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Tuesday, March 31, 2020

George Washington Carver

From Wikipedia, the free encyclopedia

George Washington Carver
George Washington Carver
Photograph circa 1910
Born1860s
DiedJanuary 5, 1943 (about 79 years old)
Resting placeTuskegee University
Alma materIowa State University
AwardsSpingarn Medal (1923)

George Washington Carver (1860s – January 5, 1943) was an American agricultural scientist and inventor. He actively promoted alternative crops to cotton and methods to prevent soil depletion. He was the most prominent black scientist of the early 20th century.

While a professor at Tuskegee Institute, Carver developed techniques to improve soils depleted by repeated plantings of cotton. He wanted poor farmers to grow alternative crops such as peanuts and sweet potatoes as a source of their own food and to improve their quality of life. The most popular of his 44 practical bulletins for farmers contained 105 food recipes using peanuts. Although he spent years developing and promoting numerous products made from peanuts, none became commercially successful.

Apart from his work to improve the lives of farmers, Carver was also a leader in promoting environmentalism. He received numerous honors for his work, including the Spingarn Medal of the NAACP. In an era of high racial polarization, his fame reached beyond the black community. He was widely recognized and praised in the white community for his many achievements and talents. In 1941, Time magazine dubbed Carver a "Black Leonardo".

Early years

The farm house of Moses Carver (built in 1881), near the place where George Carver lived as a youth

Carver was born into slavery in Diamond Grove, Newton County, near Crystal Place, now known as Diamond, Missouri, some time in the early-mid 1860s. The exact date of his birth is uncertain and was not known to Carver. However, it was before slavery was abolished in Missouri in January 1865 after the American Civil War. His master, Moses Carver, was a German American immigrant who had purchased George's parents, Mary and Giles, from William P. McGinnis on October 9, 1855, for $700.

When George was only a week old, he, a sister, and his mother were kidnapped by night raiders from Arkansas. George's brother, James, was rushed to safety from the kidnappers. The kidnappers sold the slaves in Kentucky. Moses Carver hired John Bentley to find them, but he located only the infant George. Moses negotiated with the raiders to gain the boy's return, and rewarded Bentley. After slavery was abolished, Moses Carver and his wife Susan raised George and his older brother James as their own children. They encouraged George to continue his intellectual pursuits, and "Aunt Susan" taught him the basics of reading and writing.

Black people were not allowed at the public school in Diamond Grove. George decided to go to a school for black children 10 miles (16 km) south in Neosho. When he reached the town, he found the school closed for the night. He slept in a nearby barn. By his own account, the next morning he met a kind woman, Mariah Watkins, from whom he wished to rent a room. When he identified himself as "Carver's George," as he had done his whole life, she replied that from now on his name was "George Carver". George liked Mariah Watkins, and her words, "You must learn all you can, then go back out into the world and give your learning back to the people", made a great impression on him.

At the age of 13, due to his desire to attend the academy there, he relocated to the home of another foster family in Fort Scott, Kansas. After witnessing a black man killed by a group of whites, Carver left the city. He attended a series of schools before earning his diploma at Minneapolis High School in Minneapolis, Kansas.

College education

At work in his laboratory

Carver applied to several colleges before being accepted at Highland University in Highland, Kansas. When he arrived, however, they refused to let him attend because of his race. In August 1886, Carver traveled by wagon with J. F. Beeler from Highland to Eden Township in Ness County, Kansas. He homesteaded a claim near Beeler, where he maintained a small conservatory of plants and flowers and a geological collection. He manually plowed 17 acres (69,000 m2) of the claim, planting rice, corn, Indian corn and garden produce, as well as various fruit trees, forest trees, and shrubbery. He also earned money by odd jobs in town and worked as a ranch hand.

In early 1888, Carver obtained a $300 loan at the Bank of Ness City for education. By June he left the area. In 1890, Carver started studying art and piano at Simpson College in Indianola, Iowa. His art teacher, Etta Budd, recognized Carver's talent for painting flowers and plants; she encouraged him to study botany at Iowa State Agricultural College (now Iowa State University) in Ames.

