Antidiuretic hormone

Antidiuretic hormone (ADH), also known as arginine vasopressin (AVP), is secreted by the posterior pituitary in response to rises in plasma osmolality and has the effect of increasing water reabsorption in the renal collecting ducts, thus reducing urine volume. In some animals, it also has an effect on arterioles and contributes to blood pressure regulation, hence its alternative name, but this effect is minimal in humans.

ADH Responses to Increases in Plasma Osmolality

Blume et al. (1984) presented evidence of inappropriately low secretion of ADH at altitude. They studied 13 subjects after some weeks at 5400 m and 6300 m on Everest during the American Medical Research Expedition to Everest (AMREE) in 1981 and found ADH concentration unchanged from sea level despite a significant increase in plasma osmolality with increasing altitude. At 6300 m, the serum osmolality was 302 mOsm·kg⁻¹ compared with 290 mOsm·kg⁻¹ at sea level (normal value 280–295 mOsm·kg⁻¹). An overnight dehydration test at sea level that might produce this degree of hyperosmolality would result in ADH concentrations of about 7 µU·mL⁻¹, whereas subjects on Everest had a mean value of only 0.9 µUmL⁻¹; 12-hour urinary ADH showed the same lack of response. Sodium, potassium, calcium, and phosphate concentrations were all modestly increased compared with sea-level values. A study by Ramirez et al. (1992) confirmed these observations. Here, osmolality was increased by infusion of intravenous sodium chloride (0.9%), both at sea level and at altitude (3000 m). At sea level there was the expected rise in ADH but at altitude there was no significant rise. Thus, at altitude, there seems to be a failure of the osmoregulatory mechanism(s). A later study (Ramirez et al. 1998) found evidence of reduced sensitivity of the kidney to ADH in acclimatized individuals and that infusion of exogenous ADH caused an increase of urinary ADH-sensitive water channel (aquaporin-2).

Maresh et al. (2004) explored the response in ADH secretion to a water deprivation test at sea level, on acute altitude exposure (two days) and more chronic exposure (20 days) on Pikes Peak (4300 m). Similar to other studies, they found higher plasma osmolality at altitude but no significant change in baseline levels of ADH. With water deprivation, the rise in ADH was greater at altitude, and more so on day 20 than at day 2 of their altitude stay, and the osmolality threshold which stimulated ADH release appeared to rise (Figure 16.1). An eight-day study by Bestle et al. (2002) at the Capanna Margherita (4559 m) using a hypertonic saline (5% hypertonic saline; 3.6 mL/kg over one hour) loading test found the ADH response unchanged from sea level. Both studies found the function curve of osmolality and ADH shifted to the right with ascent; that is, the set point of plasma osmolality to ADH level is elevated at altitude and continues to increase with time at altitude. Since Maresh et al. (2004) found higher baseline levels of ADH, they also showed higher osmolality at two days and more so after 20 days spent at 4300 m.

These results suggest that elevations in resting osmolality occur as the result of altitude-induced reductions in plasma volume (Maresh et al. 2004). Alternatively, blood pressure or plasma volume increases may also cause changes in the ADH-osmolality relationship via baroreceptor stimulation in the circulatory system. The fact that ADH concentration is reduced despite increases in osmolality (Bestle et al. 2002) could be a consequence of baroreceptor mediated changes in the relationship. Figure 16.2 illustrates the changed set point of the ADH response to changes in osmolality following ascent, and how higher plasma osmolality elicits higher ADH concentration after acclimatization.

Renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone (RAA) system is a complicated system of reactive and compensatory mechanisms involving by renin, angiotensinogen, angiotensin I and II, angiotensin-converting enzyme, and aldosterone that regulates fluid and sodium balance and blood pressure in both health and disease (Figure 16.3). Renin is released in response to a number of stimuli, including posture, exercise, and, possibly, hypoxia. Because sympathetic activation is a common response across all of these stimuli and acute hypoxia increases both circulating catecholamines and direct sympathetic nervous activity (Hansen and Sander 2003; Simpson et al. 2019), high altitude exposure leads to release of renin from the juxtaglomerular apparatus of the kidney.

