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Am J Physiol Heart Circ Physiol 291: H2173-H2180, 2006. First published April 28, 2006; doi:10.1152/ajpheart.01021.2005
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Evidence of impaired hypoxic vasodilation after intermediate-duration hypoxic exposure in humans

Geoffrey Gilmartin,1 Renaud Tamisier,1,2 Amit Anand,1 David Cunnington,1 and J. Woodrow Weiss1

1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and 2Sleep Laboratory, Grenoble University Hospital Hypoxia Pathophysiology Laboratory, Grenoble, France

Submitted 26 September 2005 ; accepted in final form 18 April 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Systemic hemodynamics, including forearm blood flow and ventilatory parameters, were evaluated in 21 subjects before and after exposure to 8 h of poikilocapnic hypoxia. To evaluate the role of sympathetic nervous system activation in the changes, in 10 of these subjects, we measured muscle sympathetic nerve activity (MSNA) before and after exposure, and the remaining 11 subjects received intra-arterial phentolamine infusion in the brachial artery to define vascular tone in the absence of sympathetically mediated vasoconstriction. Short-term ventilatory acclimatization occurred as evidenced by a decrease in resting PCO2 (from 42 ± 1.4 to 37 ± 0.96 mmHg) and by an increase in the slope of the ventilatory response to acute hypoxia [from 0.7 ± 0.1 to 1.2 ± 0.2 l·min–1·%SpO2 (blood O2 saturation from pulse oximetry)] after exposure. Subjects demonstrated a significant increase in resting heart rate (from 61 ± 2 to 65 ± 2 beats/min) and diastolic blood pressure (from 64.8 ± 2.7 to 70.4 ± 2.0 mmHg). MSNA did not change significantly after exposure, although there was a trend toward a decrease in burst frequency (from 19.8 ± 4.1 to 14.3 ± 1.2 bursts/min). Forearm vascular resistance showed a significant decrease after termination of exposure (from 37.7 ± 3.6 to 27.6 ± 2.7 mmHg·ml–1·min·100 g tissue, P < 0.05). Initially, progressive isocapnic hypoxia elicited significant vasodilation, but after 8 h of poikilocapnic hypoxic exposure, the acute challenge failed to change forearm vascular resistance. Local {alpha}-blockade with phentolamine restored the vasodilatory response to acute hypoxia in the postexposure setting.

acclimatization; muscle sympathetic nerve activity; vascular resistance

EXTENDED EXPOSURES TO HYPOXIA are associated with increases in ventilation that persist after termination of the exposure. This increase in ventilation, termed hypoxic acclimatization, is attributed primarily to an increase in peripheral chemosensitivity (2, 5). Acclimatization has been demonstrated to occur following exposures as brief as 8 h in human subjects (15, 16). Because afferent traffic from the peripheral chemoreceptor partly determines sympathetic activity, we postulated that a hypoxic exposure of sufficient duration to induce ventilatory acclimatization also would induce sustained sympathoexcitation that would persist after termination of the hypoxic exposure. To test this hypothesis, we assessed muscle sympathetic nerve activity (MSNA) in normal volunteers before and after an 8-h exposure to hypoxia previously shown to produce ventilatory acclimatization. Because hypoxic exposure also stimulates release of endogenous vasodilators that may persist after the exposure, we further sought to define vascular tone in our subjects by assessing vascular resistance both with and without local blockade of sympathetic input with the use of nonspecific {alpha}-blockade with local arterial infusion of phentolamine.

The goals of this study, therefore, were 1) to define the changes in MSNA associated with ventilatory acclimatization following an 8-h poikilocapnic hypoxic exposure and 2) to define the changes in vascular tone associated with any change in sympathetic activity using {alpha}-blockade.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects

Twenty-one healthy, nonsmoking, normotensive subjects who were free of vasoactive medications completed the study. All subjects underwent a screening history and physical examination to ensure they were free of significant cardiac, pulmonary, or neurological disease before written informed consent was obtained. There were 15 men and 6 women enrolled in the study. All women were studied during the week following menses, and all tested negative for pregnancy (urinary B-HCG test) to minimize the possible confounding effects of hormonal changes on vascular function. The subjects had a mean age of 26 ± 1 yr and a mean body mass index of 23 ± 0.7 kg/m2. The Committee on Clinical Investigation and the Institutional Review Board at the Beth Israel Deaconess Medical Center reviewed and approved all components of the protocol before implementation.

