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Am J Physiol Heart Circ Physiol 281: H2636-H2644, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 6, H2636-H2644, December 2001

Women at altitude: forearm hemodynamics during acclimatization to 4,300 m with alpha 1-adrenergic blockade

Stacy Zamudio1,2,5, Matthew Douglas2, Robert S. Mazzeo6, Eugene E. Wolfel3, David A. Young4, Paul B. Rock8, Barry Braun7, Stephen R. Muza8, Gail E. Butterfield7,dagger, and Lorna G. Moore1,5

1 Women's Health Research Center and 2 Departments of Anesthesiology, 3 Cardiology, and 4 Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver 80262; 5 Department of Anthropology, University of Colorado at Denver, Denver 80217-3364; 6 Department of Kinesiology and Applied Physiology, University of Colorado at Boulder, Boulder, Colorado 80309; 7 Aging Study Unit, Geriatric Research Education and Clinical Center, Veterans Affairs Palo Alto Health Services, Palo Alto, California 94304; and 8 Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts 01760-5007


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We hypothesized that blockade of alpha 1-adrenergic receptors would prevent the rise in peripheral vascular resistance that normally occurs during acclimatization. Sixteen eumenorrheic women were studied at sea level (SL) and at 4,300 m (days 3 and 10). Volunteers were randomly assigned to take the selective alpha 1-blocker prazosin or placebo. Venous compliance, forearm vascular resistance, and blood flow were measured using plethysmography. Venous compliance fell by day 3 in all subjects (1.39 ± 0.30 vs. 1.62 ± 0.43 ml · Delta 30 mmHg-1 · 100 ml tissue-1 · min-1 at SL, means ± SD). Altitude interacted with prazosin treatment (P < 0.0001) such that compliance returned to SL values by day 10 in the prazosin-treated group (1.68 ± 0.19) but not in the placebo-treated group (1.20 ± 0.10, P < 0.05). By day 3 at 4,300 m, all women had significant falls in resistance (35.2 ± 13.2 vs. 54.5 ± 16.1 mmHg · ml-1 · min-1 at SL) and rises in blood flow (2.5 ± 1.0 vs. 1.6 ± 0.5 ml · 100 ml tissue-1 · min-1 at SL). By day 10, resistance and flow returned toward SL, but this return was less in the prazosin-treated group (resistance: 39.8 ± 4.6 mmHg · ml-1 · min-1 with prazosin vs. 58.5 ± 9.8 mmHg · ml-1 · min-1 with placebo; flow: 1.9 ± 0.7 ml · 100 ml tissue-1 · min-1 with prazosin vs. 2.3 ± 0.3 ml · 100 ml tissue-1 · min-1 with placebo, P < 0.05). Lower resistance related to higher circulating epinephrine in both groups (r = -0.50, P < 0.0001). Higher circulating norepinephrine related to lower venous compliance in the placebo-treated group (r = -0.42, P < 0.05). We conclude that alpha 1-adrenergic stimulation modulates peripheral vascular changes during acclimatization.

high altitude; hypoxia; venous compliance; peripheral blood flow; vascular resistance; prazosin; norepinephrine; epinephrine


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ACTIVATION of the sympathetic nervous system (SNS), evidenced by a rise in circulating catecholamines (22, 23), is thought to play an important role in acclimatization to high altitude. Many of the alterations in cardiovascular (49), ventilatory, and metabolic function (20) that occur during acclimatization have been related to enhanced SNS activity (32). However, blockade of the beta -adrenergic limb does little to alter the acclimatization process, suggesting that the enhanced sympathetic activity is largely alpha -adrenergic in nature (20, 26, 32, 48, 49). alpha 1-Receptors are present in both arteries and veins (10, 31) and contribute to vasoreactivity in both arteries and veins in humans and other mammals (17, 37). Both the alpha 1- and alpha 2-adrenergic receptors are important contributors to vasoconstriction in arterioles and venules (10, 17), with differences noted in their relative effect depending on the vascular bed tested and the size or segment of vessel tested (10, 17, 28). Both are responsive to hypoxia, but such responses vary considerably (38). Subject safety concerns precluded the utilization of generalized blockers of the alpha -adrenergic system. We chose to study alpha 1-adrenergic receptors, as opposed to alpha 2-adrenergic receptors, because prazosin could be justified as a safe and effective drug for human use under altered physiological and environmental conditions.

Most data concerning the effects of hypoxia on alpha 1-adrenoreceptor number and function have been obtained in cell studies or in animal models. The data reported are complex and support the notion that there are differences in the effects of hypoxia and/or SNS stimulation between species, according to duration and/or type of hypoxia, and between vascular beds (6a, 38, 39). Both increases and decreases in arterial alpha 1-adrenoceptor density have been reported in response to hypoxia, whereas such changes are not observed in veins (8, 9, 39). Hypoxia stimulates reflex alpha 1-adrenergically mediated venoconstriction in some (33, 36, 41) but not all animal models (17, 28, 38). In the latter studies, it was observed that, unlike arterioles, venoconstriction was not inhibited by hypoxia. Thus, in the presence of increasing blood pressure and norepinephrine (NE) concentrations, as we (27, 49) have previously reported in humans acclimatizing to high altitude over more prolonged time periods (12-21 days), it can be anticipated that arterial and venous constriction may be stimulated by the catecholamine changes that occur during normal acclimatization.

