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Saturday, April 18, 2020

Carlsbad Caverns National Park

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Carlsbad_Caverns_National_Park

Carlsbad Caverns National Park
IUCN category II (national park)
The cave is well-known for its many calcite formations such as this column and array of stalactites
Location in the United States Show map of the United StatesShow map of New MexicoShow all
Location	Eddy County, New Mexico, United States
Nearest city	Carlsbad, New Mexico
Coordinates	32°10′31″N 104°26′38″WCoordinates: 32°10′31″N 104°26′38″W
Area	46,766 acres (18,926 ha) 339 acres (137 ha) private
Established	May 14, 1930
Visitors	465,912 (in 2018)
Governing body	National Park Service
Website	Official website

UNESCO World Heritage Site
Type	Natural
Criteria	vii, viii
Designated	1995 (19th session)
Reference no.	721
State Party	United States
Region	North America

Carlsbad Caverns National Park is an American national park in the Guadalupe Mountains of southeastern New Mexico. The primary attraction of the park is the show cave, Carlsbad Cavern. Visitors to the cave can hike in on their own via the natural entrance or take an elevator from the visitor center.

The park entrance is located on US Highway 62/180, approximately 18 miles (29 km) southwest of Carlsbad, New Mexico. Carlsbad Caverns National Park participates in the Junior Ranger Program. The park has two entries on the National Register of Historic Places: The Caverns Historic District and the Rattlesnake Springs Historic District. Approximately two thirds of the park has been set aside as a wilderness area, helping to ensure no future changes will be made to the habitat.

Carlsbad Cavern includes a large limestone chamber, named simply the Big Room, which is almost 4,000 feet (1,220 m) long, 625 feet (191 m) wide, and 255 feet (78 m) high at its highest point. The Big Room is the fifth largest chamber in North America and the twenty-eighth largest in the world.

Geology

Capitan Reef

An estimated 250 million years ago, the area surrounding Carlsbad Caverns National Park served as the coastline for an inland sea. Present in the sea was a plethora of marine life, whose remains formed a reef. Unlike modern reef growths, the Permian reef contained bryozoans, sponges, and other microorganisms. After the Permian Period, most of the water evaporated and the reef was buried by evaporites and other sediments. Tectonic movement occurred during the late Cenozoic, uplifting the reef above ground. Susceptible to erosion, water sculpted the Guadalupe Mountain region into its present-day state.

Speleogenesis

Carlsbad Caverns National Park is situated in a bed of limestone above groundwater level. During cavern development, it was within the groundwater zone.^{[citation needed]} Deep below the limestones are petroleum reserves (part of the Mid-Continent Oil Field). At a time near the end of the Cenozoic, hydrogen sulfide (H₂S) began to seep upwards from the petroleum into the groundwater. The combination of hydrogen sulfide and oxygen from the water formed sulfuric acid: H₂S + 2O₂ → H₂SO₄. The sulfuric acid then continued upward, aggressively dissolving the limestone deposits to form caverns. The presence of gypsum within the cave is a confirmation of the occurrence of this process, as it is a byproduct of the reaction between sulfuric acid and limestone. Once the acidic groundwater drained from the caverns, speleothems began to be deposited within the cavern. Erosion above ground created the natural entrance to the Carlsbad Caverns within the last million years. Exposure to the surface has allowed for the influx of air into the cavern. Rainwater and snowmelt percolating downward into the ground pick up carbon dioxide; once this water reaches a cavern ceiling, it precipitates and evaporates, leaving behind a small calcium carbonate deposit. Growths from the roof downward formed through this process are known as stalactites. Additionally, water on the floor of the caverns can contain carbonic acid and generate mineral deposits by evaporation. Growths from the floor upward through this process are known as stalagmites. Different formations of speleothems include columns, soda straws, draperies, helictites, and popcorn. Changes in the ambient air temperature and rainfall affect the rate of growth of speleothems, as higher temperatures increase carbon dioxide production rates within the overlying soil. The color of the speleothems is determined by the trace constituents in the minerals of the formation.