General Procedures

Subjects were instrumented and studied in the supine position with room temperature maintained constant at ~24°C. Hypoxic exposure and data collection were conducted at the same time of day across all subjects. Data collection was initiated after a 15-min recovery period following successful instrumentation in all subjects. Respiratory and cardiovascular variables, as well as sympathetic nerve activity, were recorded continuously, digitized at 128 Hz (model DI-720 series; DataQ instruments, Akron, OH), and stored locally on a computer hard disk. The data were later analyzed off-line with signal processing software (Windaq; DataQ Instruments).

Respiratory variables. Steady-state tidal volume and breath frequency were monitored using a pneumotachograph attached to a leak-free full-face mask. Tidal volume (VT) was obtained by integration of the flow signal. Minute ventilation (VE) was calculated by multiplying VT by the respiratory rate (fr). End-tidal CO2 tension (PETCO2) was sampled at the mask and measured using a gas analyzer (model 17630; Vacu-med, Ventura, CA). End-tidal O2 tension (PETO2) was sampled at the mask and measured using a gas analyzer (model 17630; Vacu-med). Arterial oxygen saturation (SpO2) was measured using a pulse oximeter (Biox model 3740; Ohmeda, Madison, WI).

Hypoxic ventilatory response was assessed using the Rebuck-Campbell method. Through a closed ventilatory circuit, subjects breathe an initial gas mixture containing 24% oxygen and 6% carbon dioxide balanced with nitrogen. Gas was sampled at the mouthpiece, and PETCO2 and the inspired oxygen fraction (FIO2) were continuously monitored. Isocapnic conditions were maintained by allowing a variable stream of gas from the breathing circuit to pass through a soda-lime CO2 absorber. The subject was allowed to breathe on the circuit until PETCO2 had stabilized. Once PETCO2 was stable, 100% nitrogen (1–2 liters) was added to the circuit, leading to an initial drop in FIO2. FIO2 progressively declined over the course of the maneuver as a consequence of the subject's oxygen consumption. Ventilation was recorded continuously using a 10-liter wedge spirometer (Med Science, St. Louis, MO) connected to a 7-liter bag-in-box device. VE vs. SpO2 was summarized as a linear curve, and the slope and position of the response line was derived from the line of best fit with the use of least-squares regression analysis.

Cardiovascular variables.
BLOOD PRESSURE. Continuous beat-by-beat arterial pressure was obtained using the Portapress device (TNO-Institute of Applied Physics Biomedical Instrumentation, Amsterdam, The Netherlands). In addition to standard calibration of the recording signals, Portapress measurements were validated by using noninvasive blood pressure measurements taken at 5-min intervals with an automated arm-cuff sphygmomanometer (Dinamap model; Critikon, Tampa, FL) during all recording periods. When subjects were instrumented with brachial arterial catheterization, intra-arterial pressure was continuously recorded through the arterial catheter with a catheter-transducer system (Transpac II; Abbott Critical Care Systems, Chicago, IL), and the Portapress device was not used.


HEART RATE. Heart rate (HR) was continuously recorded using a three-lead electrocardiogram (model M-90; MRL, Urbana, IL).

Forearm blood flow. Arterial blood flow was measured using venous occlusion plethysmography (EC6 plethysmography; Hokanson, Bellevue, WA) with mercury-in-Silastic strain gauges. The arm was maintained in a passive position at the level of the left atrium. The strain gauge was placed at the midpoint of the forearm. An arterial occlusion cuff was placed distal to the gauge (at the wrist) to isolate the hand during measurements. Before data collection, a series of occlusions were performed to determine the venous occlusion pressure that resulted in the steepest slope of the arterial inflow curve. Typically, venous occlusion pressures of 45–55 mmHg were used. One minute before measurement of arterial flow, the arterial occlusion cuff was inflated to 200 mmHg. After the signal had reached a stable value, the proximal venous cuff was rapidly inflated for 8 of every 15 s. For analysis, the initial flow measurement was discarded, and an average of 10–12 flow measurements was used in computation of the results. Forearm blood flow (FBF) is expressed in milliliters per 100 grams of limb tissue per minute. Forearm vascular resistance (FVR) was calculated by dividing mean arterial pressure (MAP) by FBF.