The data above suggest that alpha -adrenoreceptor-related mechanisms contribute to the altitude-associated vascular adaptations important for maintaining oxygen delivery to tissues. Previous human studies at high altitude have suggested that changes in peripheral vascular resistance and compliance are important for the maintenance of oxygen delivery and that such changes are directly related to sympathetic stimulation (46, 48). Hence, we reasoned that alpha -adrenergic blockade in human volunteers acclimatizing to an altitude of 4,300 m would inhibit some of the adaptive peripheral vascular changes during acclimatization. Specifically, we hypothesized that pharmacological blockade of alpha -adrenergic receptors would prevent or diminish the rise in forearm arterial vascular resistance that has been observed early in acclimatization (day 3 or less) and the prolonged decrease in venous compliance reported in studies of men (6, 44, 50).


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Research design. We chose to measure the peripheral vascular variables on days 3 and 10 of altitude residence because previous studies (6, 44, 50) in men showed that maximal changes in forearm hemodynamics were present by day 3 and resolved by days 5-7 of acclimatization. The results reported here are part of a much larger study that also examined hemodynamics and substrate utilization during exercise. There was hence a tradeoff between accomplishing the goals of all participating investigators and devising a workable schedule of testing. It was not possible to acquire data on the variables reported here immediately upon arrival, because subjects were scheduled for acute-exposure exercise studies (subjects arrived 2/day; the subject not studied immediately was maintained on supplemental oxygen). Because of the length and intensity of the exercise studies, measures of peripheral flow and resistance on day 1 of altitude exposure would likely have been compromised. We estimated our needed sample size by examining the mean differences and standard deviations of previously reported altitude-associated changes in forearm vascular resistance, blood flow, and venous compliance (6, 44). With the use of a two-tailed alpha  of 0.05 and beta  of 0.80, power analysis of the previously published data on vascular resistance and venous compliance suggested a sample size of seven to nine volunteers would be adequate to detect altitude-associated changes.

Forearm hemodynamics were measured on days 3 and 10 of a 12-day study period at sea level and on days 3 and 10 of 12 days of residence at high altitude in healthy women who were taking either placebo or prazosin hydrochloride (prazosin), a selective alpha 1-adrenergic receptor antagonist (alpha -adrenergic blockade). Altitude and prazosin treatment were the independent variables. Acute Mountain Sickness was evaluated, and its impact on the dependent variables was assessed. Dependent variables were venous compliance, forearm blood flow, and forearm vascular resistance (a variable calculated from blood flow and blood pressure). As indicated in the introduction, previous studies (46, 48) have suggested activation of the sympathetic nervous system is causally associated with changes in peripheral vascular resistance and blood flow. Other studies (6, 44) have suggested that hypoxia and hypocapnia mediate changes in peripheral vascular resistance and venous compliance during acclimatization. Therefore, absolute values and the altitude-associated changes in venous compliance, forearm blood flow, and forearm vascular resistance were examined in relation to circulating catecholamines. As a proxy for direct measurement of arterial gas tensions, the dependent variables were also examined in relation to end-tidal CO2 and O2 tensions (PETCO2 and PETO2, respectively) and arterial oxygen saturation (SaO2).

Volunteers. The research protocol was approved by the Institutional Review Boards of the three institutions involved in the study. Volunteers were recruited from the San Francisco Bay area, CA, via newspaper advertisements and flyers posted in local colleges and universities. Inclusion criteria were that the women be sea-level residents between the ages of 18 and 35, healthy, eumenorrheic, in average athletic condition, and not users of tobacco products. Women were excluded from participation if they had a history of high-altitude residence, pregnancy within the past 12 mo, any chronic disease, or allergies to the drugs being used. Volunteers were evaluated before admission into the study with routine blood analyses, urine analyses, electrocardiogram, nutritional assessment, physical examination, determination of usual physical activity pattern, menstrual cycle duration and regularity, pregnancy test, peak oxygen consumption, and assessment of ability to comply with the protocol. Sixteen women gave their informed consent and completed the sea-level and high-altitude phases of the study. Subject characteristics are listed in Table 1. They did not differ between the prazosin- and placebo-treated groups.

