside followed in 60 s by a bolus of 150 µg of phenylephrine hydrochloride. This technique generally produces an initial ~15 mmHg fall in arterial pressure followed by an ~15 mmHg rise in pressure above resting supine levels (8, 17). Responses of a representative study volunteer are shown in Fig. 1. During baroreflex engagement, the beat-by-beat arterial pressures from a finger photoplethysmograph (Portapres), a standard three-lead ECG, and muscle sympathetic nerve activity (MSNA) were recorded continuously at a sampling rate of 500 Hz. Longitudinal B-mode images of a common carotid artery just below the carotid bulb were also obtained during baroreflex engagement using a 7.5-MHz transducer. Commercially available hardware (3155 PCI Frame Grabber, Data Translations, Marlboro, MA) and software (DVI Acquisition, Information Integrity, Stow, MA) were used to acquire 30-Hz images to a computer triggered from the R-wave of the ECG. Fifteen consecutive carotid images were acquired with each trigger to approximate at least one third of the cardiac cycle (i.e., 500 ms of a 1,500-ms R-R interval or 40 beats/min heart rate) and therefore encompass both end-diastolic and peak-systolic diameters. Each 640 x 480-pixel image provided a resolution of 0.05 mm/pixel. We used custom software that employed a verterbi search algorithm to estimate carotid diameters. Two trials were performed at each time point. Each trial was separated by at least 15 min to allow for the recovery of blood pressure and heart rate to the preinjection levels.


Figure 1
View larger version (29K):
[in this window]
[in a new window]

  		Fig. 1. Blood pressure (BP), R-R interval, carotid diameter, and muscle sympathetic nerve activity (MSNA) from a single study volunteer during baroreflex engagement before hypoxia.

 
For each trial, the diameters were associated to the appropriate blood pressures, R-R intervals, and sympathetic activity (29, 37). The data were then averaged across 2-mmHg increments or bins. We excluded bins in the threshold and saturation regions in estimating the linear responsiveness of the integrated, mechanical, and neural aspects of the baroreflex. Integrated cardiovagal baroreflex responsiveness was estimated from the slope of the relation between R-R interval and systolic blood pressure ({Delta}R-R interval/{Delta}systolic blood pressure). The mechanical component of the vagal limb was expressed as the slope of the relation between systolic blood pressure and carotid systolic diameter ({Delta}systolic blood pressure/{Delta}systolic diameter). The neural component of the vagal limb was expressed as the slope of the relation between R-R interval and carotid systolic diameter ({Delta}R-R interval/{Delta}systolic diameter). Each aspect of the sympathetic limb was characterized in a similar fashion: integrated responsiveness ({Delta}MSNA/{Delta}diastolic blood pressure), mechanical ({Delta}diastolic blood pressure/{Delta}diastolic diameter), and neural ({Delta}MSNA/{Delta}diastolic diameter). Figure 2 depicts how estimates of baroreflex responsiveness were calculated from the data shown in Fig. 1.


Figure 2
View larger version (13K):
[in this window]
[in a new window]

  		Fig. 2. Vagal baroreflex responses (left) and sympathetic baroreflex responses (right) derived from data depicted in Fig. 1. Top: integrated response. Middle: mechanical component. Bottom: neural component of the integrated baroreflex response. SBP, systolic BP; DBP, diastolic BP.

 
Because central or peripheral hysteresis can affect the slope of these relations, we independently assessed the slopes during the falling and rising portions of the response. No systematic differences were found between slopes during the falling and rising pressures. Therefore, the slopes were estimated from data encompassing the fall and rise in blood pressure. Baroreflex responsiveness at each time point is expressed as the mean of the two trials (average trial-to-trial difference of 0.30 ms/mmHg for vagal and 0.20 AIU·burst–1·mmHg–1 for sympathetic gains).

Data Analysis

All comparisons were limited to data sets from the 10 volunteers in which adequate pre- and postsympathetic neurograms were obtained. A one-way ANOVA for repeated measures was used to compare all data across the four time points of the study. Newman-Keuls post hoc analysis was used when ANOVA indicated differences between time points. Trends were determined by orthogonal polynomials (11, 16). Data are reported as means ± SE in the text, table, and figures. P values ≤ 0.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
As depicted in Fig. 3, MSNA initially increased before when VAH has been reported to begin (43), then returned to prehypoxia levels at 7 h of exposure, and declining further at postexposure. Along with sympathetic activity, Table 1 displays the hypoxic stimulus as measured by SaO2 and the attendant changes in heart rate, ETCO2, and mean arterial pressure throughout the study.