Brachial artery cannulation and phentolamine infusion. Brachial artery cannulation was obtained using a 5-cm, 20-gauge catheter placed in the nondominant arm under sterile conditions using local anesthesia (2–3 ml of 1% Lidocaine). The catheter was continuously flushed (3 ml/h) with heparinized saline (2 U/ml). Intra-arterial pressure was continuously monitored, and medication infusion was accomplished using a three-way stopcock (Baxter, Deerfield, IL) placed in series with the transducer system. Room air arterial blood gases were also obtained before and after exposure in these subjects. Phentolamine infusion consisted of a 5-min loading dose (100 µg/min) followed by a continuous infusion (25 µg/min) until completion of the testing. Variables were measured sequentially under three conditions: normoxia, followed by normoxia + phentolamine, followed by acute isocapnic hypoxia + phentolamine.

MSNA. MSNA recordings were obtained using standard tungsten microelectrodes (FHC, Bowdoinham, ME) inserted into the peroneal nerve after localization of the nerve by surface stimulation. Signals were filtered (low pass, 2,000 Hz; high pass, 700 Hz), amplified (x70,000) and full-wave rectified. The rectified signal was integrated using a 100-ms moving window, for display on an oscilloscope and for recording (Nerve Traffic Analyzer model 662c-3; University of Iowa Bioengineering Dept., Iowa City, IA). Proper electrode position was confirmed by visualization of pulse synchronous bursts of activity occurring 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. For analysis, sympathetic bursts were identified using a specific algorithm described by Hamner and Taylor (13) using Matlab software (MathWorks, Natick, MA). For purposes of quantification, MSNA is reported as average activity during a 5-min period and expressed as burst frequency (bursts/min).

Experimental Protocols

Subjects were enrolled in one of two protocols.

MSNA protocol. Cardiovascular variables and MSNA were recorded at baseline and after exposure. MSNA recording was performed using two separate nerve recordings before and after exposure. Six of the ten subjects who completed the hypoxic exposure also completed an identical protocol using normoxic (sham) exposure. Hypoxic exposure was performed using a leak-free mask, through which subjects breathed a gas mixture containing 10% oxygen balanced with nitrogen. Nitrogen was added to the inspired gas mixture as needed to achieve an oxygen saturation of 80% in all subjects. The hypoxic exposure was considered to have begun once target oxygen saturation was achieved and was maintained for 8 h. Normoxic exposure was performed using an identical mask system through which subjects breathed room air for 8 h. Recording of all variables measured was performed before and after exposure in room air conditions and during two progressive isocapnic hypoxic ventilatory response challenges. Subjects completing both hypoxic and sham exposures were studied a minimum of 1 mo apart from their initial exposure. Sequence of participation in the two protocols was random. A time line of the protocol is shown in Fig. 1A.


Figure 1
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  		Fig. 1. A: muscle sympathetic nerve activity (MSNA) protocol schema time line. B: phentolamine (adrenergic blockade) protocol schema time line. HVR, hypoxic ventilatory response.

 
Adrenergic {alpha}-blockade protocol. Cardiovascular variables were recorded at baseline and after an 8-h poikilocapnic hypoxic exposure, identical to that utilized in the MSNA protocol. Eleven subjects completed this protocol. Recording of all variables measured was performed before and after exposure in room air conditions, during phentolamine infusion, and during two progressive isocapnic hypoxic ventilatory response challenges in the setting of phentolamine infusion. A time line of the protocol is shown in Fig. 1B.