                              
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  		Table 1.   Subject characteristics

Altitude sites and conditions. The sea-level site was located in the Palo Alto Veterans Affairs Medical Center (15 m). The high-altitude site was the Maher Memorial Laboratory on top of Pikes Peak, CO (4,300 m). Studies were conducted from March to May, 1998, at sea level and from July to August, 1998, at high altitude. Barometric pressure, temperature, and humidity were recorded on the days that we measured forearm hemodynamics. At sea level, barometric pressure ranged from 750.0 to 757.0 mmHg and at high altitude from 460.5 to 464.5 mmHg. Room temperature ranged from 24 to 29°C in both locations. Humidity ranged from 33 to 65% at sea level and from 23 to 55% at 4,300 m.

alpha -Blockade. The drug assignments were randomized, placebo controlled, and double blind. Volunteers took either placebo (lactate, designed to resemble prazosin) or prazosin and were studied in the same condition at sea level and high altitude. Volunteers taking prazosin initially took 1 mg capsules orally every 8 h for the first 24 h and then took 2 mg three times per day for a total of 6 mg/day continuously until our measurements were completed. Treatment with prazosin or placebo began 4 days before the first measurement of forearm hemodynamics. Blockade was tested by a phenylephrine challenge test 3 and 9 days after the onset of treatment with the higher dose of prazosin [the same day as the measurement of forearm hemodynamics (day 3) and 1 day before forearm hemodynamics (day 10)] at sea level and at high altitude. The degree of alpha 1-adrenergic blockade was documented by a phenylephrine challenge test, where the dose response of systolic blood pressure to incremental increases in phenylephrine, an alpha -adrenergic agonist, was determined. The dose of phenylephrine required to raise systolic blood pressure 20 mmHg above baseline was designated as PD20, which was used to document the degree of blockade (15). Phenylephrine infusions were performed on days 3 and 9 at sea level and on day 9 at high altitude. At sea level, PD20 was 1.47 ± 0.73 µg · kg-1 · min-1 before administration of prazosin and increased to 9.45 ± 2.22 µg · kg-1 · min-1 at day 3 (P < 0.05), indicating a significant degree of alpha 1-adrenergic blockade. The PD20 was 6.87 ± 2.99 µg · kg-1 · min-1 on day 9 at sea level and 15.05 µg · kg-1 · min-1 on day 9 at 4,300 m, indicating no decrement in the degree of blockade due to drug tolerance or altitude. The phenylephrine challenges revealed that blockade was adequate throughout the study. There was no evidence of reduction in blockade at high altitude (47).

Forearm hemodynamic measurements. Venous compliance, forearm blood flow, and vascular resistance were determined from plethysmographic and blood pressure measurements. All tests were conducted in fasting (minimum of 2 h) volunteers who were comfortably seated in a quiet and thermoneutral environment. Before each test session, the volunteer's forearm was measured at its widest point and fitted with a latex cuff, which was snug against the arm when inflated. The upper and lower margins of the latex cuff were marked with ink for later measurement of tissue volume, and the latex cuff was pressurized to 8 cmH20. An upper arm occlusion cuff and a wrist occlusion cuff were placed on the arm to be measured, and a pulse oximeter was placed on the middle finger of the opposite hand. The plethysmograph was calibrated by injecting 3 ml of air into the latex cuff and pressure-sensing system. Tissue volume was measured by water displacement immediately after the hemodynamic studies. All data for blood flow and venous compliance calculations were directly recorded onto a computer using a BIOPAC Systems (Goleta, CA) physiological data recording system. The data were analyzed using the Aqcknowledge software program (version 3.0, MP100WS data collection system, MacIntosh).

Blood pressure was measured in duplicate with an armcuff sphygmomanometer immediately before the measurement of forearm hemodynamics. Venous blood pressure was directly measured throughout the venous compliance test using a pressure transducer attached to a venous catheter, which was placed in a vein in the antecubital fossa at least 1 h before the blood flow and venous compliance measurements. Care was taken to assure that the arm position was adjusted so that the venous pressure transducer was at the level of the heart. Each transducer was checked for accuracy against the computer readout and a mercury manometer before each study.

For the venous compliance test, the wrist cuff was inflated and held continuously at 200 mmHg to exclude hand blood flow. The upper arm occlusion cuff was then inflated in ~3- to 5-mmHg increments (from 0 to at least 45 mmHg) at 20-s intervals. The change in forearm blood volume due to occlusion of venous outflow (venous volume) was recorded continuously on the computer for the 3-5 min of the study. Volunteers reported no ill effects from the occlusion of hand blood flow other than tingling when blood flow to the hand resumed. Direct measurement of venous pressure was accomplished in 59 of 64 venous compliance tests. In the remaining five tests, direct evaluation of venous pressure was prevented by malfunction of the catheter. In these five tests, the stepwise increasing pressure measured in the upper arm cuff was assumed to equal venous pressure. This assumption is supported by the close correlation between the pressure values noted in the upper arm cuff and those obtained from the intravenous pressure transducer within each subject (mean r2 for all subjects was 0.998 ± 0.004, range of 0.975-1.0).

Venous compliance was calculated as the change in venous volume from 0 to 30 mmHg of venous pressure (VV30). The regression of change in volume (y) against venous pressure (x) was examined as both a linear and a logarithmic regression equation. The r2 for linear measures of venous compliance averaged 0.93 ± 0.04 at sea level (range of 0.86-0.98) and 0.94 ± 0.03 at Pikes Peak (range of 0.84-0.98), whereas the logarithmic regression averaged an r2 of 0.98 ± 0.01 at sea level (range of 0.96-0.99) and 0.98 ± 0.01 on Pikes Peak (range of 0.97-0.99). Logarithmic regression yielded a significantly better fit to the data than linear regression (P < 0.001), and hence the VV30 derived from the logarithmic equation are reported here.