Figure 3
View larger version (44K):
[in this window]
[in a new window]

  		Fig. 3. MSNA and BP responses before and during baroreflex from a single study volunteer at each time point. Steady-state MSNA (left) and integrated sympathetic baroreflex response (SBR; right) are shown. AU, arbitrary unit.

 

View this table:
[in this window]
[in a new window]

  		Table 1. Cardiovascular and ventilatory variables

 
There was a linear trend for integrated vagal baroreflex responsiveness to decline across time (P = 0.07), with the lowest value recorded after volunteers were returned to room-air breathing (P = 0.08; Fig. 4). There was no corresponding systematic difference in either the mechanical component (pre-Hx, 2.43 ± 2.23; 1-h Hx, 2.45 ± 2.94; 7-h Hx, 1.83 ± 2.43; and post-Hx, 2.06 ± 1.22 µm/mmHg) or neural component (pre-Hx, 8.85 ± 1.84; 1-h Hx, 7.38 ± 1.58; 7-h Hx, 8.93 ± 1.92; post-Hx, 6.51 ± 1.05 ms/µm) of the reflex arc.


Figure 4
View larger version (13K):
[in this window]
[in a new window]

  		Fig. 4. Integrated cardiovagal (black bars) and sympathetic (gray bars) baroreflex responsiveness before, during, and after isocapnic hypoxia (Hx). Data are presented as means ± SE. *P < 0.05 vs. previous time point. AIU, arbitrary integrated unit.

 
Integrated sympathetic baroreflex responsiveness declined during the hypoxic exposure, achieving its lowest measured value at 30 to 45 min posthypoxia (Fig. 4). There was no difference in the mechanical component across time (pre-Hx, 3.23 ± 0.30; 1-h Hx, 3.28 ± 0.30; 7-h Hx, 2.95 ± 0.20; and post-Hx, 2.97 ± 0.40 µm/mmHg), as depicted in Fig. 5. However, hypoxia was associated with a decline in the neural component, with a further decline observed after returning to room-air breathing (pre-Hx, –2.70 ± 0.53; 1-h Hx, –2.59 ± 0.53; 7-h Hx, –1.60 ± 0.34; and post-Hx, –1.34 ± 0.27 AIU·beat–1·µm–1; P < 0.05 vs. pre-Hx for 7-h and post-Hx values).


Figure 5
View larger version (15K):
[in this window]
[in a new window]

  		Fig. 5. The mechanical component (black bars) and neural component (gray bars) of the sympathetic baroreflex arc before hypoxia, after 1 and 7 h of poikilocapnic hypoxia, and after return to room air. Data are presented as means (numbers shown in bars) ± SE (numbers shown in parentheses). *P < 0.05 vs. prehypoxia.

 
Carotid diastolic diameter increased during the first hour of hypoxia (pre-Hx, 6.00 ± 0.15 vs. 6.32 ± 0.23 mm, P < 0.05) and continued to be greater after 7 h of hypoxia (6.34 ± 0.22 mm). Upon the resumption of room-air breathing, the diameter was not different from prehypoxia (5.93 ± 0.17 mm).

Although there was no relation between sympathetic baroreflex responsiveness and sympathetic activity before or after just 1 h of hypoxia, the greater sympathetic baroreflex responsiveness was associated with lower sympathetic bursting rate across individuals at 7 h of hypoxia (r = –0.89, P < 0.05) and after returning to room-air breathing (r = –0.79, P < 0.05). However, within individuals, these variables were not consistently related across time points, with correlation coefficients ranging from 0.92 to –0.99 (mean = –0.23 ± 0.32). Furthermore, the baroreflex responsiveness was not related to peripheral chemoreflex drive, as suggested by ETCO2, with intra-individual correlation coefficients ranging from 0.26 to –0.57, with all P values >0.23.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We hypothesized that the decline in sympathetic activity seen after 8 h of poikilocapnic hypoxia would be associated with increased sympathetic baroreflex responsiveness. However, our data fail to support this hypothesis. Rather, they indicate that baroreflex responsiveness declined during hypoxia and was at its lowest after returning to room-air breathing. This reduction does not appear to be related to changes in the mechanical transduction of arterial pressure into the baroreceptor stretch within the carotid artery. Rather, altered neural properties within the reflex arc may underlie this unexpected reduction in responsiveness. We are aware of no previous data providing insight into changes in the baroreflex function during short-term VAH.

