Hypoxic ventilatory response
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Hypoxic ventilatory response (HVR) is the increase in
ventilation Ventilation may refer to: * Ventilation (physiology), the movement of air between the environment and the lungs via inhalation and exhalation ** Mechanical ventilation, in medicine, using artificial methods to assist breathing *** Ventilator, a ma ...
induced by
hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
that allows the body to take in and transport lower concentrations of oxygen at higher rates. It is initially elevated in lowlanders who travel to high altitude, but reduces significantly over time as people
acclimatize Acclimatization or acclimatisation ( also called acclimation or acclimatation) is the process in which an individual organism adjusts to a change in its environment (such as a change in altitude, temperature, humidity, photoperiod, or pH), a ...
.Cymerman, A; Rock, PB. . USARIEM-TN94-2. US Army Research Inst. of Environmental Medicine Thermal and Mountain Medicine Division Technical Report. Retrieved 2009-03-05.Teppema, Luc J., and Albert Dahan
"The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis."
Physiological Reviews 90.2 (2010): 675-754.
In
biological anthropology Biological anthropology, also known as physical anthropology, is a scientific discipline concerned with the biological and behavioral aspects of human beings, their extinct hominin ancestors, and related non-human primates, particularly from an e ...
, HVR also refers to human adaptation to environmental stresses resulting from high altitude. In
mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
, HVR invokes several physiological mechanisms. It is a direct result of the decrease in
partial pressure In a mixture of gases, each constituent gas has a partial pressure which is the notional pressure of that constituent gas as if it alone occupied the entire volume of the original mixture at the same temperature. The total pressure of an ideal gas ...
of oxygen in
arterial blood Arterial blood is the oxygenated blood in the circulatory system found in the pulmonary vein, the left chambers of the heart, and in the arteries. It is bright red in color, while venous blood is dark red in color (but looks purple through the tra ...
, and leads to increased ventilation. The body has different ways of coping with acute hypoxia. Mammals that rely on pulmonary ventilation will increase their ventilation to account for the lack of oxygen reaching the tissues. Mammals will also experience decreases in
aerobic metabolism Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
and oxygen demand, along with increases in ATP production. The physiological mechanisms differ in effect and in course of time. HVR is time dependent and can be divided into two phases: the first (0–5 minutes) of ventilation increase, and the second (5–20 minutes) of slow decline. The initial increase in ventilation from HVR is initiated by the
carotid bodies The carotid body is a small cluster of chemoreceptor cells, and supporting sustentacular cells. The carotid body is located in the adventitia, in the bifurcation (fork) of the common carotid artery, which runs along both sides of the neck. The ca ...
, which are bilaterally located at the port of brain circulation. Carotid bodies contain oxygen-sensitive cells that become more active in response to hypoxia. They send input to the
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...
which is then processed by
respiratory center The respiratory center is located in the medulla oblongata and pons, in the brainstem. The respiratory center is made up of three major respiratory groups of neurons, two in the medulla and one in the pons. In the medulla they are the dorsal res ...
s. Other mechanisms include
hypoxia-inducible factors Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or Hypoxia (medical), hypoxia. They are only present in ParaHoxozoa, parahoxozoan animals. Discovery The ...
, particularly ''HIF1''. Hormonal changes have also been associated with HVR, particularly those that affect the functioning of the carotid bodies.Hornbein, Thomas F., and Robert B. Schoene. ''High Altitude: An Exploration Of Human Adaptation.'' n.p., New York: Marcel Dekker, c2001., 2001. OskiCat. Web. 8 Nov. 2016. As HVR is a response to decreased oxygen availability, it shares the same environmental triggers as hypoxia. Such precursors include travelling to high altitude locations and living in an environment with high levels of
carbon monoxide Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
. Combined with climate, HVR can affect fitness and
hydration Hydration may refer to: * Hydrate, a substance that contains water * Hydration enthalpy, energy released through hydrating a substance * Hydration reaction, a chemical addition reaction where a hydroxyl group and proton are added to a compound * ...
. Especially for lowlanders who traverse past 6000 meters in altitude, the limit of prolonged human exposure to hypoxia, HVR may result in
hyperventilation Hyperventilation is irregular breathing that occurs when the rate or tidal volume of breathing eliminates more carbon dioxide than the body can produce. This leads to hypocapnia, a reduced concentration of carbon dioxide dissolved in the blood. ...
and ultimately the deterioration of the body. Oxygen consumption is reduced to a maximum of 1 liter per minute. Travelers acclimatized to high altitudes exhibit high levels of HVR, as it provides advantages such as increased oxygen intake, enhanced physical and mental performance, and lower susceptibility to illnesses associated with high altitude.
Adaptations In biology, adaptation has three related meanings. Firstly, it is the dynamic evolutionary process of natural selection that fits organisms to their environment, enhancing their evolutionary fitness. Secondly, it is a state reached by the p ...
in populations living at high altitudes range from cultural to genetic, and vary among populations. For example,
Tibetans The Tibetan people (; ) are an East Asian ethnic group native to Tibet. Their current population is estimated to be around 6.7 million. In addition to the majority living in Tibet Autonomous Region of China, significant numbers of Tibetans live ...
living at high altitudes have a more sensitive hypoxic ventilatory response than do Andean peoples living at similar altitudes, even though both populations exhibit greater
aerobic capacity VO2 max (also maximal oxygen consumption, maximal oxygen uptake or maximal aerobic capacity) is the maximum rate of oxygen consumption attainable during physical exertion. The name is derived from three abbreviations: "V̇" for volume (the dot ap ...
compared to lowlanders. The cause of this difference is most likely genetic, although developmental factors may also contribute.