For the forearm blood flow test, the upper occlusion cuff was inflated to 10 mmHg below the subject's previously measured diastolic blood pressure. Hand blood flow was excluded by inflating the wrist cuff to 200 mmHg. A series of 6-10 measurements were made at 30-s intervals by initiating a cycle of 10 s of dual cuff inflation and 20 s of deflation. The subsequent change in the pressure inside the midarm latex cuff, due to blood engorgement below the upper inflation cuff, was recorded to the computer. Calculation of blood flow was made using the following equation: flow = slope (in ml/s) × 60 ×100/ml tissue volume.

The blood pressure measured immediately before the study was converted to mean arterial pressure {[(systolic pressure × 2) + diastolic pressure]/3} and forearm vascular resistance was calculated as forearm blood flow divided by mean arterial pressure.

The within- and between-day variability of the forearm hemodynamic measures (coefficient of variation) was tested in five people at sea level. Within-day variability was 5 ± 3% for forearm blood flow, 3 ± 2% for forearm vascular resistance, and 3 ± 2% for venous compliance. Day-to-day variability was 12 ± 5% for forearm blood flow, 11 ± 7% for forearm vascular resistance, and 11 ± 6% for venous compliance. These values are similar to the 11-13% day-to-day variability in similar measurement techniques (water-filled and strain-gauge plethysmography) reported by other investigators (for a review, see Ref. 30).

Other measurements. Acute Mountain Sickness was evaluated every morning and evening throughout the study using the Lake Louise Scoring system (values >= 3 on the symptoms score are considered positive for Acute Mountain Sickness) and the Environmental Symptoms Questionnaire. The results from these two instruments did not differ, and hence, for simplicity, only the Lake Louise Scores are considered in this paper (16). Because vascular variables were measured in the morning, the AM Acute Mountain Sickness scores were used to discriminate between subjects who were ill versus not ill and are reported in RESULTS. SaO2 was measured by finger pulse-oximetry (model 47201A, Ohmeda; Boulder, CO) throughout each of the hemodynamic tests and averaged. PETCO2 and PETO2 were measured at rest on days 2 and 8 at sea level and on days 3 and 12 at high altitude using a computer-controlled open-circuit spirometry and gas analyzer system (Vmax229, SensorMedics) during ventilation studies; the results are reported elsewhere. Resting plasma catecholamine concentrations (NE and epinephrine) were acquired on the morning of the forearm hemodynamic tests (~6:30-7:00 AM, before rising from bed). Catecholamines were measured by high-performance liquid chromatography with electrochemical detection, as previously described (22).

Statistics. Data were analyzed using StatView (version 5.1, SAS Institute) software packages for the MacIntosh and SAS. A linear mixed-effects modeling approach was used to investigate the independent and interactive effects of alpha 1-adrenergic blockade, altitude, and time at altitude to arrive at a best-fit model (18). Within the context of the latter, contrasts were used to compare data from prazosin- versus placebo-treated women and from sea level versus day 3 and day 10 of altitude exposure. Data are reported as significant where P < 0.05; interaction terms are reported and were examined further using contrasts where P < 0.10. Where interactions between prazosin treatment and altitude were absent, the two groups were considered together with respect to altitude effects. Relationships between the variables previously reported as causally associated with altitude-associated changes in forearm hemodynamics (hypoxia, hypocapnia, and catecholamines) were examined using regression analysis. The data are presented as means ± SD.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

There was no difference between the two sea-level measurements of forearm hemodynamics (days 3 and 10 of a 12-day protocol designed to mirror the studies planned at high altitude). Acute Mountain Sickness scores did not differ between the prazosin- and placebo-treated women on either day 3 (3.2 ± 0.9 prazosin vs. 3.8 ± 1.0 placebo) or day 10 (2.0 ± 0.5 prazosin vs. 1.9 ± 0.6 placebo). Four women in the prazosin-treated group and six women in the placebo-treated group had scores >= 3 on day 3, while two prazosin-treated and three placebo-treated women had scores >= 3 on day 10. No subject received pharmacological treatment for Acute Mountain Sickness before completing the day 3 vascular studies. Subgroup analysis revealed no differences in the dependent variables between women who were ill versus those who were not.

Venous compliance, as assessed by VV30, was similar in the prazosin-treated and placebo-treated women at sea level (P = 0.50). Venous compliance did not differ on day 3 of altitude residence in prazosin-treated versus placebo-treated women (P = 0.95) and was decreased relative to sea level when both groups of women were considered together (P < 0.05). Prazosin treatment interacted with altitude exposure (P < 0.0001; Fig. 1) such that prazosin-treated women differed from the women taking placebo on day 10 of altitude residence. Venous compliance returned to sea-level values in the prazosin-treated women on day 10 of residence at 4,300 m (P = 0.59, sea-level versus day 10). In contrast, VV30 further declined in the women taking placebo, resulting in decreased venous compliance relative to sea level (P < 0.01) and relative to the women taking prazosin (P < 0.05). Thus prazosin treatment appeared to prevent a prolonged decline in VV30 during 10 days of altitude residence (Fig. 1).


