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Systemic Hypertension at High Altitude

2018; Lippincott Williams & Wilkins; Volume: 72; Issue: 3 Linguagem: Inglês

10.1161/hypertensionaha.118.11140

1524-4563

Offdan Narvaez‐Guerra, Karela Herrera‐Enriquez, Josefina Medina‐Lezama, Julio A. Chirinos,

Travel-related health issues

HomeHypertensionVol. 72, No. 3Systemic Hypertension at High Altitude Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBSystemic Hypertension at High Altitude Offdan Narvaez-Guerra, Karela Herrera-Enriquez, Josefina Medina-Lezama and Julio A. Chirinos Offdan Narvaez-GuerraOffdan Narvaez-Guerra From the Santa María Catholic University and PREVENCION Research Institute, Arequipa, Peru (O.N.-G., K.H.-E., J.M.-L.) , Karela Herrera-EnriquezKarela Herrera-Enriquez From the Santa María Catholic University and PREVENCION Research Institute, Arequipa, Peru (O.N.-G., K.H.-E., J.M.-L.) , Josefina Medina-LezamaJosefina Medina-Lezama From the Santa María Catholic University and PREVENCION Research Institute, Arequipa, Peru (O.N.-G., K.H.-E., J.M.-L.) and Julio A. ChirinosJulio A. Chirinos Correspondence to Julio A. Chirinos, University of Pennsylvania Perelman School of Medicine and Hospital of the University of Pennsylvania, S Tower, Room 11–138, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104. Email E-mail Address: [email protected] University of Pennsylvania Perelman School of Medicine and Hospital of the University of Pennsylvania, Philadelphia (J.A.C.). Originally published23 Jul 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.11140Hypertension. 2018;72:567–578The development of systemic hypertension is influenced by genetic, racial, geographic, and environmental determinants, including high-altitude (H-ALT). The cut-point to define H-ALT has generally been defined as >2500 meters above sea level (mASL; ≈8200 ft).1 According to a recent estimation, ≈83 million people live at >2500 mASL,2 including populations mainly from South America, Central Asia, and Eastern Africa. These highlanders are chronically exposed to relative hypoxia, which has important consequences on the cardiovascular system and on blood pressure (BP) regulation.Several recent studies have focused on the acute and subacute hemodynamic changes in lowlanders who are suddenly exposed to H-ALT. However, little is known about the precise pathophysiologic mechanisms of chronic hypertension at H-ALT, differences in the characteristics of chronic hypertension between various H-ALT settings, or the efficacy of antihypertensive agents in chronic highlanders. People living in low-income countries, such as the majority of highlanders, demonstrate higher prevalence of noncommunicable diseases, including hypertension.3 Even though the World Health Organization considers the current extent of hypertension as a global public health issue,4 the real burden of hypertension and its complications in H-ALT locations worldwide remains to be well defined. Given the large number of highlanders around the world, and the well-established role of hypertension in cardiovascular risk, hypertension at H-ALT is a highly relevant clinical and public health problem that requires increased awareness and study.In this review, we aim to summarize and integrate our current knowledge about the association between H-ALT and hypertension, the cardiovascular phenotypes observed at H-ALT, the effects of H-ALT on the cardiovascular system, and major biological pathways of BP regulation, as well as their potential therapeutic implications. Although mechanisms of acute and chronic H-ALT sometimes overlap, we attempt to make clear distinctions between acute and chronic vascular effects of H-ALT where appropriate.Known Effects of H-ALT on the Cardiovascular SystemAltitude constitutes a hypobaric hypoxic environment, in which lower atmospheric pressure determines a lower driving pressure for gas exchange in the lungs; therefore, lower oxygen is available for physiological metabolic processes, which determines different oxygen tensions at various anatomic levels (Figure 1). Chronic mountain sickness is an exaggerated response to chronic hypoxemia characterized by a markedly increased production of red blood cells as an attempt to overcome the reduced oxygen delivery