Climate

According to the Köppen climate classification system, the Carlsbad Caverns Visitor Center has a Hot semi-arid climate (Bsh).

History

Elevator house, ca. 1933–42; photo by Ansel Adams

In 1898, a teenager named Jim White explored the cavern with a homemade wire ladder. He named many of the rooms, including the Big Room, New Mexico Room, Kings Palace, Queens Chamber, Papoose Room, and Green Lake Room. He also named many of the cave's more prominent formations, such as the Totem Pole, Witch's Finger, Giant Dome, Bottomless Pit, Fairyland, Iceberg Rock, Temple of the Sun, and Rock of Ages.

Max Frisch incorporates the story about White's discovery of the caves in his novel I'm Not Stiller.

The town of Carlsbad, which lends its name to the cavern and national park, is in turn named after the Czech town formerly known by the German name Karlsbad (English spelling Carlsbad) and now known by the Czech name Karlovy Vary, both of which mean "Charles' Bath[s]."

Until 1932, visitors to the cavern had to walk down a switchback ramp that took them 750 feet (230 m) below the surface. The walk back up was tiring for some. In 1932 the national park opened up a large visitor center building that contained two elevators that would take visitors in and out of the caverns below. The new center included a cafeteria, waiting room, museum and first aid area.

Legislative history

October 25, 1923 – President Calvin Coolidge signed a proclamation (1679-Oct. 25, 1923-43 Stat. 1929) establishing Carlsbad Cave National Monument.

... a limestone cavern known as the Carlsbad Cave, of extraordinary proportions and of unusual beauty and variety of natural decoration; ... beyond the spacious chambers that have been explored, other vast chambers of unknown character and dimensions exist; ... the several chambers contain stalactites, stalagmites, and other formations in such unusual number, size, beauty of form, and variety of figure as to make this a cavern equal, if not superior, in both scientific and popular interest to the better known caves ...

— Proclamation 1679, Oct. 25, 1923, 43 Stat. 1929

April 2, 1924 – President Calvin Coolidge issued an executive order (3984) for a possible national park or monument at the site.
May 3, 1928 – a supplemental executive order (4870) was issued reserving additional land for the possible monument or park.
May 14, 1930 – an act of the United States Congress (46 Stat. 279) established Carlsbad Caverns National Park to be directed by the Secretary of the Interior and administered by the National Park Service.
June 17, 1930 – President Herbert Hoover signed Executive Order 5370 reserving additional land for classification.
November 10, 1978 – Carlsbad Caverns Wilderness was established with the National Parks and Recreation Act (95-625) signed by President Jimmy Carter.

Named rooms

Some of the following rooms are not open to the public because of inaccessibility and safety issues.