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  		Fig. 1.   Venous compliance, or the change in venous volume from 0 to 30 mmHg of venous pressure (VV30), was similar in prazosin- and placebo-treated women at sea level and on day 3 at 4,300 m. VV30 declined by 11 ± 24% in the placebo-treated and 10 ± 23% in the prazosin-treated group on day 3 of altitude acclimatization and was lower than at sea level. Venous compliance continued to decrease in the placebo-treated women and was 34 ± 22% lower than at sea level on day 10 at 4,300 m (P < 0.05). In contrast, venous compliance rose between days 3 and 10 in the prazosin-treated women and did not differ from the values observed at sea level on day 10 at 4,300 m. , Placebo-treated women; , prazosin-treated women. *P < 0.05, placebo versus prazosin; dagger P < 0.05, sea level versus high altitude. Values in placebo: day 3 at sea level, 1.58 ± 0.14; day 10 at sea level, 1.65 ± 0.13; day 3 at 4,300 m, 1.39 ± 0.12; and day 10 at 4,300 m, 1.20 ± 0.10. Values in prazosin: day 3 at sea level, 1.70 ± 0.25; day 10 at sea level, 1.54 ± 0.15; day 3 at 4,300 m, 1.38 ± 0.10; and day 10 at 4,300 m, 1.68 ± 0.19.

Forearm vascular resistance was lower in women taking prazosin across all 4 test days (P < 0.05). Forearm vascular resistance fell with altitude exposure in all women (P < 0.0001; Fig. 2) and was similar in the prazosin- and placebo-treated groups on day 3 at 4,300 m (P = 0.35). However, forearm vascular resistance increased between days 3 and 10 at 4,300 m in the placebo-treated group (P < 0.01) but not in the prazosin-treated group (P = 0.21), so that on day 10 forearm vascular resistance was lower in the prazosin-treated women (P < 0.05). Despite this difference, the rise in forearm vascular resistance in all women between days 3 and 10 was such that values on day 10 at 4,300 m did not differ from values observed at sea level (P = 0.20; Fig. 2).


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  		Fig. 2.   Forearm vascular resistance was lower in prazosin-treated women than in placebo-treated women at day 10 of altitude exposure (P < 0.05). Forearm vascular resistance was lower than at sea level on day 3 of altitude exposure in both prazosin- and placebo-treated women but rose between days 3 and 10 in both groups so that it did not differ from the values observed at sea level. , Placebo-treated women; , prazosin-treated women. *P < 0.05, placebo versus prazosin; dagger P < 0.05, sea level versus high altitude. Values in placebo: day 3 at sea level, 60.0 ± 6.2; day 10 at sea level, 63.6 ± 6.3; day 3 at 4,300 m, 39.1 ± 5.1; and day 10 at 4,300 m, 58.5 ± 9.8. Values in prazosin: day 3 at sea level, 45.4 ± 2.8; day 10 at sea level, 49.3 ± 5.2; day 3 at 4,300 m, 31.2 ± 4.1; and day 10 at 4,300 m, 39.8 ± 4.6.

Forearm blood flow did not differ between the prazosin-treated and placebo-treated groups on any test day (P = 0.41 at sea level, P = 0.64 on day 3 at 4,300 m, and P = 0.26 on day 10 at 4,300 m; Table 2). Forearm blood flow was markedly higher compared with sea level on day 3 of residence at 4,300 m (P < 0.0001; Table 2). Values returned toward those observed at sea level by day 10 of altitude residence but were still higher than at sea level (P < 0.02) when all women were considered together.

                              
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  		Table 2.   Forearm blood flow, BP, PETO2, PETO2, and SaO2 at sea level and high altitude

Systolic and diastolic blood pressures were similar in prazosin- versus placebo-treated women when all 4 test days were considered (P = 0.62 for systolic, P = 0.13 for diastolic; Table 2). Systolic blood pressure rose between days 3 and 10 of altitude residence in all women (P < 0.05). Placebo-treated women had no change in diastolic blood pressure with altitude residence (Table 2). However, on day 3 at 4,300 m, the diastolic pressure of prazosin-treated women was lower than at sea level (P < 0.01) and lower than in placebo-treated women (P < 0.01). Diastolic pressure rose in the prazosin-treated women between days 3 and 10, such that values did not differ from sea level (P = 0.56). Mean arterial pressure was lower in prazosin-treated women when all 4 test days were considered (P < 0.05). Mean arterial pressure was lower in prazosin- versus placebo-treated women on day 3 at 4,300 m and rose between days 3 and 10 (P < 0.05), but altitude values did not differ from values observed at sea level (Table 2). There was no change in mean arterial pressure with altitude in placebo-treated women. As expected under the conditions of altitude exposure, SaO2, PETCO2, and PETO2 were lower at high altitude (P < 0.0001; Table 2) but did not differ between the prazosin- and placebo-treated groups.