to tissues. This exerts deleterious effects on blood viscosity, ventilation, and acid-base balance.6 Chronic hypoxia also triggers pulmonary hypertension and right-sided heart failure because of sustained hypoxic pulmonary vasoconstriction.6Download figureDownload PowerPointFigure 1. The oxygen transport cascade. The partial pressure of oxygen gradually decreases from inspired air, to venous level, at sea level and high-altitude (H-ALT). Overall, oxygen tension is lower at H-ALT. mASL indicates meters above sea level. Adapted from Hurtado5 with permission. Copyright © 2005, John Wiley and Sons.Studies about H-ALT adaptations have elucidated that adaptive mechanisms vary between the 2 most representative H-ALT populations, Andean highlanders (AN-HLs) and Tibetan highlanders (TIB-HLs), suggesting the existence of distinct evolutionary courses in response to chronic hypoxia. Compared with TIB-HLs, AN-HLs (in whom the prevalence of chronic mountain sickness ranges from 6.8% to 33.7%)6 demonstrate higher pulmonary arterial pressures, arterial oxygen content, oxygen saturation, and hemoglobin concentration.7 In contrast, TIB-HLs exhibit greater endothelial nitric oxide (NO) production in pulmonary arteries, higher peripheral capillary density,7 and a chronic mountain sickness prevalence of 1.2% (Table).6 These data clearly indicate the presence of unique phenotypes in different H-ALT populations, which may have resulted from the fact that Tibetans settled at H-ALT lands much earlier (≈25 000 years ago) than Andeans (≈11 000 years ago).7Table. Summary of Main Differences in the Vascular Function Between Lowlanders and HighlandersPhysiological FactorsVascular VariablesLowlanders During Acute H-ALT ExposureAndean HighlandersTibetan HighlandersAltitude adaptationsCMS prevalence…6.8%–33.7%1.2%Pulmonary arterial pressures…HigherLowerNO production in pulmonary arteries…LowerHigherArterial oxygen content…HigherLowerVascular changesPeripheral capillary densityUnknownLowerHigherCirculation NO levelsUnknownHighHighcIMTUnknownUnknownDecreased*Common carotid artery diameterIncreased†UnknownIncreased*Brachial artery diameterUnknownUnknownIncreased*Carotid-femoral PWVIncreased†UnknownNot changed or Increased*Augmentation indexIncreased†UnknownNot changed*Endothelial functionFMDDecreased†UnknownDecreased*NTGDecreased†UnknownIncreased*Oxidative stressLOOHIncreased†UnknownUnknownNitritesIncreased†UnknownUnknownF(2)-isoprostaneIncreased†UnknownUnknown8-iso-PGF2αIncreased†Increased*Increased‡Blood pressureBlood pressureIncreased†LowerHigherCBFCBFIncreased†Decreased*Increased*CBF indicates cerebral blood flow; cIMT, carotid intima-media thickness; CMS, chronic mountain sickness; FMD, flow-mediated dilation; H-ALT, high-altitude; LOOH, lipid hydroperoxide; NO, nitric oxide; NTG, nitroglycerin-dependent dilation; and PWV, pulse wave velocity.*Compared with lowlanders at sea level.†Compared with sea-level measurements.‡Compared with lowlanders exposed to H-ALT.Impact of Ethnicity on the Association Between H-ALT and Systemic HypertensionWhite lowlanders acutely exposed to H-ALT demonstrate a BP increase during the initial days.8–10 The underlying mechanisms of this response include activation of the adrenergic system, increased arterial stiffness, endothelin (ET) release, and reduced vasodilatory responses (Figure 2).11,12 Additional mechanisms for this acute surge of BP will be reviewed in the following sections. Conversely, the only study that investigated changes of BP in white lowlanders exposed to H-ALT for >2 years demonstrated a reduction in systolic and diastolic BPs.13Download figureDownload PowerPointFigure 2. Pathways that may regulate blood pressure (BP) and cerebral blood flow (CBF) during acute and subacute high-altitude (H-ALT) exposure. The figure represents the complexity of the mechanisms linked to acute/subacute H-ALT exposure and increased BP, which is mediated by augmentation of the renin-angiotensin-aldosterone system, sympathetic hyperactivity (and various effects on adrenergic receptors), increased oxidative stress, and endothelial dysfunction, leading to an acute increase in large artery stiffness. The role of CBF (which is influenced by BP, nitric oxide [NO], and cerebral vascular changes) in maintaining brain oxygen delivery