Renin has little biological activity but act on its circulating substrate, angiotensinogen, cleaving it to produce the octapeptide angiotensin I, which is also devoid of substantial activity. Angiotensin-converting enzyme (ACE), found on the luminal surface of endothelial cells, converts angiotensin I to angiotensin II by cleaving the final two amino acids with the primary site of such conversion being the rich capillary network of the lung, where nearly 90% of angiotensin I is converted to angiotensin II in a single passage. Angiotensin II is a powerful vasopressor and acts on the glomerulosa cells of the adrenal cortex via AT₁ and AT₂ receptors to release aldosterone, which subsequently acts on the renal tubules to cause sodium reabsorption. Because the system is heavily involved in salt and water regulation, it has also been the subject of investigation at high altitude.

Most studies have demonstrated a reduction in plasma renin activity (PRA) at rest with high altitude exposure (Bärtsch et al. 1988; Bärtsch et al. 1991b; Bestle et al. 2002; Haditsch et al. 2015; Keynes et al. 1982; Olsen et al. 1992; Zaccaria et al. 1998), as well as reductions in resting aldosterone concentrations (Bärtsch et al. 1988; Bärtsch et al. 1991b; Keynes et al. 1982; Loeppky et al. 2005; Milledge et al. 1983b; Zaccaria et al. 1998) (Figure 16.4). A relatively greater drop in plasma aldosterone concentration to plasma renin activity increases the renin:aldosterone ratio, indicative of a reduced aldosterone response to renin. This may be partly due to direct inhibition of aldosterone synthesis in the adrenal cortex by hypoxia (Raff et al. 1996).

As aldosterone has a primary role in water and sodium reabsorption, this reduction in plasma aldosterone concentration is a beneficial adaptation that facilitates the natriuresis and diuresis required for the initial hemoconcentration upon exposure to high altitude. Indeed, it is a relatively consistent finding that, in the absence of such a response, plasma aldosterone is elevated and potentially contributes to increased fluid retention and AMS (Bärtsch et al. 1991b; Bärtsch et al. 1991a) (Figure 16.4). In addition to regulation by renin/angiotensin II, aldosterone concentration is also controlled by adrenocorticotropic hormone (ACTH) and the sodium/osmolality status of the subject. For example, Ramirez et al. (1988) found significant inhibition of aldosterone secretion in hypoxia in both lowlanders at sea level and highlanders at altitude, including a blunted aldosterone response to exogenous ACTH, possibly due to increased atrial natriuretic peptide (ANP; see ANP section below), whereas ACTH-induced secretion of cortisol was unaffected (see: Corticosteroids at altitude below).

Effect of Hypoxia and Exercise on the Aldosterone Response to Renin

Milledge and Catley (1982) showed that if after one hour of exercise the fraction of inspired oxygen was reduced, renin activity increased while aldosterone concentration decreased, indicating that the aldosterone response to renin was blunted. The same phenomenon is seen with states of chronic exercise such as trekking or climbing at altitude, as demonstrated in Figure 16.5, which shows data from studies performed at sea level, 3100 m, and 6300 m. This blunting of the aldosterone response to renin in acute hypoxia has been confirmed in several other studies. Shigeoka et al. (1985) found the response completely abolished at a F_IO₂ of 0.17, while Lawrence et al. (1990) found decreased aldosterone with unchanged PRA at a F_IO₂ of 0.12 and De Angelis et al. (1996) demonstrated increased PRA and decreased aldosterone at a simulated altitude of 5000 m in a hypobaric chamber. Additionally, Li et al. (2016) studied 138 men following rapid ascent to 3450 m and found the aldosterone response to renin was attenuated by administration of budesonide, more so than with dexamethasone or placebo. Based on this result, the authors hypothesized that the budesonide-induced dissociation of aldosterone concentration from PRA could explain the observation in some studies that budesonide was effective at preventing AMS (Chen et al. 2015; Zheng et al. 2014). Other studies (Berger et al. 2018; Lipman et al. 2018) have not shown any effect of budesonide on AMS prevention, however, and, as a result, the significance of the observed effect of budesonide on the aldosterone response to renin remains unclear.