Data Analysis

Fourteen subjects were enrolled in the MSNA protocol; 10 successfully completed the protocol. All failures to complete the protocol were due to inability to obtain stable MSNA recordings in the baseline, preexposure condition. Of the 10 subjects who completed the protocol, 5 subjects' MSNA data were excluded from analysis after detailed off-line review of the recording revealed unacceptable quality of nerve recording in either the prehypoxia or posthypoxia condition. Seventeen subjects were enrolled in the adrenergic blockade protocol; 11 successfully completed the protocol. Failure to complete the protocol was due to failure of arterial cannulation in four subjects, dyspnea during initial hypoxic ventilatory response testing in one subject, and headache during exposure in one subject.

MSNA and ventilatory parameters were averaged over 5-min windows of data collection in room air conditions before and after the hypoxic exposure. HR and MAP were averaged over the corresponding time interval during which plethysmographic forearm flow measurements were made.

Statistical analyses were performed using STATA software (STATA, College Station, TX). Baseline values were compared with postexposure values using the Student's t-test for paired data. Data are reported as means ± SE. P values of <0.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Changes in Ventilatory Control

There was no significant change in the slope of the ventilatory response to acute hypoxia after 8 h of normoxic exposure (0.40 ± 0.05 vs. 0.45 ± 0.08 l·min–1·%SpO2, P > 0.05). Subjects exposed to 8 h of poikilocapnic hypoxia, however, showed a significant increase in the slope of their ventilatory response to acute hypoxia after exposure (0.67 ± 0.1 vs. 1.21 ± 0.2 l·min–1·%SpO2, P < 0.05). A sample curve from a representative subject is shown in Fig. 2.


Figure 2
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  		Fig. 2. HVR in a representative subject. Plots are measurements of the HVR in a representative subject before and after 8 h of poikilocapnic hypoxia. The statistically significant increase in the slope [minute ventilation (in l/min) vs. arterial O2 saturation using pulse oximetry] of the linear regression lines of the plots is consistent with ventilatory acclimatization to hypoxia after 8 h.

 
In those subjects who had arterial blood gas testing performed, room air steady-state arterial PCO2 was significantly decreased after 8 h of poikilocapnic hypoxia. These results are summarized in Table 1.


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  		Table 1. Hypoxic ventilatory response

 
Changes in Hemodynamic Variables

HR and MAP. There was no significant difference in MAP (86.8 ± 6 vs. 91.2 ± 4 mmHg, P > 0.05) or HR (64.4 ± 3 vs. 63.2 ± 3 beats/min, P > 0.05) before and after normoxic exposure. MAP did increase after hypoxic exposure, although statistical significance was not reached (89.4 ± 2 vs. 93.2 ± 2 mmHg, P = 0.12). Diastolic blood pressure, however, was significantly elevated after exposure (64.8 ± 2.7 vs. 70.4 ± 2.0 mmHg, P < 0.05). Systolic blood pressure showed a trend toward an increase, as well (126.5 ± 3.3 vs. 129.6 ± 3.2 mmHg, P < 0.05). HR was significantly increased compared with baseline values after hypoxic exposure (61.0 ± 2 vs. 64.5 ± 2 beats/min, P < 0.05).

FBF and FVR.
NORMOXIC EXPOSURE (N = 6). There was no significant change in normoxic FBF (3.09 ± 0.32 vs. 2.80 ± 0.29 ml·min–1·100 g tissue–1) or FVR (29.5 ± 2.3 vs. 33.7 ± 5.4 mmHg·ml–1·min·100 g tissue, P > 0.05) after sham exposure. With acute isocapnic hypoxic challenge, there was a trend toward an increase in FBF both before and after normoxic exposure (before: 3.09 ± 0.32 vs. 4.05 ± 0.65 ml·min–1·100 g tissue–1, P = 0.27; after: 2.80 ± 0.29 vs. 3.22 ± 0.22 ml·min–1·100 g tissue–1, P = 0.33). Finally, with acute isocapnic hypoxic challenge, there was no significant change in FVR both before and after normoxic exposure (before: 29.5 ± 2.3 vs. 28.1 ± 3.5 mmHg·ml–1·min·100 g tissue, P > 0.05; after: 33.7 ± 5.4 vs. 31.2 ± 2.7 mmHg·ml–1·min·100 g tissue, P > 0.05).