Most data regarding the effects of hypoxia muscle sympathetic activity and its regulation are limited to either short-term exposures lasting no more than 30 min or long-term exposures lasting weeks or months. During short-term hypoxia, vascular sympathetic activity is elevated 20–126%, whereas baroreflex responsiveness is unchanged or slightly augmented (12, 13, 48). During long-term exposure to hypoxia, vascular sympathetic activity is elevated 200–300% (6, 15). Little is known regarding baroreflex function after long-term hypoxia. Based on these data, it is reasonable to assume that the dose-response relation between hypoxia and MSNA follows a simple threshold model. However, the current data, as well as previous data from our laboratory, show that MSNA and sympathetic baroreflex responsiveness decline to prehypoxia levels during the initial stages of VAH. Thus, taking all data together, it would appear that the hypoxia and MSNA relation displays hormesis (23). Although it is difficult to explain this finding, it must be considered that profound physiological adjustments are occurring during this period of time. The sensitivity of arterial chemoreceptors to PO2 initially declines and then is augmented along with the sensitivity of the central nervous system (31). Concurrently, there are changes in circulating factors that effect sympathetic activity, such as a decline in angiotensin II (39, 41, 49).

In humans, both cardiovagal and sympathetic baroreflex responsiveness are largely unaffected by transient (≤25 min) hypoxia (4, 5, 7, 12, 13). However, when the hypoxic stimulus is prolonged to an hour, cardiovagal baroreflex responsiveness declines (35). Our data demonstrate that when the hypoxic stimulus is prolonged to 8 h, allowing for short-term VAH, then not only does cardiovagal baroreflex tend to decline, but the responsiveness of the sympathetic limb declines as well. Similar interactions between autonomic reflex loops have been reported, even during acute exposure. For example, Somers and coworkers (38) examined the effect of baroreceptor stimulation on peripheral chemoreflex responses during transient hypoxia. They show that chemoreceptor-mediated responses are blunted during baroreflex activation by phenylephrine.

With the addition of ultrasound imaging during reflex perturbation, we were able to examine two broad components of the reflex arc: 1) the mechanical, which is an estimate of the ability of barosensory vessels to transduce arterial pressure changes into vessel stretch; and 2) the neural, which encompasses afferent, central, and efferent neural function. In our study volunteers, the carotid diameter increased during hypoxia. Because the distensibility decreases with increasing arterial diameter (27), it is reasonable to presume that the transduction of arterial pressure into the carotid stretch may be diminished during hypoxia when the carotid diameter is greater, leading to a reduction in baroreflex responsiveness. However, we did not observe any systematic decline in the mechanical component during the hypoxic exposure. This could be due to several factors. First, the dilation observed is likely due to endothelium-dependent (24, 44) or -independent (32) flow-mediated processes. Thus, the increased distensibility associated with vascular smooth muscle relaxation may offset the stretch-related decrease in distensibility. Second, estimates of arterial distensibility are often derived from data measured while arterial pressure and diameter are in a relatively steady state. As we have shown before, these pulsatile estimates do not reflect the dynamic pressure-diameter interaction that occurs during acute baroreflex perturbations (18). Lastly, the fact that we used peripheral blood pressure estimates rather than carotid pressure estimates may induce some systematic error. The use of peripheral pressure estimates in determining central vascular characteristics has been criticized in the past (28). However, a direct comparison between the central and peripheral pressure-based estimates has shown that the use of tonometry-derived carotid pressures makes no difference in the estimate of reflex relations (25). This may be due, in part, to inherent problems regarding the valid calibration of the tonometric signals (47).