Atrial natriuretic peptide

Atrial natriuretic peptide (ANP) is secreted by the atria of the heart in response to stretching rather than simply changes in pressure (Au et al. 1990). Among its actions, ANP has the effect of increasing renal sodium excretion and, therefore, promoting natriuresis and diuresis (Morice et al. 1988). When plasma volume rises, the increase in atrial pressure causes atrial stretch and secretion of ANP, which subsequently leads to diuresis and a decrease in intravascular volume and pressure. This system is further considered in relation to the regulation of plasma volume in Chapter 13.

Atrial natriuretic peptide may also have vasodilatory properties and, in particular, blunt the effect of hypoxia on pulmonary arterioles. For example, dose-dependent pulmonary vasodilation has been demonstrated in an isolated rat lung (Stewart et al. 1991) and in pigs (Adnot et al. 1988), while ANP knock-out mice have greater remodeling of the pulmonary arteries in chronic hypoxia when compared to wild-type controls (Chen et al. 2006). Similarly, Liu et al. (1989) infused ANP (20 mg min⁻¹ for 10 minutes) into four patients with HAPE and demonstrated a reduction in pulmonary artery pressure for one hour after the infusion.

ANP and Hypoxia

A variety of studies in animals and humans have examined the effect of hypoxia on plasma ANP concentrations at rest and with exercise. Ten minutes of severe hypoxia on isolated rat and rabbit heart with constant flow perfusion caused a four-fold increase in ANP released (Baertschi et al. 1986). The same group found increases in ANP concentration in whole animals exposed to hypoxia during anesthesia (Baertschi et al. 1988). There was great variability in the observed responses, which correlated with the baseline central venous pressure, but not with any other measured variables. Figure 16.6 summarizes the observed changes in ANP concentration in animal studies in hypoxia.

In humans, Kawashima et al. (1989) studied the effect of 10 minutes of hypoxia at two levels, an F_IO₂ of 0.15 and 0.10. Exposure to the former produced no change in ANP concentration while exposure to the latter increased ANP levels by 15% and also increased pulmonary artery pressure. Vonmoos et al. (1990) found that 60 minutes of breathing a hypoxic gas mixture (F_IO₂ 0.12) produced a small but significant elevation of ANP. Lawrence et al. (1990) found that the same hypoxic stimulus produced a 50% increase in ANP concentrations in subjects on a low salt diet and whose endogenous cortisol was suppressed with dexamethasone. Conversely, Ramirez et al. (1992) did not find a significant rise in ANP concentration with either acute (60 minutes) or chronic exposure to 3000 m, although the ANP response to a sodium load was greater at altitude. Antezana et al. (1995) found a reduction in ANP concentration in lowlanders at 3600 m compared with sea-level values and also reported lower concentrations in highlanders when compared to the lowlanders at high altitude. Figure 16.7 demonstrates the observed changes in ANP concentration in humans exposed to hypoxia.

The discrepancies in results between these studies may be explained by differences in study protocols and, in particular, the extent of hypoxia used. For example, Kawashima et al. (1989), Vonmoos et al. (1990), and Lawrence et al. (1990) found ANP increased using F_IO₂ <0.12, while Ramirez et al. (1992) and Antezana et al. (1995) studied hypoxia at <3600 m (F_IO₂ ∼ 0.13) and showed no change or a slight decrease in ANP concentration. This suggests that the severity of hypoxia affects the extent of hemodilution and the subsequent effects on atrial-stretch and ANP release. This notion is further supported by evidence that hypoxemia itself is a direct stimulus to ANP secretion even in the absence of atrial stretch due to hypoxia-induced hemodilution. For example, in isolated mouse atrial myocytes, Chen et al. (1997) showed that severe hypoxemia (cell media 1% O₂, PO₂ 20–30 mmHg) is a strong stimulus for ANP gene expression that peaks after five days.