Rock of Ages in the Big Room, c. 1941; photo by Ansel Adams

On the tour route

Outside the entrance to the caverns

Balloon Ballroom: Located in the ceiling above the main entrance hall, this small room was first accessed by tying a rope to a bunch of balloons and floating them into the passage.
Bat Cave: A large, unadorned rocky passage connected to the main entrance corridor. The majority of the cave's bat population lives in this portion of the cave, which was mined for bat guano in the early 20th century.
Bell Cord Room: Named for a long, narrow stalactite coming through a hole in the ceiling, resembling the rope coming through the roof of a belfry. This room is located at the end of the Left Hand Tunnel.
Bifrost Room: Discovered in 1982, it is located in the ceiling above Lake of the Clouds. Its name refers to a Norse myth about a world in the sky that was accessed from Earth by a rainbow (the "Bifrost Bridge"). The room was given this name because of its location above the Lake of the Clouds and its colorful oxide-stained formations.
Big Room or The Hall of the Giants: The largest chamber in Carlsbad Caverns, with a floor space of 357,469 square feet (33,210 m²).
Chocolate High: A maze of small passages totalling nearly a mile (1500 m) in combined length, discovered in 1993 above a mud-filled pit in the New Mexico Room known as Chocolate Drop.
Green Lake Room: The uppermost of the "Scenic Rooms", it is named for a deep, malachite-colored pool in the corner of the room. In the early 1960s, when the military was testing the feasibility of Carlsbad Cavern as an emergency fallout shelter, the Green Lake was used to look for ripples caused by a nuclear bomb test many miles away. None appeared.
Guadalupe Room: Discovered by a park ranger in 1966, this is the second largest room in Carlsbad Caverns. It is known for its dense collection of "soda straw" stalactites.
Hall of the White Giant: A large chamber containing a large, white stalagmite. Rangers regularly lead special wild-cave tours to this room.
Halloween Hall: A room roughly 30 feet in length located above the Spirit World. Named for its discovery on October 31, 2013.
King's Palace: The first of four chambers in a wing known as the "scenic rooms", it is named for a large castle-like formation in the center of the room.
Lake of the Clouds: The lowest known point in the cave. It is located in a side passage off the Left Hand Tunnel. It is named for its large lake containing globular, cloud-like rock formations that formed under water when the lake level was much higher.
Left Hand Tunnel: A long, straight passage marked by deep fissures in the floor. These fissures are not known to lead anywhere. The Left Hand Tunnel leads to the Lake of the Clouds and the Bell Cord Room.
Mabel's Room: A moderate-sized room located past the Talcum Passage in Lower Cave.
Mystery Room: A large, sloping room located off the Queen's Chamber, named for an unexplained noise heard only here. A small vertical passage at the far end connects it to Lower Cave.
New Mexico Room: Located adjacent to the Green Lake Room and accessed by means of a somewhat narrow corridor.
New Section: A section of fissures east of the White Giant formation and paralleling the Bat Cave. New discoveries are still being made in this section.
Papoose Room: Located between the King's Palace and Queen's Chamber.
Queen's Chamber: Widely regarded as the most beautiful and scenic area of the cave. Jim White's lantern went out in this chamber while he was exploring, and he was in the dark for over half an hour.
Spirit World: Located in the ceiling of the Big Room at its highest point (an area known as the Top of the Cross), this area is filled with white stalagmites that resembled angels to the room's discoverers.
Talcum Passage: A room located in Lower Cave where the floor is coated with gypsum dust.
The Rookery: One of the larger rooms in Lower Cave. Many cave pearls are found in this area.
Underground Lunchroom: Located in the Big Room at the head of the Left Hand Tunnel. It contains a cafeteria that was built in the 1950s, and is where the elevators from the visitor center exit into the cave.

Panorama of cavern's interior

Tourist information

Park map

Carlsbad Caverns had an average annual visitation of about 410,000 in the period from 2007 to 2016. Peak visitation usually occurs on the weekends following Memorial Day and the Fourth of July. Free admittance for self-guided tours is often granted on holidays such as Martin Luther King, Jr. weekend, National Park Week, and Veterans Day weekend. Camping is permitted in the back country of the park, but a permit is required from the visitor center.

One of the extra events hosted by the park is the bat flight viewing. A program is given in the early evening at the amphitheater near the main entrance prior to the start of the flight, which varies with the sunset time. Flight programs are scheduled from Memorial Day weekend through the middle of October. Optimal viewing normally occurs in July and August when the current year bat pups first join the flight of adult bats. Morning programs are also hosted pre-dawn to witness the return of bats into the cave. Once a year, a bat flight breakfast is held where visitors can eat breakfast at the park prior to the morning return of bats.

Throughout the year, star parties are hosted by the park at night. Rangers host informational programs on the celestial night sky and telescopes are also made available. These parties are often held in conjunction with special astronomical events, such as a transit of Venus.

Recent exploration

In 1985 a distinctive method of exploration was invented. In a dome area 255 feet (78 m) above the Big Room floor not far from the Bottomless Pit, a stalagmite leaned out. Using a balsa wood loop with helium-filled balloons attached, the explorers, (after several tries over several years), floated a lightweight cord up, over the target stalagmite, and back down to the ground. Then they pulled a climbing rope into position, and the explorers ascended into what they named The Spirit World.^[19] A similar, smaller room was found in the main entrance corridor, and was named Balloon Ballroom in honor of this technique.

