The epinephrine response to acute high-altitude exposure is primarily mediated via the β-adrenergic receptors and contributes immediately to improve oxygen delivery. Resulting are increases in heart rate, stroke volume (thus, increasing cardiac output), tissue vasodilation, and bronchodilation, all promoting increased o2 delivery to tissues (Fig. 1). Further, epinephrine is well known to activate both muscle and liver glycogenolysis thereby enhancing carbohydrate utilization as well as lactate production. A greater utilization of carbohydrates is a more economical use of o2 as more energy is derived per L of o2 consumed from carbohydrates (5.05 kcal·L−1) versus that from fat (4.68 kcal·L−1). Thus, optimizing the energy yield per unit of o2 would be beneficial during times of limited o2 availability such as hypoxia. Additionally, the increase in β-adrenergic stimulation contributes to the elevation in metabolic rate associated with acute high-altitude exposure (Fig. 1).
The norepinephrine response to hypoxia is somewhat different than that observed for epinephrine. Most studies indicate that when compared with sea-level values, resting plasma norepinephrine levels do not change significantly with acute hypoxia (6,7,12). However, whereas resting plasma norepinephrine remains unchanged, muscle sympathetic nerve activity has been shown to increase while breathing 8–12% o2 as well as during acute hypobaric hypoxia simulating 4000–6000 m (13). In support of this, we have been able to demonstrate that within 4 h after arrival to 4300 m, there was a significant increase in norepinephrine release from the resting legs compared with values measured at sea level. This occurred despite the fact that plasma norepinephrine levels remained unchanged (7). Thus, increases in sympathetic nervous system (SNS) activity likely occur to a variety of vascular beds during acute hypoxia; however, such activity cannot generally be detected by measurement of plasma norepinephrine content alone.
Plasma levels of norepinephrine are a function of the rate of spillover into the circulation (approximately 10–20% of the norepinephrine released by sympathetic nerves under resting conditions), a small amount secreted by the adrenal medulla, and the rate of its removal or clearance from the plasma pool. There appears to be no direct effects of hypoxia on enhancing the prejunctional release of neuronal norepinephrine nor on intraneuronal metabolism and uptake of the neurotransmitter in muscle (3), suggesting that the enhanced spillover observed in our studies is directly related to an increase in sympathetic activity. No change or increase in clearance of plasma norepinephrine has been reported during acute hypoxia (4,12). An increase in clearance would actually tend to lower plasma levels and therefore would not explain the increases associated with altitude. However, no studies exist that have examined the effect of chronic high-altitude exposure on plasma clearance of norepinephrine.
The sympathoadrenal response to exercise generally follows the pattern described above for resting conditions. The added stress of exercise (in addition to hypoxia) results in accentuated catecholamine levels for a given submaximal workload. The magnitude of the epinephrine response is dependent upon both the exercise intensity as well as the degree of hypoxia. We have shown that exercise at altitude at the same absolute workload (100 W), representing 50% and 65% o2max at sea level and 4300 m, respectively, elicits significant increases in arterial epinephrine levels (6,7,9). Epinephrine values increase linearly over time during the 45-min submaximal exercise with acute high-altitude exposure whereas values for both sea-level and chronic altitude exposure remained stable throughout the submaximal work bout. When the absolute workload is adjusted such that subjects are exercising at similar relative workloads (same % o2max) during both normoxic and hypoxic conditions, increased plasma epinephrine levels are still found to persist during acute hypoxia (9). Thus, it appears that an additive effect exists such that the stress imposed by hypoxia (directly effecting adrenal activity) and exercise (primarily an SNS stimulation of adrenal activity) yield greater epinephrine levels than that found for just each stressor alone.
During exercise, acute hypoxia results in elevated levels of plasma norepinephrine compared with sea level. When individuals exercise at the same absolute workloads achieving steady-state o2, we have shown that norepinephrine levels are significantly elevated with acute hypoxia compared with sea level (6,7,9). However, it appears that the norepinephrine response during acute hypoxia is primarily dependent upon the relative work intensity. Thus, if subjects work at a similar percentage of o2max under both conditions, the norepinephrine response is not significantly different between sea level and acute hypoxia.