Exercise in Normoxia

It is well established that ANP increases with exercise in athletic, control, and pathophysiological humans (Barletta et al. 1998; Nielsen et al. 2001; Steele et al. 1997; Wisén et al. 2011), and it has been shown that ANP release is influenced by exercise intensity; higher intensities cause increased atrial stretch (Barletta et al. 1998) (Figure 16.8). Somers et al. (1986) found that a progressive exercise test to maximum exercise resulted in an almost four-fold increase in plasma ANP with a decline to baseline after one hour at rest. Similar results have been found for short-term exercise by Schmidt et al. (1990) and by Lawrence and Shenker (1991). Trekking at low elevations (<1500 m) for five days also resulted in elevated ANP concentrations to about twice baseline values (Milledge et al. 1991). It is interesting to note that during this type of exercise, sodium retention occurs despite increased ANP concentration. It seems therefore that short, intense exercise produces increases in ANP that resolve quickly during recovery. In contrast, lower intensity and very prolonged exercise causes ANP concentration to be significantly raised for a period of days following cessation of activity (Milledge et al. 1982).

Brain natriuretic peptide

Brain natriuretic peptide (BNP), also referred to as B-type natriuretic peptide, but has not been studied as extensively in hypoxia as ANP. Although first discovered in porcine brain, it is now understood to be mainly derived from heart muscle in humans (Hall 2005). It is released as pro-BNP from heart muscle in response to ventricular stretch (Goetze et al. 2003; Kinnunen et al. 1993; Magga et al. 1994) and possibly hypoxemia (Casals et al. 2009) and, once cleaved to its active form, exerts diuretic and natriuretic effects like ANP and reduces renin and aldosterone levels (Hall 2005), and possibly counteracts some of the hypoxia-induced pulmonary vasoconstriction (Cargill and Lipworth 1995; Ge et al. 2011).

Acute hypoxemia significantly increases BNP and proBNP gene expression in human cardiomyocytes in vitro (Casals et al. 2009), in vivo (Goetze et al. 2003), and in porcine heart (Goetze et al. 2004). However, human in vivo hypoxia studies have reported contradictory findings. Toshner et al. (2008) and Feddersen et al. (2009) measured proBNP in subjects after ascent to 5200 m and 5050 m, respectively, and found no significant increase in proBNP or ANP, which Toshner et al. (2008) suggested was evidence that ventricular function is well-preserved at high altitude. Feddersen et al. (2009) also found increased nocturnal urine volumes following ascent, but these changes did not correlate with proBNP levels, indicating that BNP is not involved in altitude diuresis. Likewise, Woods et al. (2011b) found no significant rise in BNP even with an S_pO₂ of 68.1 ± 1.1% (±standard error of the mean) in hypobaric hypoxia equivalent to 5334 m. However, the same group (Woods et al. 2011a) found that BNP levels were often raised after trekking to 5150 m, especially in those with AMS. The same group reported a follow-up study of individuals trekking to 5643 m (Woods et al. 2012a) and showed that BNP and proBNP levels increased with altitude, and were still elevated after a nights rest and that those with the greater BNP response had significantly more AMS than those with less or no response. Pagé et al. (2015) found increased BNP following exercise at altitude. Concentrations were not increased at rest, however, and the highest concentrations were found in those subjects with the most severe AMS and highest pulmonary artery systolic pressures.

Heinonen et al. (2014) found no increase in the N-terminal part of proBNP after 60 minutes of normobaric hypoxia (F_IO₂ 0.11). Consistent with these observations, it has been reported that NT-proBNP is unchanged at altitude without exercise (Toshner et al. 2008). The studies that have found elevations in BNP have typically included prolonged trekking activity at high altitude (Pagé et al. 2015; Woods et al. 2011b; Woods et al. 2012a); therefore, it would seem that, in vivo, extended ventricular stretch is probably a greater stimulus to BNP secretion than hypoxemia.