Physiology


Acute hypoxic ventilatory response


Acute response (AR)

The first stage of the hypoxic ventilatory response consists of the initial reaction to a hypoxic environment leading up to the peak known as short-term potentiation (STP). The process is induced by a decrease in
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
partial pressure in blood. Type I glomus cells of
carotid bodies The carotid body is a small cluster of chemoreceptor cells, and supporting sustentacular cells. The carotid body is located in the adventitia, in the bifurcation (fork) of the common carotid artery, which runs along both sides of the neck. The ca ...
detect the change in oxygen levels and release
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
s towards the carotid sinus nerve, which in turn stimulates the brain, ultimately resulting in increased ventilation. The period of increased ventilation varies among different individuals but typically lasts under ten minutes.


Short-term potentiation (STP)

STP is the increase in ventilation after the acute hypoxic response and the eventual return of ventilation to its equilibrium after
carotid sinus In human anatomy, the carotid sinus is a dilated area at the base of the internal carotid artery just superior to the bifurcation of the internal carotid and external carotid at the level of the superior border of thyroid cartilage. The carotid ...
nerve stimulation, which causes a slowing in heart rate. This mechanism usually lasts between one and two minutes. STP is most apparent in
tidal volume Tidal volume (symbol VT or TV) is the volume of air moved into or out of the lungs during a normal breath. In a healthy, young human adult, tidal volume is approximately 500 ml per inspiration or 7 ml/kg of body mass. Mechanical vent ...
or the amplitude of phrenic neural output.


Short-term depression (STD)

STD is a temporary jump in respiratory frequency at the beginning of carotid chemo afferent stimulation or a temporary drop in respiratory frequency at the end of chemo afferent stimulation. This mechanism lasts from a span of several seconds to a few minutes. STP has only been found in the respiratory frequency of phrenic nerve stimulation, which produces contraction of the
diaphragm Diaphragm may refer to: Anatomy * Thoracic diaphragm, a thin sheet of muscle between the thorax and the abdomen * Pelvic diaphragm or pelvic floor, a pelvic structure * Urogenital diaphragm or triangular ligament, a pelvic structure Other * Diap ...
.


Ventilatory response to sustained hypoxia

A continued presence in a
hypoxic Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
environment of more than 24 hours leads to a steady flow of ventilation. This contingency in the environment causes
hypocapnia Hypocapnia (from the Greek words υπό meaning ''below normal'' and καπνός ''kapnós'' meaning ''smoke''), also known as hypocarbia, sometimes incorrectly called acapnia, is a state of reduced carbon dioxide in the blood. Hypocapnia usually ...
which decreases
ventilation Ventilation may refer to: * Ventilation (physiology), the movement of air between the environment and the lungs via inhalation and exhalation ** Mechanical ventilation, in medicine, using artificial methods to assist breathing *** Ventilator, a ma ...
.


Chronic hypoxic ventilatory response

Chronic hypoxia results in further physiological changes due to the transcription factor
hypoxia-inducible factor Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They are only present in parahoxozoan animals. Discovery The HIF transcriptional complex wa ...
(HIF). HIF is a dimer composed of the HIF-1α and HIF-1β subunit. HIF-1α is normally unable to bind with HIF-1β. However, lower oxygen partial pressure induces
post-transcriptional modification Transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, func ...
of HIF-1α, allowing HIF-1α to dimerize with HIF-1β to form HIF-1. HIF-1 induces many physiological changes that help the body adapt to the lower availability of oxygen including
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, increased
erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
production, and promoting
anaerobic Anaerobic means "living, active, occurring, or existing in the absence of free oxygen", as opposed to aerobic which means "living, active, or occurring only in the presence of oxygen." Anaerobic may also refer to: * Anaerobic adhesive, a bonding a ...
metabolism.