HYPOXIC EXPOSURE (N = 21). Normoxic FBF was significantly increased after 8 h of poikilocapnic hypoxia (2.88 ± 0.25 vs. 3.97 ± 0.35 ml·min–1·100 g tissue–1, P < 0.05). Baseline (normoxic) FVR was significantly decreased after 8 h of poikilocapnic hypoxia (37.7 ± 3.6 vs. 27.6 ± 2.7 mmHg·ml–1·min·100 g tissue, P < 0.05). Preexposure, FBF did increase in response to acute isocapnic hypoxic challenge (2.88 ± 0.25 vs. 4.01 ± 0.72 ml·min–1·100 g tissue–1, P = 0.002). Preexposure, FVR declined significantly in response to acute hypoxic challenge (37.7 ± 3.6 vs. 22.7 ± 3.3 mmHg·ml–1·min·100 g tissue, P < 0.05). After 8 h of poikilocapnic hypoxia, both FVR and FBF did not change significantly in response to acute isocapnic hypoxia (FBF: 3.97 ± 0.35 vs. 5.0 ± 0.73 ml·min–1·100 g tissue–1, P > 0.05; FVR: 27.6 ± 2.7 vs. 26.8 ± 4.7 mmHg·ml–1·min·100 g tissue, P > 0.05). The FVR results are summarized in Fig. 3.


Figure 3
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  		Fig. 3. Forearm vascular resistance (FVR) in room air and in response to acute isocapnic hypoxia. FVR was recorded at baseline (normoxia) and during acute isocapnic hypoxic challenge before and after exposure to 8 h of poikilocapnic hypoxia. The significant decrease in FVR in response to acute isocapnic hypoxia is not present after exposure.

 

{alpha}-BLOCKADE (N = 11). Preexposure, there was a significant decrease in room air FVR with administration of phentolamine in the experimental forearm (40.4 ± 4.6 vs. 20.9 ± 2.7 mmHg·ml–1·min·100 g tissue, P < 0.001). There was no change in the control FVR with administration of phentolamine in the contralateral arm (45.9 ± 5.7 vs. 47.0 ± 6.2 mmHg·ml–1·min·100 g tissue, P > 0.05). With acute hypoxic challenge, there was a significant further decrease in FVR in the setting of continued phentolamine infusion (20.9 ± 2.7 vs. 15.1 ± 1.8 mmHg·ml–1·min·100 g tissue, P < 0.01). There was a significant decrease in control FVR with acute isocapnic hypoxic challenge (47.0 ± 6.2 vs. 39.7 ± 6.1 mmHg·ml–1·min·100 g tissue, P < 0.05). After the 8-h poikilocapnic hypoxic exposure, there was a significant decrease in baseline (normoxic) FVR in the experimental forearm and a decrease in FVR that approached, but did not achieve, statistical significance in the control arm (experimental arm: 40.4 ± 4.6 vs. 24.5 ± 3.3 mmHg·ml–1·min·100 g tissue, P < 0.05; control arm: 45.9 ± 5.7 vs. 32.2 ± 3.9 mmHg·ml–1·min·100 g tissue, P = 0.10). With administration of phentolamine, there was a significant further decrease in FVR that was not seen in the control arm (experimental arm: 24.5 ± 3.3 vs. 16.5 ± 1.9 mmHg·ml–1·min·100 g tissue, P < 0.01; control arm, 32.2 ± 3.9 vs. 34.4 ± 4.7 mmHg·ml–1·min·100 g tissue, P > 0.05). With acute isocapnic hypoxic challenge, there was a significant decrease in FVR in the experimental arm in the setting of {alpha}-blockade (16.5 ± 1.9 vs. 12.8 ± 1.9 mmHg·ml–1·min·100 g tissue, P < 0.001) that was not seen in the control arm (34.4 ± 4.7 vs. 33.2 ± 7.2 mmHg·ml–1·min·100 g tissue, P > 0.05). These results are summarized in Fig. 4.