Adrenomedullin

Adrenomedullin (AD) has many biological effects including dose-dependent increases in renal blood flow, urine output, and urinary sodium excretion (Hinson et al. 2000). It is expressed in many tissues throughout the body, including the lung, kidneys, and heart (Hofbauer et al. 2000). In particular, AD is released from endothelial cells in response to hypoxia via hypoxia-inducible factor (HIF)-1 (Cormier-Regard et al. 1998; Hofbauer et al. 2000).

Toepfer et al. (1998) reported raised levels of plasma AD in subjects (all of whom had AMS) on the first and second days after arrival at 4559 m. Haditsch et al. (2007) measured plasma and urinary AD at multiple points during a trek to 5150 m and showed that urinary AD correlated significantly with nocturnal diuresis and sodium excretion, while plasma AD, although raised at altitude, did not. Their data suggest that renal AD is involved in the water and sodium diuresis of early altitude acclimatization.

The effect of exercise on the AD response is unclear. Whether exercise increases or decreases circulating AD is dependent on several factors including sympathetic nervous activity, exercise type and duration, and RAA system status. It can be said, however, that AD, along with angiotensin II and endothelin I, contribute to the status of vascular tone throughout environmental and exercise challenges. This topic has been reviewed in detail elsewhere (Krzeminski 2016).

Acute hypoxia

Acute hypoxia increases heart rate at rest and on exercise (Maher et al. 1975b), likely due to sympathetically mediated stimulation of β-adrenergic receptors on heart muscle cell membrane. Within four hours of arrival at altitude, stimulation of the adrenal medulla by hypoxemia causes an increase in arterial epinephrine (Mazzeo and Reeves 2003). Bouissou et al. (1989) also found a 32% increase in norepinephrine after 48 hours at altitude. Levels of epinephrine reach a peak on about days 2 to 4 and then decline as hypoxemia is relieved by increasing ventilation and hemoglobin concentration over the next seven to 14 days (Mazzeo and Reeves 2003). Berger et al. (2011) found that central venous and arterial epinephrine positively correlated with systolic blood pressure, heart rate, and pulmonary blood flow. Exercise results in a further rise in epinephrine depending on the work rate and degree of hypoxemia.

Norepinephrine is released by sympathetic nerves and about 10–20% spills over into the circulation. In contrast to epinephrine, norepinephrine concentration rises only slowly, in line with increasing ventilation, reaching a plateau after 10–14 days at altitude. As with epinephrine, norepinephrine concentrations rise with exercise depending upon the workload but if workloads relative to V.O_2,max are compared, the rise at altitude is similar to that seen at sea level (Mazzeo and Reeves 2003).

Beyond the commonly cited effects on the systemic circulation, consideration has also been given to the effects of sympathetic activity on the pulmonary circulation. Duplain et al. (1999) demonstrated that HAPE-susceptible individuals have increased sympathetic activity, as assessed by postganglionic nerve discharge in skeletal muscle, compared to healthy controls, while other studies have shown that sympathetic stimulation via alpha receptors augments hypoxic pulmonary vasoconstriction (Brimioulle et al. 1997; Ming and Wang 1989), and administration of the alpha antagonist, phentolamine, reduces pulmonary vascular resistance and pulmonary artery pressure in individuals with HAPE and healthy controls at high altitude (Hackett et al. 1992). Berger et al. (2011), however, also found that the rise in pulmonary artery pressure and vascular resistance is largely independent of the sympathetic nervous system. This may be due to the opposing effects of vasodilation induced by β₂-adrenergic receptor stimulation and vasoconstriction resulting from α₁-adrenergic receptor activation.