Although the reduction in sympathetic baroreflex responsiveness was not related to a decline in the mechanical component in our volunteers, the neural component was reduced during hypoxia, particularly after acclimatization. This may be due to a reduction in baroreceptor discharge rate (baroreceptor resetting) in response to the chronic stretch of the barosensory vessels. However, the receptor resetting is an acute phenomenon in response to the rapid and large changes in arterial blood pressure (20). A chronic stimulation of receptors does not lead to further reductions in afferent neural activity (20). Therefore, the difference in baroreflex responsiveness at 1 and 7 h of hypoxia cannot be explained by a resetting of the baroreceptors. Moreover, the acute reduction in baroreceptor discharge rate is not sustained when the stimulus is removed (20). The reduced medullary transduction of baroreceptor afferent activity into sympathetic efferent activity could also underlie the depressed neural component of the sympathetic limb of the baroreflex. Endogenous nitric oxide production, which can increase during hypoxia, has been shown to depress the baroreflex afferent responsiveness in animals (22). Although a reduction in afferent responsiveness should lead to a reduction in the neural component for both cardiovagal and sympathetic limbs, our data show a reduction in only the sympathetic limb. This may be due in part to the inhibitory effects of nitric oxide on sympathetic efferent outflow (36). In addition, the medullary cardiovagal and sympathetic efferent outflow may be differentially regulated as demonstrated by Ma and colleagues (21). Taken together, these previous findings may explain the selective reduction in integrated sympathetic baroreflex responsiveness seen in our data. However, our data cannot directly address this possibility.

It is plausible that the hyperventilation per se may have reduced baroreflex responsiveness. Using a closed-loop approach to characterize baroreflex function (frequency domain analysis), Van De Borne and colleagues (45) reported that isocapnic hyperventilation was associated with a decline in the {alpha}-index between systolic blood pressure and MSNA. This decline suggests that hyperventilation alone can reduce baroreflex modulation of vascular sympathetic activity (45). Conversely, using an open-loop approach (modified Oxford) Halliwill et al. (13) demonstrated that hyperventilation had no affect on baroreflex responsiveness. Therefore, it remains unclear as to whether hyperventilation per se can reduce baroreflex function, although it is important to note that neither Van De Borne et al. (45) nor Halliwill et al. (13) reported that hyperventilation affected mean MSNA levels.

Given that baroreflex responsiveness and sympathetic activity were not consistently related within individuals, it is unlikely that the decline in sympathetic activity is primarily mediated through the baroreflex. This appears to be true during transient hypoxic exposure as well (12). However, our data cannot address the possibility that, although blunted, the baroreflex inhibited sympathetic activity to some extent. The effect of angiotensin II on MSNA should be considered. Acute hypoxia has been shown to reduce arterial angiotensin II concentrations (39, 41, 49). Since angiotensin II stimulates sympathetic outflow from the medulla, the hypoxia-mediated decline in angiotensin II may play a role in reducing sympathetic activity during VAH. However, since we did not collect blood for analysis, our data cannot address this possibility.

It is interesting to note that upon the cessation of the hypoxic stimulus, the forearm vascular resistance remained below preexposure levels, whereas the carotid diameters returned to baseline values. Both peripheral and cerebral blood flow velocities increase during poikilocapnic hypoxia. However, forearm blood flow remains elevated after hypoxia (42), whereas cerebral blood flow returns to preexposure levels after exposure (30). With this in mind, the reduced forearm vascular resistance is likely due to reduced vascular sympathetic activity along with enhanced nitric oxide production causing vasodilation in the more muscular peripheral radial and ulnar arteries and arterioles. In contrast, the blood flow through the carotid artery likely returned to baseline levels, reducing shear stress. Moreover, the less muscular artery is likely less affected by the reduced vascular sympathetic outflow.

Limitations

A consistent subject of debate in the study of autonomic regulation is the proper metric for expressing cardiovagal baroreflex responsiveness. Because of the inverse, curvelinear relation between R-R interval and heart rate, a rather large change in R-R interval can result in a small change in heart rate, potentially obscuring changes in autonomic regulation. Since heart rate is linearly related to cardiac output, and thus blood pressure, this metric may be most appropriate when examining the ability of the baroreflex to buffer changes in arterial blood pressure. However, in the current investigation, our experimental question was related to changes in the autonomic control of afferent neural activity. Therefore, since carotid afferent frequency is linearly related to R-R interval in cats and humans (3, 19), this metric seems most appropriate for this investigation.