In 1993, a series of small passages totaling nearly a mile in combined length was found in the ceiling of the New Mexico Room. Named "Chocolate High", it was the largest discovery in the cave since the Guadalupe Room was found in 1966.

The Bottomless Pit was originally said to have no bottom. Stones were tossed into it, but no sound of the stones striking the bottom was heard. Later exploration revealed the bottom was about 140 feet (43 m) deep and covered with soft dirt. The stones made no sound when they struck the bottom because they were lodged in the soft soil.

On October 31, 2013, a cave technician exploring the Spirit World area discovered a new chamber hundreds of feet up from the main area. Dubbed "Halloween Hall" for the date of its discovery, the fresh find marks the biggest discovery for the caverns in more than 25 years. The room's diameter is about 100 feet (30 m), and more than 1,000 bat bones were discovered inside the room.

Other caves

The park contains over 119 caves. Three caves are open to public tours. Carlsbad Caverns is the most famous and is fully developed with electric lights, paved trails, and elevators. Slaughter Canyon Cave and Spider Cave are undeveloped, except for designated paths for the guided "adventure" caving tours.

Lechuguilla Cave is well known for its delicate speleothems and pristine underground environment. Guano mining occurred in the pit below the entrance in the 1910s. After gaining permission from the national park managers to dig into a rubble pile where wind whistled between the rocks when the weather changed, cavers broke through into a room in 1986. Over 120 miles (190 km) of cave passage has been explored and mapped. It has been mapped to a depth of 1,600 feet (490 m), making it the second deepest limestone cave in the U.S. To protect the fragile environment, access is limited to permitted scientific expeditions only.

Bats

Mexican free-tailed bats emerging from the natural entrance and flying to the nearest water

Seventeen species of bats live in the park, including many Mexican free-tailed bats. It has been estimated that the population of Mexican free-tailed bats once numbered in the millions but has declined drastically in modern times. The cause of this decline is unknown but the pesticide DDT is often listed as a primary cause. A study published in 2009 by a team from Boston University questions whether millions of bats ever existed in the caverns.

Many techniques have been used to estimate the bat population in the cave. The most recent and most successful of these attempts involved the use of thermal imaging camera to track and count the bats. A count from 2005 estimated a peak of 793,000.

The Mexican free-tailed bats are present from April or May to late October or early November. They emerge in a dense group, corkscrewing upwards and counterclockwise, usually starting around sunset and lasting about three hours. (Jim White decided to investigate the caverns when he saw the bats from a distance and at first thought they were a volcano or a whirlwind.) Every early evening from Memorial Day weekend to mid October (with possible exceptions for bad weather), a ranger gives a talk on the bats while visitors sitting in the amphitheater wait to watch the bats emerge.

Other attractions

Carlsbad Cavern amphitheater

Ten hiking trails and an unpaved drive provide access to the desert scenery and ecosystem. The developed portion around the cave entrance has been designated as The Caverns Historic District.

A detached part of the park, Rattlesnake Springs Picnic Area, is a natural oasis with landscaping, picnic tables, and wildlife habitats. As a wooded riparian area in the desert, it is home to remarkable variety of birds; over 300 species have been recorded. About 500 species have been recorded in the whole state of New Mexico. Rattlesnake Springs is designated a historic district on the National Register of Historic Places. The National Audubon Society has designated Rattlesnake Springs an Important Bird Area (IBA). The natural entrance to the caverns is also an IBA because of its colony of cave swallows, possibly the world's largest.

Antibiotic-resistant bacteria have been discovered in the isolated and little-visited Lechuguilla Cave within the park.

Receptor antagonist

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Receptor_antagonist

Antagonists will block the binding of an agonist at a receptor molecule, inhibiting the signal produced by a receptor-agonist coupling.

A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.

Etymology

The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, competitor, villain, enemy, rival", which is derived from anti- ("against") and agonizesthai ("to contend for a prize").