Chronic hypoxia

Extended stay at altitude induces chronically heightened and continuing catecholamine and sympathetic nervous activity, even while heart rate and cardiac output fall back toward sea-level values after several days at high altitude. During exercise, maximum heart rate is typically 140–150 beats min⁻¹ at 5800 m compared with 180–200 beats min⁻¹ at sea level (Chapter 18). This reduction in maximal heart rate and cardiac output takes place at a time when the plasma and urinary catecholamines are higher than at sea level. Cunningham et al. (1965), for example, reported elevated plasma and 24-hour urinary catecholamines during 17 days at 4559 m on Monte Rosa. There was no significant change in epinephrine but the increase in norepinephrine was greater on day 12 at altitude. Pace et al. (1964) found similar results at 3850 m, with urinary norepinephrine excretion rising slowly during 14 days at altitude without change in urinary epinephrine secretion. In Operation Everest II, at extreme altitude (P_B ∼282 mmHg) after 40 days in the chamber, resting plasma norepinephrine was raised but epinephrine was reduced. On maximum exercise, likely owing to the concomitant reductions in maximal oxygen consumption, values for both catecholamines fell with increasing altitude (Young et al. 1989a). At least at rest, in subjects who had spent more than 10 weeks above 6000 m, the plasma norepinephrine concentration was found to be almost three times normal (Anand et al. 1993).

Calbet (2003) studied nine subjects during a nine-week stay at 5260 m and found an increase in systemic blood pressure with elevations in plasma epinephrine and norepinephrine. Both systolic and diastolic pressures were significantly increased, likely reflecting heightened vascular tone and hypertension as a result of the increased adrenergic activity. Blood norepinephrine spillover from the leg was also increased compared with sea-level values. On the same expedition, Hansen and Sander (2003) measured sympathetic activity directly by peroneal microneurography after four weeks at altitude and found activity to be about three times sea-level values, suggesting that increased sympathetic activity persisted for many weeks after return to sea level.

Bogaard et al. (2002) studied the effect of blocking either the sympathetic or parasympathetic arms of the autonomic system in a group of subjects at 3800 m on the heart rate and cardiac output on exercise. Propranolol had the expected effect of reducing heart rate, and glycopyrrolate increased the maximum heart rate to sea-level values. However, neither pharmacological blockade had any effect on maximum cardiac output, V.O_2,max, or work rate at altitude, though, of course, these values were lower than sea level. Mazzeo et al. (2003) showed that blocking the α-adrenergic system in a group of female subjects at 4300 m resulted in increased norepinephrine levels compared with unblocked controls both at rest and with exercise. Women appear to have the same sympathoadrenal response to altitude as men with no differences attributable to the menstrual cycle (Mazzeo and Reeves 2003).

High altitude residence

Gosney et al. (1991) studied the adrenal and pituitary glands of five lifelong residents of La Paz who lived at 3600–3800 m and compared their glands with those of controls from sea level. The adrenal glands were significantly bigger, by about 50%. The pituitary glands were not larger but contained more corticotrophins. They surmised that greater amounts of ACTH were required to maintain adrenal function, perhaps because of hypoxic inhibition of adrenocortical sensitivity. However, in contrast, Ramirez et al. (1988) found no such inhibition.

Sherpa high altitude residents do not suffer the same heart rate limitation on maximal exercise as noted above. Their heart rates can go up to 190–198 beats min⁻¹ at 4880 m (Lahiri and Milledge, 1967). It is also noteworthy that directly measured sympathetic nerve activity is blunted in the Sherpa compared to lowlanders at 5000 m (Simpson et al. 2019).

Hypoxia and endothelin

After Horio et al. (1991) showed that ET-1 increased in rats with increasing hypoxia, a number of studies in humans at altitude have shown that the rise in ET-1 is heavily influenced by the degree of exercise and hypoxia (Antezana et al. 1995; Boos et al. 2016; Cargill et al. 1995; Morganti et al. 1995).