Figure 4
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  		Fig. 4. FVR in room air and in response to acute isocapnic hypoxia in a setting of phentolamine infusion and control. Changes in FVR were recorded before and after 8 h of exposure to poikilocapnic hypoxia with local administration of phentolamine (experimental forearm) compared with contralateral (control) forearm.

 
MSNA.

There was no change in MSNA after 8 h of normoxic exposure (26.7 ± 6.1 vs. 25.9 ± 6.1 bursts/min, P > 0.05). After 8 h of hypoxic exposure, there was a decrease in MSNA that approached but failed to reach statistical significance (19.8 ± 4.1 vs. 14.3 ± 1.2 bursts/min, P = 0.13). Representative individual tracings are shown in Fig. 5 for three subjects.


Figure 5
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  		Fig. 5. Representative MSNA tracings. Data are representative neurograms from 3 subjects; bpm, beats/min. Subject 1 demonstrates a decrease in activity, and subject 2 demonstrates no significant change, whereas subject 3 shows an increase in activity. Overall, there was a trend toward a decrease in activity postexposure.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The major findings of this study are as follows: 1) similar to other investigators, we found that an 8-h exposure to poikilocapnic hypoxia produced changes in ventilation consistent with hypoxic acclimatization; 2) postexposure, when subjects had returned to normoxia, vascular resistance was significantly decreased, but diastolic blood pressure was significantly increased compared with the preexposure baseline; 3) acute exposure to isocapnic hypoxia by rebreathing produced vasodilation before the 8-h exposure but no change in vascular resistance after the exposure; 4) local {alpha}-blockade with phentolamine restored the vasodilatory response to acute hypoxia following exposure; and, finally, 5) despite the evidence for increased peripheral chemoreflex sensitivity that accounts for acclimatization, there was no increase in sympathetic nerve activity; in fact, there was a trend toward a decrease in MSNA after exposure.

The time course of the human ventilatory response to hypoxia has been extensively investigated. With acute exposure to hypoxia, there is an abrupt increase in ventilation followed by a decline over the course of a 20-min exposure (11). Follow-up evaluations of this "roll-off" suggest significant contributions of both central and peripheral chemoreceptors in the response (10, 17). The response is determined primarily by the severity and duration of the hypoxia with lesser modulation by carbon dioxide levels (9, 11).

As the duration of the hypoxic exposure is increased to 8 h, there is a further significant increase in ventilation characterized as short-term acclimatization (10, 11). Interestingly, whereas the acute response to hypoxia has a significant contribution from both the central and peripheral chemoreceptors, short-term acclimatization appears to be primarily mediated through the peripheral chemoreceptor rather than through central mechanisms (8, 12). Changes in the carotid body are central to the process of short-term acclimatization (23).

In the present study, we have demonstrated the presence of short-term acclimatization as evidenced by both a significant decrease in resting arterial PCO2 and a statistically significant rise in the slope of the ventilatory response to progressive isocapnic hypoxic challenge after the 8-h exposure to poikilocapnic hypoxia. These results are consistent with a previous study of the impact of intermediate-duration hypoxia on ventilatory control (27). On the basis of the current understanding of the mechanisms of ventilatory acclimatization, we suggest that our exposure has resulted in a change in peripheral chemoreflex sensitivity at the level of the carotid body (23). It is in this setting that the changes in vascular tone, MSNA, and the response to acute hypoxia must be considered.

The time course of the cardiovascular response to hypoxia remains less well defined than the ventilatory responses described above. Recently, published work has evaluated the changes in HR in response to 20-min and 2-h exposures to hypoxia. With acute hypoxia, there is evidence of increased HR that may be related to resetting of the baroreflex sensitivity and withdrawal of vagal input (29). With exposure to 20 min of isocapnic hypoxia, there was a sustained increase in HR above baseline (25). Interestingly, after 2 h of either intermittent or continuous poikilocapnic hypoxia, there was no significant change in HR (26). We have documented a significant increase in resting HR after 8 h of poikilocapnic hypoxia. Although it is clearly in the setting of an altered peripheral chemoreceptor response to hypoxia, the exact mechanisms of the elevation in HR remain to be defined. With decreased vascular resistance, however, it seems likely that the increase in HR plays an important role in mediating the increase in arterial pressure that we observed.

