Bosentan Reduces Pulmonary Artery Pressure in High Altitude Residents

Kojonazarov, Baktybek; Isakova, Jainagul; Imanov, Bakytbek; Sovkhozova, Nurmira; Sooronbaev, Talant; Ishizaki, Takeshi; Aldashev, Almaz

doi:10.1089/ham.2011.1107

Cited by 29 publications

(15 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Other relevant measures did not differ [51]. However, an acute hemodynamic study showed a beneficial effect of bosentan on PASP (measured by echocardiography) in 15 Kyrgyz patients with invasively proven high altitude PH: a single oral dose of bosentan led to a decrease in PASP from 46 to 37 mm Hg after 3 h, while CO and pulsoxymetric saturation remained stable [52]. Another echocardiography study in healthy volunteers showed that a single dose of bosentan blunted the rise in PASP caused by acute (90 min) hypoxia exposure [53].…”

Section: Long-term Changes Of the Cardiopulmonary System Due To Hymentioning

confidence: 99%

Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

Grimminger

Richter

Tello

et al. 2017

Canadian Respiratory Journal

View full text Add to dashboard Cite

With rising altitude the partial pressure of oxygen falls. This phenomenon leads to hypobaric hypoxia at high altitude. Since more than 140 million people permanently live at heights above 2500 m and more than 35 million travel to these heights each year, understanding the mechanisms resulting in acute or chronic maladaptation of the human body to these circumstances is crucial. This review summarizes current knowledge of the body's acute response to these circumstances, possible complications and their treatment, and health care issues resulting from long-term exposure to high altitude. It furthermore describes the characteristic mechanisms of adaptation to life in hypobaric hypoxia expressed by the three major ethnic groups permanently dwelling at high altitude. We additionally summarize current knowledge regarding possible treatment options for hypoxia-induced pulmonary hypertension by reviewing in vitro, rodent, and human studies in this area of research.

show abstract

Section: Long-term Changes Of the Cardiopulmonary System Due To Hymentioning

confidence: 99%

Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

Grimminger

Richter

Tello

et al. 2017

Canadian Respiratory Journal

View full text Add to dashboard Cite

show abstract

“…Given that HA exposure has long been recognized as a cardiac stress (12) and endothelin (ET) receptor blockade with bosentan ameliorates an increase in pulmonary artery pressure (13) with hypoxia, we hypothesized that a decreased level of EDNRB would play a protective role in HA hypoxia. In addition, it appears that EdnrA-specific antagonism affects only pulmonary hypertension with no effect on cardiac performance (14).…”

Section: Significancementioning

confidence: 99%

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Stobdan

Zhou

Ao-Ieong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB −/+ heterozygote mice are treated with lower levels of oxygen (O 2 ), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O 2 ) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O 2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB −/+ compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB −/+ mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB −/+ and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.is often referred to as a biosignature, a chemical marker in the atmosphere closely associated with life, and in a complex organism, such as humans, various physiological systems have evolved to maintain an optimal O 2 homeostasis. Arguably, humans living at high altitude (HA) for thousands of years ought to have undergone a significant level of natural selection to adjust to the challenging hypoxic condition. Human adaptation to HA hypoxia, which can be protective to tissues, can potentially be harnessed for better therapeutic modalities for sea-level diseases that involve hypoxia and ischemia in their pathogenesis. Indeed, lessons from such an "experiment in nature" can be derived from HA adaptation and can advance lowaltitude medicine (1). With the advent of newer technology including next-generation sequencing (seq), this idea has recently led to intensive efforts, and a number of publications have appeared on studies of human populations living at HA (2-4). These studies also draw added significance not only to sea-level human diseases but also to more than 140 million people living at an altitude above 2,500 m, where the hypoxic condition presents a major challenge for survival (5). Although a number of laboratory methods that mimic hypoxia adaptation using model organisms (6) have been used as tools to identify causative genetic pathways (7,8), studies in human populations living at different H...

show abstract

“…Second, endothelin-1 (Edn1), the ligand that binds to both receptors, increases during HA exposure [5] and lead to pulmonary hypertension. Third, the receptor antagonist Bosentan, although non-specific, is given to reduce pulmonary artery pressure [6]. Fourth, the improvements post receptor antagonist treatment likely occurs through blocking EdnrB because in spite of the higher ratio of EDNRA/EDNRB (4 to 1) in the heart [7], KO studies have ruled-out any important role of EdnrA in maintaining cardiac function [8].…”

Section: Introductionmentioning

confidence: 99%

Cardiac-specific knockout and pharmacological inhibition of Endothelin receptor type B lead to cardiac resistance to extreme hypoxia

et al. 2018

View full text Add to dashboard Cite

Under normal condition, cardiomyocytes-specific EdnrB knockout mice, both heterozygote and homozygote, are phenotypically normal. Under hypoxic condition, a lower level or complete deletion of cardiomyocyte EdnrB conserves cardiac function by maintaining high cardiac index. Similarly, mice treated with both specific (BQ-788) and non-specific (Bosentan) EDNRB blockers are tolerant to hypoxia by maintaining better cardiac function. The oxygen perfusion under extreme hypoxia is better in the mice with lower EDNRB, as depicted by lower lactate level at 5% oxygen. Our current study systematically confirms, both genetically and pharmacologically, the protective role of a lower EDNRB under extreme hypoxia stress. Overall, it supports our hypothesis that studies on human hypoxia adaptation provide new insight to common disease pathogenesis and treatments.

show abstract

Bosentan Reduces Pulmonary Artery Pressure in High Altitude Residents

Abstract: Increased ET-1 levels play an important role in development of HAPH.

Cited by 29 publications

References 43 publications

Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Cardiac-specific knockout and pharmacological inhibition of Endothelin receptor type B lead to cardiac resistance to extreme hypoxia

Contact Info

Product

Resources

About