ACCLIMATIZATION TO HIGH-ALTITUDE
During acclimatization, arterial epinephrine levels decline toward sea-level values. As noted above, resting epinephrine concentrations fall as arterial oxygenation increases suggesting that concentrations are likely related to increases in oxygen-carrying capacity and reduction in the severity of hypoxemia. This decline in circulating epinephrine levels, in conjunction with the documented downregulation of β-receptors in the heart (5), contributes to the reduction in resting heart rate observed over time at altitude. The combination of a waning β-stimulation and decreased receptor sensitivity likely plays a role in the decline in resting cardiac output over time at altitude to sea-level values.
The norepinephrine response, however, as measured by both arterial and urinary levels, reacts in a very different manner than that observed for epinephrine. Although plasma norepinephrine levels during acute exposure are similar to those found for sea level, concentrations rise significantly with time during the acclimatization period (−70–100%). Furthermore, urinary norepinephrine gradually increases, reaching a plateau on days 6–7 and staying elevated throughout the remaining 21 d at 4300 m. This increase in SNS activity with chronic altitude exposure is further supported by measurements of net norepinephrine release across resting muscle. A dramatic reversal from net norepinephrine uptake by resting leg at sea level to that of net release after chronic exposure clearly reflects enhanced sympathetic nerve activity (7). This indicates that spillover from sympathetic nerves directed to skeletal muscle is a major contributor to the elevation observed in resting plasma norepinephrine with prolonged exposure to hypoxia. The Pikes Peak studies are the first to examine the effect of chronic hypoxia on skeletal muscle SNS activity, and to demonstrate a dissociation of sympathetic nerve activity (increasing) and adrenal medullary responses (decreasing) over time at high altitude (6,7,8).
The mechanisms responsible for the increase in sympathetic activity that occur over time at altitude, however, remain to be determined. A direct effect of hypoxia on sympathetic nerve activity is not likely because sympathetic activity continues to increase with time at altitude while the degree of hypoxemia is decreasing. We have found a high correlation between the decline in plasma volume with the rise in norepinephrine over time at altitude (r = −0.89). A reduction in blood or plasma volume is known to activate the sympathetics (via baroreceptor activity) in an attempt to maintain arterial pressure. However, a baroreceptor-mediated increase in sympathetic activity is unlikely as blood pressure is significantly elevated during acclimatization (13). The declining plasma volume with rising norepinephrine levels is probably a result, rather than a cause, of the increase in sympathetic activity. End-tidal Co2 pressure (PETCo2) is inversely (r = −0.90, P < 0.001) and min ventilation (VE) is positively correlated with norepinephrine excretion rates (r = 0.68, P < 0.01 (1), Fig. 2B). This is compatible with the concept that ventilatory parameters are partially responsible for activating sympathetic nerve activity. Interactions between ventilatory drive and sympathetic nerve activity during acute stimulation (hypoxia) of both peripheral and central chemoreceptors have been documented (11). Furthermore, reticulospinal neurons, acting as central oxygen sensors, are directly excited by hypoxia resulting in an initiation of sympathetic activity and circulatory adjustments (11). Increasing drive from chemoreceptors, as well as altered sensitivity, over time at altitude is potentially responsible for both the ventilatory and sympathetic adaptations during acclimatization. These mechanisms likely act to protect the brain from sustained hypoxia (11).
Sympathetic neural release of norepinephrine is known to produce vasoconstriction via the α-adrenergic receptors resulting in an increase in vascular resistance. As a result, systemic vascular resistance is found to increase over time while at 4300 m, following a pattern very similar to that found for sympathetic nerve activity. This increase in vascular resistance translates into elevations in systemic arterial blood pressure over time at altitude, both of which appear to be directly related to the increase in sympathetic nerve activity. Additionally, our studies using α-adrenergic blockade indicate that the changes in sympathetic nerve activity also play a role in the alterations in both substrate utilization as well as immune function during chronic altitude exposure. Our recent finding that the sympathetics via α-adrenergic mechanisms are responsible for the continued elevation in interleukin-6 while at altitude has implications for not only immune function but also the well-documented finding of cachexia associated with high-altitude exposure (10). Thus, alterations in sympathetic nerve activity have significant implications to both the physiologic and metabolic adjustments associated with acclimatization (Fig. 3).