Receptors

Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly. The activity of receptors can also be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the active site or the allosteric site. In addition, antagonists may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity to exert their effects.

The term antagonist was originally coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by 'blocking' the receptor from the agonist. This definition also remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H₁ receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.

Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states. The discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may actually depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug.

Pharmacodynamics

Efficacy and potency

By definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, however, antagonists inhibit the function of agonists, inverse agonists, and partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist. The potency of an antagonist is usually defined by its half maximal inhibitory concentration (i.e., IC₅₀ value). This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC₅₀ value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar. The lower the IC₅₀ the greater the potency of the antagonist, and the lower the concentration of drug that is required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects.

Affinity

The affinity of an antagonist for its binding site (K_i), i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and K_i determination is independent of the affinity, efficacy or concentration of the agonist used. However, it is important that equilibrium has been reached. The effects of receptor desensitization on reaching equilibrium must also be taken into account. The affinity constant of antagonists exhibiting two or more effects, such as in competitive neuromuscular-blocking agents that also block ion channels as well as antagonising agonist binding, cannot be analyzed using Schild regression. Schild regression involves comparing the change in the dose ratio, the ratio of the EC₅₀ of an agonist alone compared to the EC₅₀ in the presence of a competitive antagonist as determined on a dose response curve. Altering the amount of antagonist used in the assay can alter the dose ratio. In Schild regression, a plot is made of the log (dose ratio-1) versus the log concentration of antagonist for a range of antagonist concentrations. The affinity or K_i is where the line cuts the x-axis on the regression plot. Whereas, with Schild regression, antagonist concentration is varied in experiments used to derive K_i values from the Cheng-Prusoff equation, agonist concentrations are varied. Affinity for competitive agonists and antagonists is related by the Cheng-Prusoff factor used to calculate the K_i (affinity constant for an antagonist) from the shift in IC₅₀ that occurs during competitive inhibition. The Cheng-Prusoff factor takes into account the effect of altering agonist concentration and agonist affinity for the receptor on inhibition produced by competitive antagonists.

Types

Competitive

Competitive antagonists bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists "compete" for the same binding site on the receptor. Once bound, an antagonist will block agonist binding. Sufficient concentrations of an antagonist will displace the agonist from the binding sites, resulting in a lower frequency of receptor activation. The level of activity of the receptor will be determined by the relative affinity of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist will increase the proportion of receptors that the agonist occupies, higher concentrations of the antagonist will be required to obtain the same degree of binding site occupancy. In functional assays using competitive antagonists, a parallel rightward shift of agonist dose–response curves with no alteration of the maximal response is observed.

Competitive antagonists are used to prevent the activity of drugs, and to reverse the effects of drugs that have already been consumed. Naloxone (also known as Narcan) is used to reverse opioid overdose caused by drugs such as heroin or morphine. Similarly, Ro15-4513 is an antidote to alcohol and flumazenil is an antidote to benzodiazepines.

Competitive antagonists are sub-classified as reversible (surmountable) or irreversible (insurmountable) competitive antagonists, depending on how they interact with their receptor protein targets.^[21]. Reversible antagonists, which bind via noncovalent intermolecular forces, will eventually dissociate from the receptor, freeing the receptor to be bound again. Irreversible antagonists bind via covalent intermolecular forces. Because there is not enough free energy to break covalent bonds in the local environment, the bond is essentially "permanent", meaning the receptor-antagonist complex will never dissociate. The receptor will thereby remain permanently antagonized until it is ubiquitinated and thus destroyed.

Non-competitive

A non-competitive antagonist is a type of insurmountable antagonist that may act in one of two ways: by binding to an allosteric site of the receptor, or by irreversibly binding to the active site of the receptor. The former meaning has been standardised by the IUPHAR, and is equivalent to the antagonist being called an allosteric antagonist. While the mechanism of antagonism is different in both of these phenomena, they are both called "non-competitive" because the end-results of each are functionally very similar. Unlike competitive antagonists, which affect the amount of agonist necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist. This property earns them the name "non-competitive" because their effects cannot be negated, no matter how much agonist is present. In functional assays of non-competitive antagonists, depression (physiology) of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced. The rightward shift will occur as a result of a receptor reserve (also known as spare receptors) and inhibition of the agonist response will only occur when this reserve is depleted.