The studies of brief-duration hypoxia described above do suggest an increase in systolic blood pressure and MAP during acute isocapnic hypoxia, but these effects do not persist beyond the brief exposure of 20 min (24, 25). Exposure to continuous hypoxia for 2 h did, however, result in a persistent elevation in MAP upon return to normoxic conditions (26). Nocturnal exposure to hypobaric hypoxia in normal subjects for 8 h also has been demonstrated to influence arterial pressure after termination of the exposure (1). In that study, there was a significant increase of 4 mmHg in diastolic pressure alone within 30 min of exposure, which persisted for 90 min after exposure was discontinued (1).

These changes in HR and blood pressure follow a time course of response, suggesting that acute changes in chemo- and baroreflex sensitivity may be important in mediating the changes. As mentioned above, heightened chemoreflex gain might be expected to induce tachycardia and peripheral vasoconstriction via increased sympathetic activity. Similarly, decreased baroreflex activation would be expected to induce an increase in HR through vagal withdrawal and an increase in arterial pressure through sympathoexcitation. The lack of an increase in MSNA combined with the decrease in FVR, however, makes alterations in these peripheral reflexes unlikely to completely account for the hemodynamic changes we observed.

The mechanism by which FVR is modified by hypoxia has been an area of much interest. Vasodilatation seen during short-duration exposures occurs despite increases in sympathetic nervous system activity. Uncoupling of the effects of increased sympathetic nervous system input due to a decreased responsiveness to adrenergic input has been postulated as one possible mechanism. However, vasoconstriction seen in normoxic conditions is preserved in the setting of hypoxia, with Tyramine infusion leading to increased release of catecholamines (6, 7). Interestingly short-term hypoxic exposure has produced sympathoexcitation with no changes in FVR in several studies (4, 21, 24, 29). It would appear that in the setting of sympathoexcitation following brief hypoxia, vasodilation is most appropriately explained by a change in the balance between sympathoexcitation and local vasodilators favoring vasodilation (25, 28).

Adenosine, a potent vasodilator, has been demonstrated to increase in skeletal muscle and contribute to vasodilation in response to systemic hypoxia (18, 19). Endothelium-derived prostaglandins also have a clear role in modulating skeletal muscle vasodilation in response to hypoxia (20). Interestingly, adenosine has been shown to elicit both nitric oxide (NO) and prostaglandin release during hypoxia, and, in fact, NO release may well be dependent on prostaglandin synthesis (22). Although these data do argue for a significant role for local vasodilating mechanisms in the skeletal muscle vasodilation seen in response to systemic hypoxia, there remains little evidence to guide insights into the mechanisms by which vasodilation persists beyond the hypoxic exposure itself.

In our study there was a decrease in FVR that persisted after the hypoxic exposure. Interestingly, there was a failure to further vasodilate to acute hypoxia after exposure to 8 h of poikilocapnic hypoxia. With local {alpha}-blockade, there was preserved vasodilation in response to acute hypoxic challenge. This pattern of response suggests an abnormal response to acute hypoxic challenge in subjects who have previously been exposed to 8 h of poikilocapnic hypoxia, explained in part by altered {alpha}-receptor-mediated mechanisms. Alternatively, there may be a relative maximal effect of local vasodilators preventing further vasodilation to acute hypoxia, although the return to a normal response in the setting of {alpha}-blockade seems to argue against this mechanism.