After acclimatization, the adrenal medullary responsiveness during exercise has a pattern similar to that found at rest. Compared with arrival, arterial epinephrine levels are dramatically reduced returning toward sea-level values, despite exercising at similar absolute as well as relative workloads (6,7,9). Similar findings have been reported by others (15), confirming this acclimatization in adrenal medullary function during exercise. As at rest, it would appear that the improved arterial oxygen saturation associated with acclimatization is responsible for this adaptation during exercise.
Compared with sea level and arrival at altitude, arterial norepinephrine levels and systemic vascular resistance are elevated throughout the duration of submaximal exercise, no matter whether the exercise was conducted at the same absolute or relative intensity. Similar increases are found for systemic vascular resistance during exercise. These findings are consistent with the chronic elevation in sympathetic nerve activity demonstrated under resting conditions.
Little is known about adaptations of women to acute and chronic high-altitude exposure. The few studies available have suggested gender differences in substrate metabolism, ventilatory response, and arterial oxygen content, as well as the time course for hematological changes. We recently performed three separate experiments on women at 4300 m. The findings from these studies indicate that the sympathoadrenal responses to both acute and chronic hypoxia, as well as to exercise, are similar to those found for men (8,9). Plasma epinephrine levels are elevated both at rest and during exercise in women acutely exposed to high altitude. After 12 d of acclimatization, epinephrine levels return to sea-level values. At 4300 m, sympathetic nerve activity increases progressively leveling off by days 5–7, findings similar to those in men. A possible consequence for women relates to the finding that the incidence of preeclampsia is significantly higher among women who reside at high altitude when compared with sea level, and recent studies have suggested an elevation in sympathoadrenal activity as a possible mechanism (2). Finally, we were unable to detect any differences in sympathoadrenal responses between menstrual cycle phases.
When an individual, male or female, arrives at high altitude, resting and exercise epinephrine levels increase over the first few days, with the resultant advantage to oxygen transport of increased heart rate, stroke volume, cardiac output, and vasodilation from β-adrenergic stimulation. Augmented glycolysis increases the efficiency of oxygen utilization. The cost of these changes is increased metabolic rate and lactate production. Over time, as acclimatization increases arterial oxygenation, the hypoxic stress and the epinephrine levels subside, as does heart rate, cardiac output, and lactate production. As the epinephrine levels begin to fall, norepinephrine levels are rising with the consequences of increased arterial and venous tone, increased systemic vascular resistance, decreased plasma volume, and further decreases in cardiac output. Teleologists point to energy conservation, saying that it is cheaper and more effective to move air by increasing ventilation than for the heart to pump blood. Although they may be right, we still claim ignorance as to both physiological functions of and mechanisms for these changes. Even the time courses that we have elaborated here are still far from precise.
However, one wonders if the lessons learned from altitude exposure might be applied to other stresses such as those imposed by heat, cold, hemorrhage, or microgravity where there is an acute response initially to adjust to a disruption in homeostasis followed by a more prolonged adaptation. For example, the adaptations could, and probably do, largely reflect alterations in the sympathoadrenal system. Furthermore, the α and β components of the sympathetic system may not be activated in parallel, but rather present different activation patterns to orchestrate most effectively the responses of the various body systems to the imposed stress. Finally, alterations in adrenergic receptor characteristics (density, affinity) as well as in the signal transduction pathways need to be investigated more thoroughly in response to these varied stressors.
1. Asano, K., R.S. Mazzeo, E.E. Wolfel, and J.T. Reeves. Relationship of sympathetic activation to ventilation in man at 4,300 m altitude. Aviat. Space Environ. Med. 68: 104–110, 1997.