Plasma NE and epinephrine concentrations were higher in prazosin-treated women at sea level (data not shown). NE was similar to sea-level values on day 3 of altitude exposure but rose markedly by day 10 in both groups (P < 0.000l). Epinephrine rose markedly by day 3 at high altitude in both groups (P < 0.0001) but had returned to sea-level values by day 10. There was no significant difference in plasma catecholamine concentrations in the prazosin- versus placebo-treated group on days 3 and 10 at high altitude, although epinephrine was 30% greater in the prazosin-treated group on day 3 at 4,300 m. Higher concentrations of plasma epinephrine within each treatment group were related to lower forearm vascular resistance across all test days (Fig. 3). Hence, plasma epinephrine was positively related to forearm blood flow (y = 0.99 + 16.94x, r2 = 0.22, r = 0.46, P < 0.001 across all test days). Plasma epinephrine was also positively associated with the altitude-associated change (reduction) in forearm vascular resistance at 4,300 m (y = -10.08 + 381.99x, r2 = -0.19, r = -0.44, P < 0.05) and increase in blood flow (y = -0.114 + 15.084x, r2 = 0.24, r = 0.49, P < 0.05, data not shown). Across all test days, placebo- but not prazosin-treated women with lower plasma NE concentrations had greater venous compliance (Fig. 4). With respect to measures of end-tidal gases and oxygenation, women with higher SaO2 had greater venous compliance on day 3 at 4,300 m (y = -1.508 + 0.035x, r2 = 0.30, r = 0.55, P < 0.05, data not shown). Women with lower PETCO2 had greater venous compliance on day 10 at 4,300 m (y = 3.951 - 0.09x, r2 = -0.31, r = -0.56, P < 0.05, data not shown). Prazosin treatment did not influence the magnitude or direction of these relationships. PETO2 did not relate to any of the dependent variables. Venous compliance was not related to blood flow or vascular resistance.


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  		Fig. 3.   Forearm vascular resistance was negatively associated with plasma epinephrine concentrations. The direction and magnitude of this relationship was similar in prazosin- and placebo-treated women. A: prazosin-treated women, y = 58.962 - 282.727x, r2 = 0.17, P < 0.05. B: placebo-treated women, y = 77.076 - 387.875x, r2 = 0.18, P < 0.05. open circle , Sea-level data; , high-altitude data.



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  		Fig. 4.   Greater venous compliance was associated with lower plasma norepinephrine concentrations in women taking placebo (y = 1.72 - 0.53x, r2 = 0.18, r = -0.42, P < 0.05). triangle , Sea level; , day 3 at 4,300 m; open circle , day 10 at 4,300 m.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Our data support the hypothesis that alpha 1-adrenergic receptor stimulation is an important contributor to the peripheral vascular changes that occur during acclimatization. The hypothesis that pharmacological blockade of alpha 1-adrenergic receptors would diminish the rise in peripheral vascular resistance associated with acclimatization was supported. Venous compliance was decreased on day 3 at 4,300 m and remained low in placebo-treated women, whereas the day 3 fall in venous compliance resolved by day 10 in prazosin-treated women. All of our volunteers had a marked decrease in forearm vascular resistance and increase in forearm blood flow by day 3 of residence at high altitude. While both groups returned toward sea-level values by day 10, the rise in resistance was less in prazosin-treated women, who thus had lower resistance than the placebo-treated group on day 10. These data suggest that alpha 1-adrenergic stimulation contributes to the return of forearm vascular resistance to sea-level values. Plasma NE concentrations were inversely related to venous compliance in placebo-treated women only, suggesting that NE-mediated alpha 1-adrenergic stimulation contributes to the prolonged decline in forearm venous compliance that occurs during acclimatization. Higher plasma epinephrine concentrations were associated with altitude-associated decreases in forearm vascular resistance in both placebo- and prazosin-treated women, suggesting that beta 2-adrenergic stimulation may have favored arterial vasodilatation (3).

Both at rest and during exercise, the findings from studies (13, 21, 27, 46) of the central as well as the peripheral circulation suggest that blood flow is regulated at high altitude to preserve oxygen delivery to critical organs and tissues. In a study (1) of men at 4,300 m, resting leg blood flow did not change with acute or chronic hypoxia (18 days), whereas in another study (46) at 4,300 m resting leg blood flow decreased with acclimatization (21 days). This decrease was due to vasoconstriction, which in turn was due to heightened sympathetic stimulation during acclimatization (46). In both studies, leg O2 extraction at rest and during exercise was similar to sea level due to increased arteriovenous O2 extraction, which in turn was due to increased CaO2.