Given that the microelectrode was removed after 1 h of hypoxia and then replaced before the 7-h hypoxia measurement, the reproducibility of MSNA is an important issue. First, it should be noted that the key dependent variable, sympathetic baroreflex responsiveness, is based on the change in MSNA rather than the absolute levels of MSNA. Nonetheless, intra-individual MSNA is highly reproducible, even when measured several years apart (9). Moreover, MSNA recorded in the leg is strongly associated with MSNA measured simultaneously in the arm (33, 40, 46). Taken together, this should provide assurance that our measurements of both steady-state MSNA and sympathetic baroreflex responsiveness, taken in the same proximity but different site within the peroneal nerve, can be compared quantitatively.

Conclusions

These data provide evidence that baroreflex function is inhibited during the initial stages of VAH. Furthermore, by the addition of continuous ultrasound images of the carotid artery during baroreceptor stimulation, we have been able to provide data that strongly suggest that the reduction in baroreflex responsiveness is likely due to changes in the medullary afferent-efferent integration, possibly associated with ventilatory acclimatization to hypoxia. Although our data do not directly address this hypothesis, taken together with previous data in animals, it is likely. Furthermore, in contrast to previous work that has only examined the chemoreceptor-baroreceptor interactions before acclimatization, our work suggests that this transition period during hypoxia encompasses a unique integration between chemoreceptor, baroreceptor, and end-organ function.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research was supported by National Heart, Lung, and Blood Institute Grant HL-072648-01A1.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. E. Hunt, Applied Health Science, Wheaton College, 501 College Ave., Wheaton, IL 60187 (e-mail: brian.hunt{at}wheaton.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Bascom DA, Clement ID, Cunningham DA, Painter R, Robbins PA. Changes in peripheral chemoreflex sensitivity during sustained, isocapnic hypoxia. Respir Physiol 82: 161–176, 1990.[CrossRef][Web of Science][Medline]
  2. Bisgard GE. Increase in carotid body sensitivity during sustained hypoxia. Biol Signals 4: 292–297, 1995.[Web of Science][Medline]
  3. Borst C, Karemaker JM, Dunning AJ, Bouman LN, Wagner J. Frequency limitation in the human baroreceptor reflex. J Auton Nerv Syst 9: 381–397, 1983.[CrossRef][Web of Science][Medline]
  4. Bristow JD, Brown EB Jr, Cunningham DJ, Goode RC, Howson MG, Sleight P. The effects of hypercapnia, hypoxia and ventilation on the baroreflex regulation of the pulse interval. J Physiol 216: 281–302, 1971.[Abstract/Free Full Text]
  5. Bristow JD, Brown EB Jr, Cunningham DJ, Goode RC, Howson MG, Sleight P. The influence of ventilation, carbon dioxide and hypoxia on the baroreceptor reflex in man. J Physiol 198: 102passim–103p, 1968.[Medline]
  6. Calbet JA. Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans. J Physiol 551: 379–386, 2003.[Abstract/Free Full Text]
  7. Cunningham DJ, Petersen ES, Pickering TG, Sleight P. The effects of hypoxia, hypercapnia, and asphyxia on the baroreceptor-cardiac reflex at rest and during exercise in man. Acta Physiol Scand 86: 456–465, 1972.[Web of Science][Medline]
  8. Ebert TJ, Morgan BJ, Barney JA, Denahan T, Smith JJ. Effects of aging on baroreflex regulation of sympathetic activity in humans. Am J Physiol Heart Circ Physiol 263: H798–H803, 1992.[Abstract/Free Full Text]
  9. Fagius J, Wallin BG. Long-term variability and reproducibility of resting human muscle nerve sympathetic activity at rest, as reassessed after a decade. Clin Auton Res 3: 201–205, 1993.[CrossRef][Medline]