2. Greenwood, J.P., E.M. Scott, J.B. Stoker, J.J. Walker, and D.A. Mary. Sympathetic neural mechanisms in normal and hypertensive pregnancy in humans. Circulation. 104: 2200–2204, 2001.
3. Johnson, T.S., J.B. Young, and L. Landsberg. Sympathoadrenal responses to acute and chronic hypoxia
in the rat. J. Clin. Invest. 71: 1263–1272, 1983.
4. Leuenbeger, U., K. Gleeson, K. Wroblewski, S. Prophet, R. Zelis, C. Zwillich, and L. Sinoway. Norepinephrine
clearance is increased during acute hypoxemia in humans. Am. J. Physiol. 261: H1659–H1664, 1991.
5. Maher, J.T., J.C. Denniston, D.L. Wolfe, and A. Cymerman. Mechanism of the attenuated cardiac response to β-adrenergic stimulation in chronic hypoxia
. J. Appl. Physiol. 44: 647–651, 1978.
6. Mazzeo, R.S., E.E. Wolfel, G.E. Butterfield, and J.T. Reeves. Sympathetic responses during 21 days at high altitude (4,300 m) as determined by urinary and arterial catecholamines
. Metabolism. 43: 1226–1232, 1994.
7. Mazzeo, R.S., G.A. Brooks, G.E. Butterfield, D.A. Podolin, E.E. Wolfel, and J.T. Reeves. Acclimatization to high altitude increases muscle sympathetic activity both at rest and during exercise
. Am. J. Physiol. 269: R201–R207, 1995.
8. Mazzeo, R.S., A. Child, G.E. Butterfield, J.T. Mawson, S. Zamudio, and L.G. Moore. Catecholamine response during 12 days of high altitude exposure (4,300 m) in women. J. Appl. Physiol. 84: 1151–1157, 1998.
9. Mazzeo, R.S., A. Child, G.E. Butterfield, B. Braun, P.B. Rock, E.E. Wolfel, S. Zamudio, and L.G. Moore. Sympathoadrenal responses to submaximal exercise
in women after acclimatization to 4,000 m. Metabolism. 49: 1036–1042, 2000.
10. Mazzeo, R.S., D. Donovan, M. Fleshner, G.E. Butterfield, S. Zamudio, E.E. Wolfel, and L.G. Moore. Interleukin-6 response to exercise
and high-altitude exposure: Influence of α-adrenergic blockade. J. Appl. Physiol. 91: 2143–2149, 2001.
11. Reis, D.J., E.V. Golanov, D.A. Ruggieroand M.K. Sun. Sympatho-excitatory neurons of the rostral ventrolateral medulla are oxygen sensors and essential elements in the tonic and reflex control of the systemic and cerebral circulations. J. Hypertens. Suppl. 12: S159–S180, 1994.
12. Rowell, L.B., D.G. Johnson, P.B. Chase, K.A. Comess, and D.R. Seals. Hypoxemia raises muscle sympathetic activity but not norepinephrine
in resting humans. J. Appl. Physiol. 66: 1736–1743, 1989.
13. Saito, M., T. Mano, S. Iwase, K. Koga, H. Abe, and Y. Yamazaki. Responses in muscle sympathetic activity to acute hypoxia
in humans. J. Appl. Physiol. 65: 1548–1552, 1988.
14. Wolfel, E.E., M.A. Selland, R.S. Mazzeo, and J.T. Reeves. Systemic hypertension at 4,300 m is related to sympathoadrenal activity. J. Appl. Physiol. 76: 1643–1650, 1994.
15. Young, A.J., P.M. Young, R.E. McCullough, L.G. Moore, A. Cymerman, and J.T. Reeves. Effect of beta-adrenergic blockade blockade on plasma lactate concentration during exercise
at high altitude. Eur. J. Appl. Physiol. 63: 315–322, 1991.
Keywords:©2003 The American College of Sports Medicine
catecholamines; norepinephrine; epinephrine; hypoxia; exercise