is also represented. Blue arrows indicate stimulation, red lines indicate inhibition. *Desensitization/downregulation. ACE indicates angiotensin-converting enzyme; ALD, aldosterone; ARs, adrenergic receptors; AT-I, angiotensin-I; AT-II, angiotensin-II; DD ACE genotype frequency, deletion of repeat element in ACE gene; ET-1, endothelin 1; and NE, norepinephrine.Different results have been described in highlanders. The prevalence of hypertension at different H-ALT locations ranges from 8.6%14 to 55.9%,15 however, various factors, such as geographical location, ethnicity, and sample population, must be taken into consideration when comparing different prevalence of hypertension. A retrospective study that included 16 913 TIB-HLs reported a significant correlation between altitude and the prevalence of hypertension with a 2% increase for every ≈100 m (≈330 ft)-increase in altitude above 3000 mASL (≈9800 ft).16 Nonetheless, this study was limited by the use of different definitions of hypertension and a lack of adjustment for demographic, metabolic, and anthropomorphic factors. A subsequent retrospective analysis that included a multiethnic sample of 40 854 subjects living at >2400 mASL (≈7900 ft) showed that in TIB-HLs, for every 1000-m (≈3300 ft) increase in altitude, BP increased by ≈17/9.5 mm Hg.17 However, in non-Tibetans (mainly AN-HLs), the same increase in altitude was not significantly associated with changes in BP.17 Similarly, an earlier cross-sectional study demonstrated a lower prevalence of hypertension among AN-HLs, as compared with Andean lowlanders.18Taken together, available data suggest a positive association between altitude and hypertension in TIB-HLs, in contrast to AN-HLs, among whom a neutral to negative correlation seems to be present (Table). However, available studies are limited because they do not account for potential confounders, including environmental and lifestyle factors. Even though TIB-HLs seem to have higher BP levels than AN-HLs, TIB-HLs exhibit higher capillary density than AN-HLs.7 In addition, higher circulating NO levels have been observed in both AN-HLs19 and TIB-HLs,20 as compared with lowlanders, but in TIB-HLs, these increased levels have been associated with greater oxygen delivery (Figure 3).21 Therefore, the underlying correlates of BP may be different between AN-HLs and TIB-HLs. Further population-specific data are required to fully characterize the biological mechanisms linking H-ALT and hypertension, and the precise association between H-ALT and hypertension risk, while accounting for environmental, geographical, racial, lifestyle, and socioeconomic factors. Important pathways that may mediate the relationship between H-ALT and increased BP (as occurs in TIB-HLs) are summarized in Figure 3.Download figureDownload PowerPointFigure 3. Pathways that may mediate increased blood pressure (BP) in chronic highlanders (as reported in Tibetan populations). Increased concentrations of hypoxia-inducible factors (HIFs), and subsequently erythropoietin (EPO), exert various effects on vascular mechanisms of BP maintenance, including increased production of endothelin-1 (ET-1), vascular neointima formation, polycythemia, and decreased responsiveness to vasodilators, all of which may contribute to increased BP. The relationships between arterial stiffness, endothelial dysfunction, changes in capillary density, increased NO bioavailability, and BP are also represented. Blue arrows indicate stimulation, red lines indicate inhibition. *DD ACE genotype is associated with hypertension in female Tibetan highlanders. ACE indicates angiotensin-converting enzyme; AT-II, angiotensin-II; ATR1, angiotensin receptor type 1; DD ACE genotype frequency, deletion of repeat element in ACE gene; NO, nitric oxide; PDGF-BB, platelet-derived growth factor BB; PHD, propyl-hydroxylase domain enzyme; and PPARγ, peroxisome proliferator-activated receptor-γ.An important limitation of available studies is the lack of standardized well-validated measurements of BP. Furthermore, available studies tended to focus on office BP, whereas the importance of ambulatory and home BP and the circadian patterns of BP variability is increasingly recognized. It is essential that methodological issues on BP monitoring, hypertension