  10. Gilmartin G, Tamisier R, Anand A, Cunnington D, Weiss JW. Evidence of impaired hypoxic vasodilation after intermediate-duration hypoxic exposure in humans. Am J Physiol Heart Circ Physiol 291: H2173–H2180, 2006.[Abstract/Free Full Text]
  11. Glass G, Hopkins K. Statistical Methods in Education and Psychology. Boston: Allyn and Bacon, 1996.
  12. Halliwill JR, Minson CT. Effect of hypoxia on arterial baroreflex control of heart rate and muscle sympathetic nerve activity in humans. J Appl Physiol 93: 857–864, 2002.[Abstract/Free Full Text]
  13. Halliwill JR, Morgan BJ, Charkoudian N. Peripheral chemoreflex and baroreflex interactions in cardiovascular regulation in humans. J Physiol 552: 295–302, 2003.[Abstract/Free Full Text]
  14. Hamner JW, Taylor JA. Automated quantification of sympathetic beat-by-beat activity, independent of signal quality. J Appl Physiol 91: 1199–1206, 2001.[Abstract/Free Full Text]
  15. Hansen J, Sander M. Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia. J Physiol 546: 921–929, 2003.[Abstract/Free Full Text]
  16. Hubert LJ. The use of orthogonal polynomials for trend analysis. Am Educ Res J 10: 241–244, 1973.[Free Full Text]
  17. Hunt BE, Fahy L, Farquhar WB, Taylor JA. Quantification of mechanical and neural components of vagal baroreflex in humans. Hypertension 37: 1362–1368, 2001.[Abstract/Free Full Text]
  18. Hunt BE, Farquhar WB, Taylor JA. Does reduced vascular stiffening fully explain preserved cardiovagal baroreflex function in older, physically active men? Circulation 103: 2424–2427, 2001.[Abstract/Free Full Text]
  19. Kunze DL. Reflex discharge patterns of cardiac vagal efferent fibres. J Physiol 222: 1–15, 1972.[Abstract/Free Full Text]
  20. Landgren S. On the excitation mechanism of the carotid baroceptors. Acta Physiol Scand 26: 1–34, 1952.[Web of Science][Medline]
  21. Ma X, Abboud FM, Chapleau MW. Analysis of afferent, central, and efferent components of the baroreceptor reflex in mice. Am J Physiol Regul Integr Comp Physiol 283: R1033–R1040, 2002.[Abstract/Free Full Text]
  22. Matsuda T, Bates JN, Lewis SJ, Abboud FM, Chapleau MW. Modulation of baroreceptor activity by nitric oxide and S-nitrosocysteine. Circ Res 76: 426–433, 1995.[Abstract/Free Full Text]
  23. Mattson MP. Hormesis defined. Ageing Res Rev 7: 1–7, 2008.[CrossRef][Web of Science][Medline]
  24. Messina EJ, Sun D, Koller A, Wolin MS, Kaley G. Role of endothelium-derived prostaglandins in hypoxia-elicited arteriolar dilation in rat skeletal muscle. Circ Res 71: 790–796, 1992.[Abstract/Free Full Text]
  25. Monahan KD, Tanaka H, Dinenno FA, Seals DR. Central arterial compliance is associated with age- and habitual exercise-related differences in cardiovagal baroreflex sensitivity. Circulation 104: 1627–1632, 2001.[Abstract/Free Full Text]
  26. Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol 79: 205–213, 1995.[Abstract/Free Full Text]
  27. Nichols WW, O'Rourke MF. McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles (5th ed.). New York: Oxford University Press, 2005.
  28. O'Rourke MF, Nichols WW. Does reduced vascular stiffening fully explain preserved cardiovagal baroreflex function in older physically active men? Circulation 105: E11, 2002.[CrossRef][Medline]
  29. Pickering TG, Davies J. Estimation of the conduction time of the baroreceptor-cardiac reflex in man. Cardiovasc Res 7: 213–219, 1973.[Abstract/Free Full Text]
  30. Poulin MJ, Fatemian M, Tansley JG, O'Connor DF, Robbins PA. Changes in cerebral blood flow during and after 48 h of both isocapnic and poikilocapnic hypoxia in humans. Exp Physiol 87: 633–642, 2002.[Abstract]
  31. Powell FL, Milsom WK, Mitchell GS. Time domains of the hypoxic ventilatory response. Respir Physiol 112: 123–134, 1998.[CrossRef][Web of Science][Medline]