Whereas our findings on venous compliance generally parallel the results of studies in male volunteers at altitudes ranging from 3,800 to 4,300 m, our data on forearm vascular resistance and blood flow differ. There have been three previous serial studies of forearm hemodynamics during altitude exposure involving a total of 21 male volunteers. In all three studies, there was a significant increase in forearm vascular resistance and a decrease in blood flow by the third day of altitude residence, which resolved by days 5-7 of altitude residence (6, 44, 50). This is in direct contrast with our findings in young women, who had a significant fall in forearm vascular resistance and increase in blood flow on day 3 at 4,300 m, which had not yet returned to sea-level values by day 10 of altitude residence. The difference may be one of timing rather than kind; in men, the first 24 h of altitude exposure was associated with a marked fall in vascular resistance and increase in blood flow, similar to what we observed in women on day 3 of residence at 4,300 m (44, 50). A longer time course for peripheral vascular changes in women could account for both the decreased resistance at day 3 and the lack of full return to sea-level values as late as day 10. Our data are consistent with previous studies (6, 44, 50) showing a prolonged decline in venous compliance with altitude exposure. We observed a significant decline in venous compliance by day 3, which continued to become more marked in the placebo-treated subjects on day 10.

Methodological differences between this and the previous studies in men might contribute to the differences observed in forearm arterial vascular response. However, water-filled versus strain-gauge plethysmographic techniques are similar in accuracy, and both are similar to the air-filled double latex cuff method used in the present study (5, 30, 34). Given the similarity and accuracy of the various techniques, we do not think that methodological differences are likely to account for the sex difference we observed in forearm vascular resistance and blood flow.

Previous studies of men at high altitude have yielded positive correlations between epinephrine and hypoxia, epinephrine and lactate during exercise (23), NE and mean arterial pressure (47), and exercise NE levels and systemic vascular resistance (19). The relationships reported here among circulating catecholamines, vascular resistance, and venous compliance are consistent with previous reports. As in our previous study of women, the volunteers in the present study had a rise in epinephrine during the first few days of altitude residence, which rapidly returned to normal. NE increased later during altitude residence (22). In this, as in another of our studies (21), alpha 1-adrenoreceptor blockade with prazosin produced a marked sympathoadrenal compensatory response (21). Prazosin exerts a vasodilatory effect by inhibiting the vasoconstriction caused by NE release at vascular smooth muscle nerve endings (3). As reviewed by Mazzeo and colleagues (21), the normal increase in whole body sympathetic nerve activity prompted by altitude exposure results in an increase in mean arterial pressure and shunting of blood flow from skeletal muscle to other tissues. A modest increase in circulating epinephrine stimulates beta 2-adrenergic receptors to cause arterial vasodilatation (3). In the present study, by day 3 at high altitude, prazosin- and placebo-treated subjects had epinephrine concentrations greater than at sea level and within the range reported to stimulate the beta 2-associated increase in blood flow (3). Furthermore, small increases in epinephrine may cause blood pressure to fall, and this might be especially true in the presence of alpha 1-adrenergic blockade. Hence, we speculate that the fall in mean arterial pressure among prazosin-treated subjects on day 3 at 4,300 m might be due to their higher epinephrine concentrations (30% higher than placebo) acting in conjunction with alpha 1-adrenergic blockade. Epinephrine concentrations returned to sea-level values by day 10, which is consistent with the return of forearm vascular resistance to sea-level values. Likewise, whereas NE had not increased relative to sea level by day 3 at 4,300 m, it more than doubled by day 10, perhaps contributing to the prolonged decline in venous compliance in the placebo-treated but not prazosin-treated women. The consistency of the relationships among vascular resistance and venous compliance and changes in catecholamines supports the likelihood that SNS stimulation directly contributes to the altitude-related vascular changes we report here, accounting for >20% of the total variation in blood flow and resistance.

Previous studies (6, 44, 50) suggest that hypoxia and hypocapnia are causally related to the changes in forearm vascular resistance and compliance. We found no relationship among the vascular changes and measurements of PETCO2 and PETO2 on day 3 of altitude residence and only a weak correlation between hypocapnia and increased venous tone on day 10. The relationship between greater venous constriction and higher SaO2 on day 3 is consistent with previous reports; one would reason that women hyperventilating would have both lower PETCO2 and higher SaO2 (6, 44, 50). Taken together, the regression analyses suggest that those women adapting more readily to high altitude had less change in forearm vascular resistance and compliance. Recent data suggest that a short-term increase in SNS activity does not change venous compliance, as indicated by similarity in the slope of the pressure-volume curves with versus without rapid short-term SNS stimulation. Instead, the unstressed volume of the forearm veins is decreased by SNS stimulation (14). Regardless of whether adrenergic mechanisms play a direct or indirect role in altitude-associated changes in venous tone, it is clear that sustained venoconstriction occurs in humans at altitude in this as well as other studies (6, 44, 50). It is also well documented that plasma volume declines markedly with hypoxia. The veins serve as the major reservoir for plasma volume, and studies in men suggest that the time course for acclimatization-associated decrease in venous compliance parallels that of decline in plasma volume. Because hemoconcentration is important for maintained O2 delivery during acclimatization, venoconstriction, whether due to direct SNS stimulation or not, appears to be an important contributor to acclimatization to high altitude.