An antagonist that binds to the active site of a receptor is said to be "non-competitive" if the bond between the active site and the antagonist is irreversible or nearly so. This usage of the term "non-competitive" may not be ideal, however, since the term "irreversible competitive antagonism" may also be used to describe the same phenomenon without the potential for confusion with the second meaning of "non-competitive antagonism" discussed below.

The second form of "non-competitive antagonists" act at an allosteric site. These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. They do not compete with agonists for binding at the active site. The bound antagonists may prevent conformational changes in the receptor required for receptor activation after the agonist binds. Cyclothiazide has been shown to act as a reversible non-competitive antagonist of mGluR1 receptor.

Uncompetitive

Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind to a separate allosteric binding site. This type of antagonism produces a kinetic profile in which "the same amount of antagonist blocks higher concentrations of agonist better than lower concentrations of agonist". Memantine, used in the treatment of Alzheimer's disease, is an uncompetitive antagonist of the NMDA receptor.

Silent antagonists

Silent antagonists are competitive receptor antagonists that have zero intrinsic activity for activating a receptor. They are true antagonists, so to speak. The term was created to distinguish fully inactive antagonists from weak partial agonists or inverse agonists.

Partial agonists

Partial agonists are defined as drugs that, at a given receptor, might differ in the amplitude of the functional response that they elicit after maximal receptor occupancy. Although they are agonists, partial agonists can act as a competitive antagonist in the presence of a full agonist, as it competes with the full agonist for receptor occupancy, thereby producing a net decrease in the receptor activation as compared to that observed with the full agonist alone. Clinically, their usefulness is derived from their ability to enhance deficient systems while simultaneously blocking excessive activity. Exposing a receptor to a high level of a partial agonist will ensure that it has a constant, weak level of activity, whether its normal agonist is present at high or low levels. In addition, it has been suggested that partial agonism prevents the adaptive regulatory mechanisms that frequently develop after repeated exposure to potent full agonists or antagonists. E.g. Buprenorphine, a partial agonist of the μ-opioid receptor, binds with weak morphine-like activity and is used clinically as an analgesic in pain management and as an alternative to methadone in the treatment of opioid dependence.

Inverse agonists

An inverse agonist can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses. Constitutively active receptors that exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist but also inhibit the basal activity of the receptor. Many drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors. Antihistamines, originally classified as antagonists of histamine H₁ receptors have been reclassified as inverse agonists.

Reversibility

Many antagonists are reversible antagonists that, like most agonists, will bind and unbind a receptor at rates determined by receptor-ligand kinetics.

Irreversible antagonists covalently bind to the receptor target and, in general, cannot be removed; inactivating the receptor for the duration of the antagonist effects is determined by the rate of receptor turnover, the rate of synthesis of new receptors. Phenoxybenzamine is an example of an irreversible alpha blocker—it permanently binds to α adrenergic receptors, preventing adrenaline and noradrenaline from binding. Inactivation of receptors normally results in a depression of the maximal response of agonist dose-response curves and a right shift in the curve occurs where there is a receptor reserve similar to non-competitive antagonists. A washout step in the assay will usually distinguish between non-competitive and irreversible antagonist drugs, as effects of non-competitive antagonists are reversible and activity of agonist will be restored.

Irreversible competitive antagonists also involve competition between the agonist and antagonist of the receptor, but the rate of covalent bonding differs and depends on affinity and reactivity of the antagonist. For some antagonist, there may be a distinct period during which they behave competitively (regardless of basal efficacy), and freely associate to and dissociate from the receptor, determined by receptor-ligand kinetics. But, once irreversible bonding has taken place, the receptor is deactivated and degraded. As for non-competitive antagonists and irreversible antagonists in functional assays with irreversible competitive antagonist drugs, there may be a shift in the log concentration–effect curve to the right, but, in general, both a decrease in slope and a reduced maximum are obtained.