Blauw et al. (1995) studied the effect of acute hypoxia (S_pO₂ 80%) and ET-1 infusion on forearm blood flow. Forearm blood flow was not changed by hypoxia, but plasma ET-1 concentration was increased. They concluded that hypoxia causes release of ET-1 from the pulmonary circulation but that this had no influence on peripheral vascular tone. Cruden et al. (1998) measured both ET-1 and big ET-1 in mountaineers ascending above 2500 m. A precursor peptide cleaved into ET-1, big ET-1 is a considerably less potent vasoconstrictor than ET-1, but exists in large enough quantities in plasma to produce high levels of ET-1. Both were increased on ascent to >2500 m, indicating that the increase in ET-1 was due to increased production and not decreased elimination. After three weeks at altitude, levels had returned to baseline values. Exercise had no effect on endothelin levels. In a separate study, they also found increases in both ET-1 and big ET-1 with cold exposure (Cruden et al. 1999).

Berger et al. (2009) studied the changes in ET-1 concentrations across the pulmonary circulation in 34 subjects at low and high altitude (4559 m). While there was net clearance of ET-1 across the pulmonary circulation at low altitude, at high altitude levels pulmonary venous concentrations were higher than pulmonary arterial concentrations, indicative of net gain of endothelin with transpulmonary transport. Both the absolute concentration and the veno-arterial concentration difference correlated with the pulmonary artery systolic pressure.

Endothelin and HAPE

Droma et al. (1996b) reported detailed findings from a single case of HAPE with pulmonary hypertension and found ET-1 levels elevated on admission. The levels reverted to normal as the patient recovered and pulmonary artery pressure fell. The same team (Droma et al. 1996a) later demonstrated that HAPE-susceptible subjects had a greater hypoxic vascular response than controls but no significant change in ET-1 levels with a short hypoxic challenge (five minutes, F_IO₂ 0.10).

Sartori et al. (1999) studied HAPE-susceptible and HAPE-resistant mountaineers following ascent to 4559 m and demonstrated 33% higher ET-1 concentrations in the HAPE-susceptible individuals when compared to the controls as well as a significant direct relationship between changes in ET-1 concentration and pulmonary artery pressure from low to high altitude.

While these studies suggest that differences in endothelin metabolism may affect the risk of HAPE, no studies have demonstrated that administration on ET-1 antagonists are useful in HAPE prevention. Modesti et al. (2006) administered bosentan in a randomized, double-blind manner to healthy individuals at sea level and following ascent to 4559 m and demonstrated reductions in pulmonary artery systolic pressure and slight improvements in arterial oxygen saturation. The study did not include HAPE-susceptible individuals, however, and, as a result, no conclusions can be drawn about its role in prophylaxis.

As discussed further in Chapter 18, maximum exercise capacity is reduced at high altitude and part of this limitation may be related to hypoxia-induced increases in pulmonary vascular resistance and pulmonary artery pressure and subsequent effects on right ventricular function. A potential role for endothelin in the changes in exercise capacity is suggested by a study by Naeije et al. (2010) in which they administered the endothelin receptor antagonist, sitaxentan, in a randomized double-blind manner to healthy subjects in both normobaric and hypobaric hypoxia and noted reductions in pulmonary vascular resistance and a 30% improvement in maximum oxygen uptake following sitaxentan administration.

Endothelin and long-term altitude residents

Low birth weight is a feature of pregnancy at high altitude (Chapter 4), and data suggest that ET-1, as well as nitric oxide (NO) concentrations, may account, in part, for this observation. Julian et al. (2008) measured blood flow in uterine arteries (UA) as well as ET-1 and NO metabolites (NO_x) in venous blood of mothers in Denver (1600 m) and in Leadville (3100 m) and found that birth weight correlated with UA blood flow in both groups. The higher the ratio of ET-1/NO_x, the more UA vasoconstriction and the lower the blood flow to the uterus. In both groups, this ratio was correlated with birth weight. However, in the low altitude mothers, ET-1/NO_x ratios were clustered at the low end of the range, while the high altitude mothers’ ratios were spread out to higher ratios, suggesting that increased ET-1 and/or decreased NO production resulted in lower uterine blood flows and smaller babies at altitude.