diagnosis, and the use of validated devices22 be taken into account in the design of future studies of H-ALT. Whereas H-ALT may not affect the performance of oscillometric or mercury BP monitors,23 general considerations about device validity and methods of office, home, and ambulatory measurements will need to be adequately considered.Vascular Structure and Function at H-ALTAcute/Subacute ExposureCompared with sea-level measurements, acute (3 days) H-ALT exposure in white lowlanders has been associated with reduced flow-mediated brachial artery dilation (a marker of endothelium-dependent vascular function) and nitroglycerin-dependent dilation (a marker of endothelium-independent vascular smooth muscle function), both of which persist after subacute (12–14 days) H-ALT exposure (Figure 2).24 Augmentation index (a marker of arterial wave reflections) has been shown to increase,25 whereas carotid-femoral pulse wave velocity (a measure of large artery stiffness) was unchanged (after 2 days)25 or increased (after 3–14 days)24 at H-ALT. White lowlanders demonstrate higher levels of lipid hydroperoxide (a marker of oxidative stress) and nitrite (NO2−) after exposure to H-ALT (Figure 2).24 These vascular changes after acute/subacute exposure to H-ALT have been attributed at least partially to oxidative stress since lipid hydroperoxide levels correlated with the reduction in nitroglycerin-dependent dilation–mediated dilation (Figure 2).24The role of circulating NO2− in this setting is intriguing. On one hand, NO2− can be a byproduct of NO metabolism, and thus a marker of production. On the other hand, NO2− is a direct precursor of NO via the nitrate-NO2−-NO pathway, and the reduction of NO2− to NO occurs preferentially in hypoxic and acidotic environments (Figure 2).26 Increased NO bioavailability associated with acute H-ALT exposure has been described.21,24 Acute H-ALT–associated NO2− rise may be an adaptive mechanism to maintain circulatory homeostasis via vasodilation.27 The physiological response to altitude manifests as blood redistribution toward the brain to protect this organ from the deleterious effects of hypoxia.24 In experimental models, hypoxia has been associated with increased NO bioavailability, which resulted in increased cerebral blood flow (CBF; Figure 2).28 Interestingly, inorganic nitrate (which increased NO2− levels) does not produce important cerebral vasodilation at sea level,29 but this phenomenon may be different at H-ALT given the differences in cerebral microvascular Po2. This issue requires further research.Chronic ExposureCompared with white lowlanders at sea level, TIB-HLs demonstrate lower carotid intima media thickness,30 higher common carotid artery diameters,24,30 higher brachial artery diameters (after adjustment for body surface area),30 higher nitroglycerin-dependent dilation–mediated dilation, lower flow-mediated dilation,30 and lower carotid pulse pressure, with similar augmentation index (Figure 3).30 Discordant findings have been reported for carotid-femoral pulse wave velocity.24,30 Overall, these results indicate that, in contrast to the adverse changes in pulsatile hemodynamics and arterial stiffness associated with acute hypobaric hypoxia among chronic lowlanders, arterial remodeling in chronic highlanders involve eccentric conduit artery remodeling, with or without increased arterial stiffness. Key differences in physiological and clinical parameters between lowlanders acutely exposed to H-ALT and chronic highlanders are summarized in the Table.Pathways of BP Regulation at H-ALTAdrenergic Nervous SystemAcute/Subacute ExposureThere is a close relationship between acute hypobaric hypoxia and the activation of the sympathetic nervous system (SNS). Acute exposure to H-ALT and subsequent hypoxemia are followed by the activation of peripheral arterial chemoreceptors that stimulate the adrenergic center in the medulla, increasing adrenergic activity (Figure 2).31 Plasma and urine catecholamine concentrations (especially norepinephrine) remain unchanged within the first 1 to 2 days of acute H-ALT exposure but increase thereafter.8,32 Sympathetic hyperactivity has been reported during acute (4 days)33 and prolonged (50 days)34 H-ALT exposure among white lowlanders (Figure 2).During acute H-ALT