Adrenergic receptor

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Adrenergic_receptor

β₂ adrenoreceptor (PDB: 2rh1) shown binding carazolol (yellow) on its extracellular site. β₂ stimulates cells to increase energy production and utilization. The membrane the receptor is bound to in cells is shown with a gray stripe.

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, β₂ agonists and α₂ agonists, which are used to treat high blood pressure and asthma, for example.

Many cells have these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system (SNS). The SNS is responsible for the fight-or-flight response, which is triggered by experiences such as exercise or fear-causing situations. This response dilates pupils, increases heart rate, mobilizes energy, and diverts blood flow from non-essential organs to skeletal muscle. These effects together tend to increase physical performance momentarily.

History

Epinephrine

Norepinephrine

By the turn of the 19th century, it was agreed that the stimulation of sympathetic nerves could cause different effects on body tissues, depending on the conditions of stimulation (such as the presence or absence of some toxin). Over the first half of the 20th century, two main proposals were made to explain this phenomenon:

There were (at least) two different types of neurotransmitters released from sympathetic nerve terminals, or
There were (at least) two different types of detector mechanisms for a single neurotransmitter.

The first hypothesis was championed by Walter Bradford Cannon and Arturo Rosenblueth, who interpreted many experiments to then propose that there were two neurotransmitter substances, which they called sympathin E (for 'excitation') and sympathin I (for 'inhibition').

The second hypothesis found support from 1906 to 1913, when Henry Hallett Dale explored the effects of adrenaline (which he called adrenine at the time), injected into animals, on blood pressure. Usually, adrenaline would increase the blood pressure of these animals. Although, if the animal had been exposed to ergotoxine, the blood pressure decreased. He proposed that the ergotoxine caused "selective paralysis of motor myoneural junctions" (i.e. those tending to increase the blood pressure) hence revealing that under normal conditions that there was a "mixed response", including a mechanism that would relax smooth muscle and cause a fall in blood pressure. This "mixed response", with the same compound causing either contraction or relaxation, was conceived of as the response of different types of junctions to the same compound.

This line of experiments were developed by several groups, including DT Marsh and colleagues, who in February 1948 showed that a series of compounds structurally related to adrenaline could also show either contracting or relaxing effects, depending on whether or not other toxins were present. This again supported the argument that the muscles had two different mechanisms by which they could respond to the same compound. In June of that year, Raymond Ahlquist, Professor of Pharmacology at Medical College of Georgia, published a paper concerning adrenergic nervous transmission. In it, he explicitly named the different responses as due to what he called α receptors and β receptors, and that the only sympathetic transmitter was adrenaline. While the latter conclusion was subsequently shown to be incorrect (it is now known to be noradrenaline), his receptor nomenclature and concept of two different types of detector mechanisms for a single neurotransmitter, remains. In 1954, he was able to incorporate his findings in a textbook, Drill's Pharmacology in Medicine, and thereby promulgate the role played by α and β receptor sites in the adrenaline/noradrenaline cellular mechanism. These concepts would revolutionise advances in pharmacotherapeutic research, allowing the selective design of specific molecules to target medical ailments rather than rely upon traditional research into the efficacy of pre-existing herbal medicines.

Pharmacology

Adrenergic ligands are endogenous proteins that modulate and evoke specific cardiovascular effects. Adrenergic antagonists reverse the natural cardiovascular effect, based on the type of adrenoreceptor being blocked. For example, if the natural activation of the α₁-adrenergic receptor leads to vasoconstriction, an α₁-adrenergic antagonist will result in vasodilation.

Some adrenergic antagonists, mostly β antagonists, passively diffuse from the gastrointestinal tract. From there, they bind to albumin and α1-acid glycoprotein in the plasma, allowing for a wide spread through the body. From there, the lipophilic antagonists are metabolized in the liver and eliminated with urine while the hydrophilic ones are eliminated unchanged.