In 24 individuals with chronic mountain sickness (CMS), Ge et al. (2011) found higher serum ET-1, BNP, and vascular endothelial growth factor (VEGF) concentrations in the CMS group compared to healthy controls, which were positively correlated with mean pulmonary arterial pressure. They also found lower serum endothelial nitric oxide synthase in the CMS group. High ET-1, BNP, and VEGF could be a result of chronic hypoxia, or a reactive compensation to high pulmonary arterial pressure caused by high altitude. These findings further support the notion that natriuretic peptides and vasoactive agents modulate adaptation to extended hypoxemia and may be useful markers of pathophysiological prognostic evaluation.

Basal metabolic rate

The basal metabolic rate is elevated during the first two weeks at moderate altitude and correlates with the free T₄ (Stock et al. 1978a). At higher altitudes (above 5500 m), it remains elevated for months (Gill and Pugh 1964), as does T₄ (Mordes et al. 1983). Mordes et al. (1983) also found evidence of impaired conversion of T₄ to T₃ at 6300 m. Perhaps there is a change in the set point for the pituitary negative feedback system, resulting in higher levels of TSH. They also found that the response of the pituitary to an injection of thyrotropin-releasing hormone was enhanced at 6300 m compared with sea level. A similar finding has been reported by Ramirez et al. (1995) in resident highlanders at 2600 m.

Iodine deficiency and goiter

Historically, iodine deficiency was a significant problem in mountainous areas of the world including the Pyrenees, Alps, Andes, and Himalaya. This mainly related to geological factors causing iodine deficiency in the soil and, hence, in the diet. Because hypoxia stimulates thyroid function, iodine deficiency causes more exaggerated hyperplasia, which contributes to extremely high rates of goiter in high altitude regions. Following initiation of universal salt iodization in 1993, iodine deficiency is less of an issue in mountainous regions (Tamang et al. 2019a; Tamang et al. 2019b) and, as a result, the incidence of goiter and other disorders of iodine deficiency have decreased significantly (Ministry of Health and Population 2007).

Glucose and insulin concentrations

On acute exposure to hypoxia, there is a rise in fasting blood glucose of about 1.7 mmol L⁻¹, followed by a fall toward control values by the end of a week. The effect of prolonged high altitude on plasma insulin concentration is variable, studies having found both reductions or no change (Bailey et al. 2004; Blume and Pace 1967; Debevec et al. 2014; Riedl et al. 2012; Stock et al. 1978a) and elevations (Bosco et al. 2019; Siervo et al. 2014; Williams 1975; Young et al. 1989b). A recent meta-analysis (Matu et al. 2018) found a positive association between severity of hypoxic exposure and the magnitude of increases in insulin, and suggested that extreme altitude may account for the larger increases in insulin some studies have seen. Increases in insulin may be part of the altitude-induced stress response indicated by the concurrent rise in plasma catecholamine and cortisol levels. In subjects acclimatized to high altitude, fasting blood glucose was found to be lower than at sea level by some (Blume and Pace 1967; Stock et al. 1978a) but unchanged by others (Sawhney et al. 1986). Singh et al. (1974) found a persistently raised glucose concentration after 10 months at altitude. Together these data indicate the degree of variability of the effects of chronic hypoxia on both insulin and glucose changes in lowlanders, Bosco et al. (2019), Benso et al. (2007), Sawhney et al. (1986), Siervo et al. (2014), and Braun et al. (2001) reported increases in glucose and/or insulin, while Stock et al. (1978a), Debevec et al. (2014), and Bailey et al. (2004) all found decreases in both. This disparity between studies demonstrates the range of methods and ascent styles used, which may also account for some variability. For example, Braun et al. (2001) tested after 52 hours of hypobaric hypoxia; Debevec et al. (2014) tested after 10 days of normobaric hypoxia; Benso et al. (2007) tested after some time (details not reported) at 5200 m and immediately following an ascent of Everest without supplemental oxygen; Siervo et al. (2014) assessed a group of 24 at Everest base camp, eight of whom summited Everest; and Bosco et al. (2019) tested two days after descent to 1300 m following 22 days at 5050 m or higher and a trek of 450 km overall. Changes in blood insulin and glucose concentrations at high altitude are summarized in Figure 16.10.