exposure, daytime mean arterial pressure is not suppressed with propranolol administration.8 Among white lowlanders acutely exposed to H-ALT, carvedilol and nebivolol reduced systolic BP at H-ALT compared with placebo, but they were unable to completely suppress the BP rise at H-ALT compared with sea level9; however, subjects receiving nebivolol showed better exercise performance than those receiving carvedilol, at H-ALT.35 Similarly, prazosin in women acutely exposed to H-ALT failed to block the rise in BP at H-ALT compared with sea level.10The limited response to antiadrenergic drugs during acute H-ALT exposure may be related to changes in adrenergic receptor density at H-ALT (Figure 2). A decrease in β-adrenergic receptor density in the left ventricle after exposure to simulated H-ALT has been shown in rats,36 which may be prevented by low doses of propranolol before H-ALT exposure.37 Similarly, subacute H-ALT exposure has been shown to reduce α1-adrenergic receptor density in adult sheep common carotid and cerebral arteries.38 Downregulation of α2-adrenergic receptors has also been reported, which seems to play an important role in SNS hyperactivity during prolonged H-ALT exposure (≈50 days).39Therefore, even though H-ALT exposure is associated with an ongoing activation of the SNS, it is also associated with downregulation of adrenergic receptors (possibly as a result of increased receptor occupancy).37 Additional factors, including uncoupling of cardiac β-adrenergic receptor s,40 decreased presynaptic uptake of norepinephrine in cardiac adrenergic synapses41 (which may increase β-adrenergic receptors desensitization), and higher levels of Gi-protein (inhibitory) of cardiac β-adrenergic receptors, may also be at play (Figure 2).41 Similarly, whether the downregulation of α2-adrenergic receptors at H-ALT39 affects the therapeutic efficacy of α methyldopa (an α2-adrenergic receptor agonist predominantly used for the treatment of hypertension in pregnancy) is unknown. Overall, the implications of these effects on the potential efficacy of adrenoreceptor blockers for the treatment of chronic hypertension at H-ALT require further research.There may exist a complex relationship between H-ALT, changes in adrenergic receptors of cerebral arteries, changes in CBF, and BP (Figure 2). A decreased contractile response to norepinephrine after H-ALT exposure has been shown in sheep.42 The impairment of arterial cerebral autoregulation during acute H-ALT exposure43 is accompanied by an increase in CBF, which reaches a peak after 3 days, gradually decreasing to normal levels thereafter.44 This response seems to exert a preferential maintenance of CBF to the brain stem to maintain oxygen delivery to the cardiorespiratory centers.43 The effects of SNS activation on the regulation of CBF at H-ALT remain unclear.44 Nonetheless, it has been postulated that in the presence of impaired arterial cerebral autoregulation at H-ALT, the rise of BP may result in a pressure-passive increase in CBF.44 A recent study showed that when a conflict exist between maintaining brain O2 delivery and controlling CBF to prevent brain damage from overperfusion-pressure, priority is given to brain O2 delivery.45 In this regard, the rise of BP during acute H-ALT exposure may help maintain brain oxygenation and metabolism (Figure 2). Importantly, limited data indicate the presence of reversible and irreversible brain abnormalities on magnetic resonance imaging in mountain climbers.46,47 Given these considerations, care should be taken when assessing the risk/benefit ratio of using short-term antihypertensive regimens to blunt acute BP responses to H-ALT among chronic lowlanders because the latter may provide protection against hypoxic brain damage.Chronic ExposureSympathetic hyperactivity has been described in native AN-HLs33,34; however, they demonstrate lower CBF than lowlanders, whereas TIB-HLs seem to exhibit higher CBF than lowlanders (Table).43 Differences in brain metabolism (such as decreased brain glucose metabolic uptake among AN-HLs),48 and increased NO bioavailability with greater oxygen delivery in TIB-HLs, may be related to CBF differences between these groups.43 To our knowledge, no data on the efficacy of adrenergic blocking agents in hypertensive