Most adaptive changes occur in the first days and weeks following arrival at altitude, and this is the period when acute mountain sickness with cerebral and/or pulmonary oedema may occur. Recent studies in animals and man have highlighted the role of the autonomic nervous system in adaptation and in particular the importance of sympathetic activation following high altitude exposure.
Cardiovascular effects
Acute hypobaric hypoxia results in an increase in resting heart rate and blood pressure and this is seen both during altitude exposure [
5] and during simulated exposure using a hypobaric chamber [
68]. Vogel et al. [
68,
69] demonstrated that the rate of ascent influenced the magnitude of the tachycardia. Gradual increases in altitude over two weeks resulted in larger heart rate changes compared with an abrupt ascent. Later, as subjects acclimatise at altitudes up to about 4,500 m, much of the increase in heart rate is lost and resting heart rates return towards their sea level values.
Acute hypoxia also causes an increase in cardiac output both at rest and for given levels of exercise. This was seen both when breathing hypoxic gas at sea level [
34,
68,
69] and on acute exposure to high altitude [
21]. As subjects acclimatise to the altitude cardiac output decreases although the heart rate can remain high with a low stroke volume. This may be due to a loss of plasma volume [
23,
54].
The effect of hypoxia on the pulmonary circulation is rapid, resulting in an increase in pulmonary vascular resistance and pulmonary hypertension [
49]. The maximum response occurs within 5 min [
65]. Breathing 11% oxygen for 30 min increases pulmonary artery pressure from 16 to 25 mmHg [
72]. The effect of hypoxia on the pulmonary circulation is even more pronounced during exercise, as demonstrated in the Operation Everest II studies [
24] where pulmonary artery pressure increased during near-maximal exercise at 8840 m to 54 mmHg.
The mechanism of pulmonary artery vasoconstriction initially involves inhibition of O
2 sensitive K
+ channels leading to depolarization of pulmonary artery smooth muscle cells and activation of voltage gated Ca
2+ channels causing Ca
2+ influx and vasoconstriction [
48]. This process is immediately reversed by breathing oxygen. However, lowlanders exposed to high altitude for 2–3 weeks develop pulmonary hypertension that is not completely reversed by oxygen breathing [
24] suggesting remodelling of pulmonary arterioles. Remodelling involves proliferation of smooth muscle cells and thickening of the artery wall [
57].
Sympathetic activity
Acute hypoxia is a potent activator of sympathetic activity [
39,
56]. Studies in several species, including dogs, rats and rabbits, showed that hypoxia stimulated the sympathoadrenal system. Acute hypoxia in spontaneously breathing anaesthetized animals causes increases in sympathetic nerve activity, increased release of catecholamines, increases in heart rate and regional vasoconstriction [
28,
60]. However the effects of hypoxia on the human sympathetic nervous system are more difficult to determine and often indirect methods of assessment have been employed.
One method of assessment of sympathetic activity in humans is from blood or urine levels of catecholamines. However, catecholamine levels are the net resultant of secretion, spill-over, reuptake and excretion [
59,
18] and results must be interpreted with caution. Mazzeo et al. [
40] measured arterial noradrenaline and adrenaline concentrations in subjects at sea level, then after 4 h then 21 days at altitude (4,300 m). They reported an initial decrease in noradrenaline but by day 21 it had increased to 52% above sea level values. Arterial adrenaline values doubled following acute altitude exposure then declined to only 26% above sea-level by day 21. In a later study, however, the same authors [
41] measured 24 h urinary noradrenaline and adrenaline excretion and venous plasma catecholames in women at sea level and during 12 days of exposure to 4,300 m and reported increases in both urinary noradrenaline and adrenaline excretion after only one day at altitude and increases in plasma catecholamines on day 4 at altitude. During the 12 day period noradrenaline continued to increase as assessed both from urinary excretion and in the plasma samples. Adrenaline values however fell back to those recorded at sea level. Rostrup [
59] reported initial decreases in both plasma noradrenaline and adrenaline which subsequently recovered. Results from simulated hypoxia are also conflicting with an increase in urinary adrenaline but no change in noradrenaline [
29] or no change in either [
71]. These results illustrate the difficulty in assessing autonomic activity from blood or urine catecholamines, but they do suggest that in the early stages of exposure to altitude there is an increase mainly in adrenaline, but that later it is noradrenaline that predominates.