Neurology

The
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
plays a key role in the hypoxic ventilatory response. The process is triggered by the
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
's detection of a low blood oxygen level. In particular, the neurotransmitter
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
has been shown to have a direct correlation to a rise in ventilation. A study conducted in dogs investigated how their cardiovascular systems respond to various levels of oxygen before and after being given
MK-801 Dizocilpine (INN), also known as MK-801, is a pore blocker of the ''N''-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is ...
, which is a glutamate antagonist. With the MK-801, there was a noticeable decrease in both heart rate and breaths per minute under hypoxia. According to the study, the fact that the HVR was lessened when glutamate was inhibited demonstrates that glutamate is essential to the response.


High altitude adaptation

Populations residing in altitudes above 2,500 meters have adapted to their hypoxic environments. Chronic HVR is set of adaptations found among most human populations historically native to high-altitude regions, including the
Tibetan Plateau The Tibetan Plateau (, also known as the Qinghai–Tibet Plateau or the Qing–Zang Plateau () or as the Himalayan Plateau in India, is a vast elevated plateau located at the intersection of Central, South and East Asia covering most of the Ti ...
, the Andean Altiplano, and the Simian Plateau. Up to 140 million people in total reside in such areas, although not all possess these adaptations. Populations that have permanently settled in high altitude locations show virtually no reaction to acute
hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
. Natives of the Andes and the Himalayas have been shown to develop adaptation to
hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
from birth to neonatal years in the form of larger lungs and greater gas exchange surface area. This response can be attributed to genetic factors, but the development of the resistance to acute
hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
is highly affected by when the individual is exposed to high altitude; while genetic factors play an indefinite role in a person's HVR, because long term migrants do not show reduction in their reactions of high altitude even after living in high altitudes in long term, the discrepancy suggests that reaction to HVR is the combination of environmental exposure and genetic factors.


Anthropology


Populations


Andeans

The Andean peoples are one of three central populations of study that have a decreased HVR. These populations notably inhabit areas in and around the
Andes The Andes, Andes Mountains or Andean Mountains (; ) are the longest continental mountain range in the world, forming a continuous highland along the western edge of South America. The range is long, wide (widest between 18°S – 20°S ...
mountain range, which has an average altitude of . HVR has been studied in inhabitants of
Cusco Cusco, often spelled Cuzco (; qu, Qusqu ()), is a city in Southeastern Peru near the Urubamba Valley of the Andes mountain range. It is the capital of the Cusco Region and of the Cusco Province. The city is the list of cities in Peru, seventh m ...
, Peru, which lies at . Living in such high altitudes has led to cultural adaptations, including the consumption of
coca tea Coca tea, also called mate de coca, is an herbal tea (infusion) made using the raw or dried leaves of the coca plant, which is native to South America. It is made either by submerging the coca leaf or dipping a tea bag in hot water. The tea is mo ...
. Coca tea is an extract made by boiling the leaves of the coca plant in water and contains the stimulant
Cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...
. For millennia, Andeans have used coca tea as a treatment for acute altitude sickness, and to this day it is still given to those travelling to the high altitude regions of Peru, though, its effectiveness has been disputed. In a 2010 study published in the ''Journal of Travel Medicine'', the consumption of coca tea was actually associated with an ''increase'' in the incidence of altitude sickness experienced by travelers visiting the city of Cusco, Peru. It has been found that the ventilatory response is substantially less pronounced in the Andean populations than in the Tibetans, with the HVR response of Tibetans roughly double that of Andeans at an altitude of around . The altitude adaptations also appear to be less permanent than those seen in the Tibetan populations, as the Andeans have a much higher prevalence of
Chronic Mountain Sickness Chronic mountain sickness (CMS) is a disease in which the proportion of blood volume that is occupied by red blood cells increases (polycythaemia) and there is an abnormally low level of oxygen in the blood (hypoxemia). CMS typically develops after ...
(CMS), where the body develops a harmful reaction to low oxygen levels over many years.