chronic highlanders are currently available.Renin-Angiotensin-Aldosterone SystemAcute/Subacute ExposureAcute H-ALT exposure transiently suppresses the renin-angiotensin-aldosterone system. The HIGHCARE-HIMALAYA study (High Altitude Cardiovascular Research) demonstrated an initial reduction of plasma renin, angiotensin, and aldosterone concentrations in white lowlanders at H-ALT, followed by an increase of these values after 12 days (Figure 2).49 Men demonstrate more profound falls of plasma renin level at H-ALT.50 Compared with placebo, telmisartan decreased BP in healthy white lowlanders acutely exposed to 3400 mASL (≈11 200 ft) but failed to do so at 5400 mASL (≈17 700 ft).49 The loss of antihypertensive properties of telmisartan at 5400 mASL could be explained not only by the effects of higher altitude on BP dysregulation but also by the timing of ascent in this study since the participants stayed for 3 days at 3400 mASL and arrived after 5 additional days to 5400 mASL, allowing time for the progressive recovery of renin-angiotensin-aldosterone system activity after H-ALT exposure.49 This interesting observation reminds us that the rate of ascent to H-ALT should also be taken into consideration in studies assessing the effects of antihypertensive agents in lowlanders acutely exposed to H-ALT.Chronic ExposureData on plasma angiotensin-I–converting enzyme (ACE) levels at H-ALT are conflicting,51 but there is growing interest on ACE gene polymorphisms, which seem to play a role in vascular adaptations to H-ALT. The insertion (I)/deletion (D) ACE polymorphism describes the insertion or deletion of a DNA repeat element in intron 16 of the ACE gene.52 Subjects with the DD, ID, and II genotypes demonstrate higher, intermediate, and lower levels of plasma ACE, respectively.52 Higher DD genotype frequencies have been found in lowlanders that developed increased BP during subacute (30 days) H-ALT exposure, demonstrating the combination of environmental and preexisting genetic factors in the development of subacute hypertensive responses at H-ALT (Figure 2).53 A meta-analysis showed that the frequency of the DD genotype in highlanders (including Andeans and Tibetans) is lower than in lowlanders54; however, the DD genotype was associated with hypertension in female TIB-HLs (Figure 3).55 Whether these genetic differences impact the efficacy of ACE inhibitors at H-ALT is unknown.A randomized trial assessed the antihypertensive efficacy of valsartan compared with enalapril among 142 mild hypertensives living at different altitudes (100 mASL or ≈330 ft, 1538 mASL or ≈5000 ft, and 2600 mASL or ≈8500 ft) during a 4-week period.56 Both medications demonstrated similar efficacy (on office BP) independent of altitude, with valsartan having a better safety profile.Little data are available about the role of plasma aldosterone in chronic H-ALT. Concentrations in TIB-HLs have been shown to be higher than in healthy lowlanders,20 but to our knowledge, no data are available in this regard among AN-HLs. The relationship between plasma aldosterone and BP during chronic exposure to HA or the potential role of aldosterone receptor blockade in H-ALT in chronic highlanders is unknown.Carbonic AnhydraseAcute/Subacute ExposureAlthough carbonic anhydrase (CA) inhibitors are mainly used for the prevention and treatment of acute mountain sickness, they can impact BP via effects on the peripheral vasculature, the heart, and the nervous system.57 Acetazolamide has shown to significantly blunt the rise of systolic BP, diastolic BP, and augmentation index in white lowlanders acutely exposed to H-ALT.25 Mechanistic studies involving CA inhibition on lowering BP at H-ALT have not been performed. Nonetheless, indirect mechanisms may explain the effect of CA inhibitors. CA demonstrates NO2− anhydrase activity, which promotes NO generation from NO2−, particularly at low pH, and acetazolamide has shown augment (rather than inhibit) the NO2− anhydrase of CA, which may mediate the vasodilatory properties of this drug.58 In addition, acetazolamide seems to counteract the SNS activation at H-ALT via lowering the sensitivity of peripheral chemoreceptors59 through direct inhibition of CA in type I cells of the carotid body and other vascular mechanisms independent of CA