1. Introduction
2. Hypoxic Pulmonary Vasoconstriction
3. Pulmonary Circulation in Sea Level Residents upon Acute Exposure to High Altitude
3.1. Factors Modulating the Magnitude of the Hypoxic Pulmonary Vascular Responses
3.2. Pulmonary Hypertension in HIgh Altitude Pulmonary Edema
3.3. Prevention and Treatment of Pulmonary Hypertension in High Altitude Pulmonary Edema
3.3.1. Non-Pharmacological Prevention of Pulmonary Hypertension in High Altitude Pulmonary Edema
3.3.2. Pharmacological Prevention of Pulmonary Hypertension in High Altitude Pulmonary Edema
3.4. Treatment of Pulmonary Hypertension in High Altitude Pulmonary Edema
4. Pulmonary Circulation in Sea Level Residents Chronically Exposed to High Altitude
5. Pulmonary Circulation in Healthy High Altitude Residents
6. High Altitude Pulmonary Hypertension and Chronic Mountain Sickness
6.1. Hypoxia Inducible Factors (HIFs)–Prolyl Hydroxylase Domain (PHD) Enzymes–von Hippel–Lindau Tumor Suppressor (VHL) Protein System
6.2. Variability in Hypoxic Pulmonary Vasoconstriction
6.3. Erythrocytosis
6.4. Fetal Programming
6.5. Iron Deficiency
7. Other Clinical Forms of Pulmonary Hypertension at High Altitude
8. Prevention and Treatment of Pulmonary Hypertension in High Altitude Dwellers
8.1. Potential of Drugs Approved for Treatment of Pulmonary Arterial Hypertension
8.2. Drug Repurposing
8.3. Novel Potential Therapeutic Targets
9. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drugs | Mechanism of Action | Effects | References |
---|---|---|---|
Inhaled NO | Soluble guanylate cyclase stimulator | attenuates hypoxia-induced PVR increase in ventilated dogs | [139] |
improves survival of HAPE rats at extreme altitude (hypobaric chamber) | [140] | ||
decreases PAP and PVR in hypoxia-breathing lambs | [105,141] | ||
Sildenafil | Phosphodiesterase 5 inhibitor | attenuates hypoxia-induced human and rats PA constriction | [142] |
attenuates hypoxia-induced RVSP increase in ventilated rats | [143] | ||
Tadalafil | Phosphodiesterase 5 inhibitor | inhibits hypoxia-induced isolated rat PA constriction | [144] |
prevents an increase in RVSP in ventilated hypoxia-breathing rats | [145] | ||
Bosentan | Endothelin receptor receptor A/B antagonist | decreases PAP in isolated perfused rat lung | [146] |
prevents PAP increase in hypoxia exposed rats | [147] | ||
Nifedipine | Calcium channel blocker | reduces PVR in hypoxia-breathing awake piglets | [148] |
Dexamethasone | Anti-inflammatory and immunosuppressive agent | increases NOS expression and improves hypoxia-induced PAEC dysfunction | [130] |
stimulates the expression of Na transporters and prevents hypoxia-induced inhibition of alveolar reabsorption | [133] | ||
improves lung epithelial Na+ channels and Na+/K+-ATPase and increases alveolar fluid clearance in rats | [132] | ||
improves pulmonary capillary endothelial permeability and prevents HAPE development in rat model | [131] | ||
Acetazolamide | Carbonic anhydrase inhibitor | prevents an increase in PAP and PVR in conscious hypoxia-breathing dogs | [149] |
inhibits hypoxia-induced Ca2+ influx in PASMCs | [150] |
Drugs | Mechanism of Action | Effects | References |
---|---|---|---|
Inhaled NO | Soluble guanylate cyclase stimulator | decreases sPAP and improves oxygenation in HAPE-prone subjects at HA | [112] |
reduces mPAP and PVR in HAPE patients at HA | [113] | ||
decreases PAP and PVR in hypoxia-breathing healthy subjects | [112] | ||
Sildenafil | Phosphodiesterase 5 inhibitor | prevents an increase in PAP and PVR in hypoxia-breathing healthy subjects | [20,151] |
decreases sPAP and improves exercise capacity under hypoxic breathing and at HA in healthy subjects | [114] | ||
decreases sPAP and improves blood oxygenation upon acute HA exposure in healthy subjects | [117] | ||
attenuates sPAP increase and RV dysfunction upon acute HA exposure in healthy subjects | [22] | ||
Tadalafil | Phosphodiesterase 5 inhibitor | attenuates an increase in PAP and prevents HAPE development | [64] |
Bosentan | Endothelin receptor receptor A/B antagonist | prevents an increase in sPAP and PVR in hypoxia breathing healthy subjects | [125,126,127] |
prevents an increase in sPAP and improves arterial oxygen saturation in healthy subjects exposed to HA | [122] | ||
Sitaxentan | Endothelin receptor antagonist | prevents an increase of PAP and PVR and exercise capacity decline in hypoxia-breathing healthy subjects | [129] |
reduces PVR and improves lung diffusion capacity and exercise capacity in healthy subjects exposed to HA | [152] | ||
reduces PAP and PVR and improves exercise capacity in healthy subjects exposed to HA | [129] | ||
Nifedipine | Calcium channel blocker | reduces PAP and improves HAPE symptoms | [66] |
attenuates an increase in PAP and prevents HAPE development | [63] | ||
Dexamethasone | Anti-inflammatory and immunosuppressive agent | attenuates an increase in PAP and prevents HAPE development | [64] |
attenuates an increase in TRG and PVR and improves oxygenation in COPD patients at HA | [153] | ||
attenuates an increase in TRG and improves exercise capacity | [154] | ||
Acetazolamide | Carbonic anhydrase inhibitor | prevents an increase in TRG in hypoxia-breathing healthy subjects | [136] |
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