The data reported here suggest that there might be sex differences in the time course of vascular response to acclimatization. While we cannot assume that men and women respond exactly alike to basal or stimulated changes in catecholamine concentrations, the data reported here do not suggest that sex differences are mediated by catecholamines, because the time course and magnitude of changes in epinephrine and NE are similar in women versus men (22, 23). It is possible, though, that the vasodilator effects of estrogen could have contributed to a more prolonged time course for the return of forearm blood flow to sea-level values. Vasodilatation by estradiol is mediated by stimulation of endothelial alpha 2-receptors (increasing endothelial production of nitric oxide and vasodilator prostaglandins) (24, 29, 40, 43) and by activation of vascular smooth muscle alpha 2-receptors, which decreases sensitivity to NE (2). The presence of estradiol may thus have contributed to the prolonged increase in blood flow at 4,300 m. However, a direct relationship between circulating estradiol concentrations and vascular variables was not observed. Studies in postmenopausal women or in larger samples of premenopausal women using a within-subject crossover design are needed to fully test the influence of cycle phase on the vascular variables examined in this study.

The data reported here are part of a larger study funded by the Department of Defense Women's Health Initiative. The purpose of the larger project "Women at Altitude" was twofold. First, we wanted to examine the process of acclimatization to high altitude in women, who have not been systematically studied in the past but who now comprise ~15% of the active duty military force. This goal required measuring and interpreting the effects of the menstrual cycle, if any, on the cardiovascular and metabolic variables known to be important in the acclimatization process. It is known that ovarian hormones interact with sympathoadrenal mechanisms of vascular control in a number of ways (45). For example, the luteal phase of the menstrual cycle is associated with dilatation of both veins and arteries despite increased SNS activity (or SNS activity may be increased as a compensatory response to the vasodilatation) (4, 25). Unfortunately, it proved impossible to measure the women during our 12-day protocols within the time frames considered by the larger scientific community as optimal for evaluation of cycle effects, i.e., within-subject-matched sea-level and high-altitude studies occurring between days 3 and 9 of the follicular phase and between days 3 and 7 of the luteal phase. Moreover, as has been reported in other studies of healthy young women, 25% of the cycles monitored in our study were abnormal (42). Menstrual cycle data were therefore dropped from the present report but may be obtained from the first author upon request.

In three previous serial studies (6, 44, 50) of forearm hemodynamics during acute and chronic altitude exposure, the within- or between-day variability of the plethysmographic measurement technique was not examined. The changes we measured were generally in excess of the day-to-day variability of the method. We found that forearm blood flow increased by 58% and resistance decreased by 39% on day 3, changes much larger than the variability of the method. Venous compliance declined by 15% on day 3 at 4,300 m, a statistically significant value, but very close to being within the day-to-day variability observed at sea level. However, the subsequent decline in placebo-treated women was 34%, too great to be attributable to day-to-day variation. We observed an average forearm blood flow at sea level (in placebo-treated volunteers) of 1.7 ± 0.9 ml · 100 ml-1 · min-1 and of 1.6 ± 0.5 ml/Delta 30 mmHg for venous compliance, somewhat lower than the average values of 3.0 ml · 100 ml-1 · min-1 and 3.6 ml/Delta 30 mmHg, respectively, reported for men (6, 44, 50). However, our results agreed generally with previously published data on forearm blood flow and venous compliance in healthy women (12, 35).

Our data support the conclusion that alpha 1-adrenergic receptor stimulation is an important modulator of the peripheral vascular changes that occur during acclimatization and that epinephrine is closely associated with changes in forearm resistance, whereas NE is related to changes in venous compliance.


    ACKNOWLEDGEMENTS

The intellectual and methodological contributions of Dr. John T. Reeves and Gene McCullough are gratefully acknowledged. The project would not have been possible without the efforts of Rosanne McCullough, Dr. Anne Friedlander, the nursing staff, the dieticians, and the student workers of the Geriatric Research Education and Clinical Center-Aging Study Unit, Veterans Affairs Palo Alto Health Services. The hormone assays critical to the entire Women at Altitude project were performed by Michelle Mayo and Dr. Catherine Gabaree, Director of the Central Laboratory of the United States Army Research Institute of Environmental Medicine. The good will and tolerance of the volunteers was much appreciated-without them, the study would truly have been impossible.


    FOOTNOTES

dagger Deceased 28 December 1999.

This work was funded by Department of Defense Army Women's Health Initiative Contract DAMD17-95-C-5100, Women at Altitude: The Influence of Menstrual Cycle Phase and alpha -Adrenergic Blockade on High Altitude Acclimatization.

Address for reprint requests and other correspondence: S. Zamudio, Univ. of Colorado Health Sciences Center, Dept. of Anesthesiology B-113, 4200 E. 9th Ave., Denver, CO 80262 (E-mail: Stacy.Zamudio{at}uchsc.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.

Received 4 April 2000; accepted in final form 10 August 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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