  32. Quan A, Ward ME, Kulandavelu S, Adamson SL, Langille BL. Endothelium-independent flow-induced dilation in the mouse carotid artery. J Vasc Res 43: 383–391, 2006.[CrossRef][Web of Science][Medline]
  33. Rea RF, Wallin BG. Sympathetic nerve activity in arm and leg muscles during lower body negative pressure in humans. J Appl Physiol 66: 2778–2781, 1989.[Abstract/Free Full Text]
  34. Robbins PA. Hypoxic ventilatory decline: site of action. J Appl Physiol 79: 373–374, 1995.[Abstract/Free Full Text]
  35. Sagawa S, Torii R, Nagaya K, Wada F, Endo Y, Shiraki K. Carotid baroreflex control of heart rate during acute exposure to simulated altitudes of 3,800 m and 4,300 m. Am J Physiol Regul Integr Comp Physiol 273: R1219–R1223, 1997.[Abstract/Free Full Text]
  36. Sakuma I, Togashi H, Yoshioka M, Saito H, Yanagida M, Tamura M, Kobayashi T, Yasuda H, Gross SS, Levi R. NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone? Circ Res 70: 607–611, 1992.[Abstract/Free Full Text]
  37. Smith SA, Stallard TJ, Littler WA. Estimation of sinoaortic baroreceptor heart rate reflex sensitivity and latency in man: a new microcomputer assisted method of analysis. Cardiovasc Res 20: 877–882, 1986.[Abstract/Free Full Text]
  38. Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest 87: 1953–1957, 1991.[Web of Science][Medline]
  39. Stalcup SA, Lipset JS, Mellins RB. Modulation of converting enzyme activity by hypoxia and its physiological effects. Ciba Found Symp 78: 293–311, 1980.[Medline]
  40. Sundlof G, Wallin BG. The variability of muscle nerve sympathetic activity in resting recumbent man. J Physiol 272: 383–397, 1977.[Abstract/Free Full Text]
  41. Szidon P, Bairey N, Oparil S. Effect of acute hypoxia on the pulmonary conversion of angiotensin I to angiotensin II in dogs. Circ Res 46: 221–226, 1980.[Abstract/Free Full Text]
  42. Tamisier R, Hunt BE, Gilmartin GS, Curley M, Anand A, Weiss JW. Hemodynamics and muscle sympathetic nerve activity after 8 h of sustained hypoxia in healthy humans. Am J Physiol Heart Circ Physiol 293: H3027–H3035, 2007.[Abstract/Free Full Text]
  43. Tansley JG, Clar C, Pedersen ME, Robbins PA. Human ventilatory response to acute hyperoxia during and after 8 h of both isocapnic and poikilocapnic hypoxia. J Appl Physiol 82: 513–519, 1997.[Abstract/Free Full Text]
  44. Toporsian M, Govindaraju K, Nagi M, Eidelman D, Thibault G, Ward ME. Downregulation of endothelial nitric oxide synthase in rat aorta after prolonged hypoxia in vivo. Circ Res 86: 671–675, 2000.[Abstract/Free Full Text]
  45. Van De Borne P, Mezzetti S, Montano N, Narkiewicz K, Degaute JP, Somers VK. Hyperventilation alters arterial baroreflex control of heart rate and muscle sympathetic nerve activity. Am J Physiol Heart Circ Physiol 279: H536–H541, 2000.[Abstract/Free Full Text]
  46. Wallin BG, Victor RG, Mark AL. Sympathetic outflow to resting muscles during static handgrip and postcontraction muscle ischemia. Am J Physiol Heart Circ Physiol 256: H105–H110, 1989.[Abstract/Free Full Text]
  47. Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ. The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol 525: 263–270, 2000.[Abstract/Free Full Text]
  48. Xie A, Skatrud JB, Puleo DS, Morgan BJ. Exposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol 91: 1555–1562, 2001.[Abstract/Free Full Text]
  49. Zakheim RM, Molteni A, Mattioli L, Park M. Plasma angiotensin II levels in hypoxic and hypovolemic stress in unanesthetized rabbits. J Appl Physiol 41: 462–465, 1976.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
295/4/H1794    most recent
131.2008v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hunt, B. E.
Right arrow Articles by Weiss, J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hunt, B. E.
Right arrow Articles by Weiss, J. W.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.