The changes in catecholamines are more consistent during exposure to chronic hypoxia. Calbet [
10] measured systemic and skeletal muscle noradrenaline and adrenaline spillover in lowlanders after exposure to 5,260 m. After 9 weeks plasma noradrenaline and adrenaline concentrations were approximately 4 and 2 fold higher than the sea level values. These values were similar to those in patients with compensated chronic heart failure [
2].
The heart rate at maximal exercise is reduced at altitude. In Operation Everest II maximal heart rates decreased from 160 at sea level to 118 at 8,848 m [
54]. Given the evidence for elevated catecholamines at altitude, at least during chronic exposure, this suggests a down regulation of the cardiac β -adrenergic receptors. Studies in rats following prolonged exposure to hypobaric hypoxia have shown a decreased β-adrenergic receptor density [
30,
67]. Short exposures to hypoxia (1–15 days) did not affect β-adrenergic receptor density. However by 21 days there was a 24% reduction. Leon-Velarde et al [
35] exposed rats to a simulated altitude of 5,500 m for 21 days and also found a 24% reduction in β-adrenergic receptor density in both left and right ventricles. They also reported an increase in α
1-adrenergic receptor density in the left ventricle, although Morel et al [
48], who exposed rats to 5,500 m for 15 days, found no change in α
1-adrenergic receptor density in either left or right ventricle. Density of adenosine receptors has also been shown to be decreased by 46% following 30 day exposure to 5,500 m simulated altitude in the rat while muscarinic receptor density increased by 49% [
31].
Changes in receptor density have also been estimated indirectly in man by determining the rate of isoprenaline infusion required to increase heart rate by 25 beats/min. The required rate increased with increasing exposure to altitude and this was attributed to a down regulation of the β-adrenergic receptors [
56]. Platelet α
2-adrenergic receptor density decreased after 4 weeks exposure to 5,050 m [
19]. Changes in α
2-adrenergic receptor density on platelets may indicate a similar change in the central nervous system [
53]. In the central nervous system α
2-adrenergic receptors are known to play an important role in cardiovascular regulation [
22]. Stimulation of these receptors in the ventrolateral medulla has been shown to reduce sympathetic and increase parasympathetic outflow [
55]. If a change in the density of these receptors occurred it may explain many of the effects of altitude on the autonomic system.
The effect on the parasympathetic system has been assessed in humans from the responses to muscarinic blockade. Following short exposures to hypoxia the changes in heart rate following muscarinic blockade became smaller [
11]. However, Boushel et al. [
8] exposed subjects to an altitude of 5,260 m for 9 weeks and then studied the effects of muscarinic blockade both at rest and during exercise, and suggested that there was an enhanced parasympathetic activity and that this was responsible for the reduction in heart rate seen during chronic adaptation to altitude.
Arterial baroreflex
Studies in humans of baroreflex control at altitude or simulated altitude have yielded contradictory results. Sagawa et al. [
61], using the neck chamber method, reported that acute exposure to simulated altitude of 4,300 m had no effect on carotid baroreflex set point for heart rate control but there was a 50% reduction in the gain of the reflex. Halliwill and Minson [
25,
26], on the other hand, using nitroprusside and phenylephrine, found that hypoxic breathing increased set point but did not change gain. Studies of “spontaneous” baroreflex gain have indicated that it decreases at altitude or simulated altitude [
5,
6,
7,
63]. Interpretation of these findings is complicated by the differences in baseline blood pressures and heart rate. Recently, Cooper et al. [
15] reported that although acute hypoxia did not change baroreceptor control of heart rate it did decrease the gain of the vascular resistance response without changing “set point”.