inhibition.60Chronic ExposureThe role of CA and the effects of CA inhibition on hypertensive highlanders have not been studied.Endothelin-1ET is a bioactive peptide whose subtypes, ET-1, ET-2, and ET-3, have different physiological effects.61 ET-1 binds to 2 different receptor subtypes, ETA (ET type A receptor) and ETB receptors (ET type B receptor), which are predominant in cardiac muscle cells and vascular smooth cells, and produce a potent vasopressor response.61 ET type B receptor (also expressed in the vascular endothelium) is of special interest because it also generates a vasodilatory response, mediated by endothelial NO release,62 which indicates a balanced interaction between ligands and receptors in the ET system.Acute/Subacute ExposureIncreased ET type A receptor and ET type B receptor mRNA levels in the lung, heart, and thoracic aorta, as well as selective ET-1 upregulation in the pulmonary arteries and plasma, have been reported in rats exposed to subacute (28 days) normobaric hypoxia.63 In healthy humans, plasma and urine ET-1 levels increase during acute H-ALT exposure (Figure 2),64 which may be because of hypoxia-related decreased activity of endopeptidases that degrade ET-1.64 During acute H-ALT exposure, administration of bosentan (ET-1 antagonist) did not show significant effects on the systemic arterial BP; however, it significantly reduced systolic pulmonary artery pressure and mildly increased arterial oxygen saturation, as compared with placebo.65Chronic ExposureET-1 levels in TIB-HLs are lower than in Indian lowlanders,66 suggesting that ET-1 downregulation could represent an adaptive mechanism for chronic hypobaric hypoxia in these populations. However, a recent study found that ET-1 levels are significantly higher in Tibetan males compared with Han males living at H-ALT and are associated with a higher baseline brachial artery diameters and reduced brachial artery flow-mediated dilation.67 These apparently paradoxical observations illustrate a common important problem with the interpretation of data from phenotypic comparison studies between lowlander and highlanders, which can be substantially confounded by genetic, ethnic, lifestyle, and other factors.Currently, there are no available data on ET-1 variations in AN-HLs or the use of ET-1 antagonist agents for the treatment of hypertension in highlanders. The role of the ET system at H-ALT, including the complex interactions between H-ALT, ET type B receptor allele expression, adaptive mechanisms in different H-ALT populations, and the hypoxia-inducible factor (HIF) pathway, still needs to be elucidated.68Calcium ChannelsCa2+ plays a key role in the vascular response elicited by ET-1. This response involves an initial increase of Ca2+ from intracellular stores, followed by sustained Ca2+ increase because of influx from the extracellular space.69 Because the rise of Ca2+ also augments the synthesis of ET-1,70 it is possible that inhibition of voltage-dependent Ca2+ influx using calcium channel blockers (CCB) blunts the deleterious effects of ET-1 on vascular function in hypertension.69 Lacidipine71 and nifedipine72 have shown to improve endothelial function in patients with hypertension, which may be related to higher NO availability.73 Chronic oral treatment with nifedipine reduces the vasoconstriction response induced by ET-1 and phenylephrine.72 It remains unclear whether H-ALT could alter these mechanisms in humans.Acute/Subacute ExposureEven though CCBs are widely used for the treatment and prevention of H-ALT-pulmonary edema,6 no study has evaluated the effects of a CCB agent alone during acute H-ALT exposure. The concomitant use of slow-release CCB nifedipine gastrointestinal therapeutic system plus telmisartan in Peruvian hypertensive lowlanders acutely exposed to H-ALT resulted in lower 24-hour systolic BP and diastolic BP, with acceptable treatment tolerance rates.74Available data in animals indicate that prolonged exposure to H-ALT (110 days) does not affect sensitivity to nifedipine in sheep coronary arteries.75 After the same period of exposure to H-ALT, increased activity (more sensitive to activation and higher affinity for Ca2+) of large-conductance Ca2+-activated K+ channels was found in basilar arteries of ovine adults.76 This behavior o