Tibetans

The
Tibetan people The Tibetan people (; ) are an East Asian ethnic group native to Tibet. Their current population is estimated to be around 6.7 million. In addition to the majority living in Tibet Autonomous Region of China, significant numbers of Tibetans live ...
are an ethnic group native to
Tibet Tibet (; ''Böd''; ) is a region in East Asia, covering much of the Tibetan Plateau and spanning about . It is the traditional homeland of the Tibetan people. Also resident on the plateau are some other ethnic groups such as Monpa people, ...
that live throughout the
Tibetan Plateau The Tibetan Plateau (, also known as the Qinghai–Tibet Plateau or the Qing–Zang Plateau () or as the Himalayan Plateau in India, is a vast elevated plateau located at the intersection of Central, South and East Asia covering most of the Ti ...
. They live at altitudes up to , and are thus of extreme interest to researchers investigating HVR in high altitude populations. One of these populations are the
Sherpa people The Sherpa are one of the Tibetan ethnic groups native to the most mountainous regions of Nepal, Tingri County in the Tibet Autonomous Region and the Himalayas. The term ''sherpa'' or ''sherwa'' derives from the Sherpa language words ("east") ...
, a group of Tibetans who are sought after for their knowledge of and skill with navigating through the
Himalayas The Himalayas, or Himalaya (; ; ), is a mountain range in Asia, separating the plains of the Indian subcontinent from the Tibetan Plateau. The range has some of the planet's highest peaks, including the very highest, Mount Everest. Over 100 ...
. Historically, Sherpas have been contracted to guide expeditions up
Mount Everest Mount Everest (; Tibetan: ''Chomolungma'' ; ) is Earth's highest mountain above sea level, located in the Mahalangur Himal sub-range of the Himalayas. The China–Nepal border runs across its summit point. Its elevation (snow heig ...
, but the practice has since declined in light of exploitation of the Sherpa guides. The energy and ease at which the Sherpa ascend and descend mountains is due to their ability to use oxygen more efficiently. This ability to excel at
mountaineering Mountaineering or alpinism, is a set of outdoor activities that involves ascending tall mountains. Mountaineering-related activities include traditional outdoor climbing, skiing, and traversing via ferratas. Indoor climbing, sport climbing, a ...
has shifted their culture around it. Tourism has become a driving force for the financial income of the Sherpa people. The Sherpa are able to make much more money acting as travel guides due to their local knowledge, and climbing ability. Genetic evidence suggests that the Tibetan peoples diverged from the larger Han Chinese population any time around 1,000 B.C.E. to 7,000 B.C.E. Given the significant mutations to the
EPAS1 Endothelial PAS domain-containing protein 1 (EPAS1, also known as hypoxia-inducible factor-2alpha (HIF-2α)) is a protein that is encoded by the ''EPAS1'' gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factors ...
gene that contribute to the Tibetan resistance to altitude sickness, this suggests that the extreme evolutionary pressure on the Tibetan peoples has produced one of the fastest natural selection effects seen in a human population. The adaptations of Tibetans to their hypoxic ventilatory response interact with other adaptations to promote successful reproduction. For example, Tibetans have evolved a greater oxygen saturation during infancy, leading to a lower rate of child mortality than experienced by non-adapted populations at altitude.


Amhara

The
Amhara people Amharas ( am, አማራ, Āmara; gez, ዐምሐራ, ʾÄməḥära) are a Semitic-speaking ethnic group which is indigenous to Ethiopia, traditionally inhabiting parts of the northwest Highlands of Ethiopia, particularly inhabiting the Amhara ...
are the occupants of the central and northern
Highlands Highland is a broad term for areas of higher elevation, such as a mountain range or mountainous plateau. Highland, Highlands, or The Highlands, may also refer to: Places Albania * Dukagjin Highlands Armenia * Armenian Highlands Australia *Sou ...
of
Ethiopia Ethiopia, , om, Itiyoophiyaa, so, Itoobiya, ti, ኢትዮጵያ, Ítiyop'iya, aa, Itiyoppiya officially the Federal Democratic Republic of Ethiopia, is a landlocked country in the Horn of Africa. It shares borders with Eritrea to the ...
in the
Amhara Region The Amhara Region ( am, አማራ ክልል, Åmara Kilil), officially the Amhara National Regional State (), is a regional state in northern Ethiopia and the homeland of the Amhara people. Its capital is Bahir Dar which is the seat of the Reg ...
, where the elevation ranges consistently between 1500 m (4,921 ft) to 4550 m (14,928 ft). For over 5,000 years
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s have been living near the
Simien Mountains The Simien Mountains (Amharic: ስሜን ተራራ or Səmen; also spelled Simen and Semien), in northern Ethiopia, north east of Gondar in Amhara region, are part of the Ethiopian Highlands. They are a World Heritage Site and include the Simien M ...
at altitudes above 3,000m and over that time they genetically
adapted In biology, adaptation has three related meanings. Firstly, it is the dynamic evolutionary process of natural selection that fits organisms to their environment, enhancing their evolutionary fitness. Secondly, it is a state reached by the po ...
to the hypoxic conditions of high
altitude Altitude or height (also sometimes known as depth) is a distance measurement, usually in the vertical or "up" direction, between a reference datum and a point or object. The exact definition and reference datum varies according to the context ...
.


References

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