Both short- and long-term exposure to hypoxia has been shown to contribute to significant sympathoexcitation (3, 4, 14, 21, 29). Brief hypoxia shows the presence of sympathoexcitation in the setting of a significant decrease in vascular resistance after termination of the exposure (24). Prolonged exposure to hypoxia of 4 wk in duration is clearly associated with an elevation in MSNA that outlasts the exposure but with an absence of a significant change in vascular resistance upon return to normoxic conditions despite the persistent elevation of sympathetic nerve activity (14). In contrast to short- and long-term exposures to hypoxia, there is little known about the effects of intermediate-duration exposures to hypoxia in MSNA activity. The relatively small number of subjects in whom we obtained pre- and postexposure recordings of MSNA limited the power of our study to assess a difference in sympathetic activity after exposure, but there was a trend toward a decrease, rather than an increase, in MSNA after return to normoxia. MSNA was seen to increase in only a single subject. This trend is remarkable, because the ventilatory changes argue strongly for increased peripheral chemosensitivity postexposure. The restoration of hypoxic vasodilatation in the setting of local {alpha}-receptor blockade suggests that alterations in sympathetic nervous system activity input to skeletal muscle during acute hypoxia are integral to the changes seen, although given the limited MSNA data successfully obtained, we are not able to integrate this finding with our assessment of MSNA. A study with a larger sample size is needed to determine whether intermediate-duration exposure to hypoxia reduces sympathetic activity or simply fails to produce an increase. Either result is surprising, however, and difficult to explain.

In summary, baseline (normoxic) vascular resistance is decreased after hypoxic exposure, and with acute hypoxic challenge, there is impaired vasodilation that is restored in the setting of local {alpha}-blockade. In the setting of an absence of change in resting MSNA activity compared with the preexposure condition, this suggests that there is an alteration of MSNA-mediated vascular responses to acute hypoxia. This altered response to acute hypoxia may be unique to hypoxic exposures of this duration, because it is not demonstrated in either the shorter- or longer-term exposures.

Although the present findings add important information to our understanding of the impact of intermediate-duration hypoxia on the regulation of vascular tone, several limitations must be acknowledged. Although our findings of increases in both HR and diastolic blood pressure associated with a decrease in FVR imply an alteration in cardiac output, we had no measurement of cardiac output in this study. This is important, because we measured blood flow in a regional circulation (the forearm); thus our calculation of vascular resistance may not reflect changes in other vascular beds, such as the visceral beds. In addition, baroreflex responsiveness may well be altered in the setting of intermediate-duration hypoxia and may be contributing to the changes in homodynamic variables seen, but no direct measurement of baroreflex sensitivity was made as part of this study. Future study of the changes seen after intermediate-duration hypoxia should include assessment of the baroreflex sensitivity and measurement of cardiac output if the mechanism of elevation of blood pressure and altered MSNA are to be fully understood. Furthermore, pre- and postexposure MSNA recordings were unable to be obtained in a number of subjects, limiting our ability to draw conclusions about the sympathetic response to a hypoxic exposure of this duration. In addition, the acute hypoxic challenge consisted only of the hypoxic ventilatory response testing, and the subjects were not maintained in a stable hypoxic condition to allow reasonable assessment of the MSNA response to graded acute hypoxia before and after the exposure. This limits our ability to define the MSNA response to acute hypoxia in this study. Future study also should include a clear assessment of the MSNA response to acute hypoxia to guide insights into the mechanisms suggested above. Finally, although the nonspecific {alpha}-blockade we used does provide insight into the contribution from MSNA in control of vascular resistance following intermediate-duration hypoxia, future investigations are needed to define the role of local vasodilating substances in maintaining skeletal muscle vasodilation that persists beyond the hypoxic exposure.

In conclusion, our results suggest that intermediate-duration hypoxia may represent a distinct point in the continuum of response to hypoxia. Human subjects exposed to intermediate-duration hypoxia demonstrate ventilatory acclimatization, suggesting increased peripheral chemoreflex sensitivity but, despite this, fail to demonstrate significant sympathoexcitation. In addition, they show both a decrease in vascular resistance and an impaired vasodilatory response to acute hypoxia that is restored in the setting of local {alpha}-blockade. The nature of these vascular changes and the sympathetic response to intermediate-duration hypoxia deserve further investigation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: G. Gilmartin, Division of Pulmonary and Critical Care and Sleep Medicine, GZ-402, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215 (e-mail: ggilmart{at}bidmc.harvard.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
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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