When he began there in 1891, he was the first black student at Iowa State. Carver's Bachelor's thesis for a degree in Agriculture was "Plants as Modified by Man", dated 1894. Iowa State University professors Joseph Budd and Louis Pammel convinced Carver to continue there for his master's degree. Carver did research at the Iowa Experiment Station under Pammel during the next two years. His work at the experiment station in plant pathology and mycology first gained him national recognition and respect as a botanist. Carver received his master of science degree in 1896. Carver taught as the first black faculty member at Iowa State. 

Despite occasionally being addressed as "doctor," Carver never received an official doctorate, and in a personal communication with Louis H. Pammel, he noted that it was a "misnomer", given to him by others due to his abilities and their assumptions about his education. With that said, both Simpson College and Selma University awarded him honorary doctorates of science in his lifetime. Iowa State later awarded him a doctorate of humane letters posthumously in 1994.

Tuskegee Institute

George Washington Carver (front row, center) poses with fellow faculty of Tuskegee Institute in this c. 1902 photograph taken by Frances Benjamin Johnston.

In 1896, Booker T. Washington, the first principal and president of the Tuskegee Institute (now Tuskegee University), invited Carver to head its Agriculture Department. Carver taught there for 47 years, developing the department into a strong research center and working with two additional college presidents during his tenure. He taught methods of crop rotation, introduced several alternative cash crops for farmers that would also improve the soil of areas heavily cultivated in cotton, initiated research into crop products (chemurgy), and taught generations of black students farming techniques for self-sufficiency.

Carver designed a mobile classroom to take education out to farmers. He called it a "Jesup wagon" after the New York financier and philanthropist Morris Ketchum Jesup, who provided funding to support the program.

To recruit Carver to Tuskegee, Washington gave him an above average salary and two rooms for his personal use, although both concessions were resented by some other faculty. Because he had earned a master's in a scientific field from a "white" institution, some faculty perceived him as arrogant.[22] Unmarried faculty members normally had to share rooms, with two to a room, in the spartan early days of the institute.

One of Carver's duties was to administer the Agricultural Experiment Station farms. He had to manage the production and sale of farm products to generate revenue for the Institute. He soon proved to be a poor administrator. In 1900, Carver complained that the physical work and the letter-writing required were too much. In 1904, an Institute committee reported that Carver's reports on yields from the poultry yard were exaggerated, and Washington confronted Carver about the issue. Carver replied in writing, "Now to be branded as a liar and party to such hellish deception it is more than I can bear, and if your committee feel that I have willfully lied or [was] party to such lies as were told my resignation is at your disposal." During Washington's last five years at Tuskegee, Carver submitted or threatened his resignation several times: when the administration reorganized the agriculture programs, when he disliked a teaching assignment, to manage an experiment station elsewhere, and when he did not get summer teaching assignments in 1913–14. In each case, Washington smoothed things over. 

Photograph of George Washington Carver taken by Frances Benjamin Johnston in 1906.

Carver started his academic career as a researcher and teacher. In 1911, Washington wrote a letter to him complaining that Carver had not followed orders to plant particular crops at the experiment station. This revealed Washington's micro-management of Carver's department, which he had headed for more than 10 years by then. Washington at the same time refused Carver's requests for a new laboratory, research supplies for his exclusive use, and respite from teaching classes. Washington praised Carver's abilities in teaching and original research but said about his administrative skills:
When it comes to the organization of classes, the ability required to secure a properly organized and large school or section of a school, you are wanting in ability. When it comes to the matter of practical farm managing which will secure definite, practical, financial results, you are wanting again in ability.
In 1911, Carver complained that his laboratory had not received the equipment which Washington had promised 11 months before. He also complained about Institute committee meetings.[30] Washington praised Carver in his 1911 memoir, My Larger Education: Being Chapters from My Experience. Washington called Carver "one of the most thoroughly scientific men of the Negro race with whom I am acquainted." After Washington died in 1915, his successor made fewer demands on Carver for administrative tasks.

While a professor at Tuskegee, Carver joined the Gamma Sigma chapter of Phi Beta Sigma fraternity. He spoke at the 1930 Conclave that was held at Tuskegee, Alabama, in which he delivered a powerful and emotional speech to the men in attendance.

From 1915 to 1923, Carver concentrated on researching and experimenting with new uses for peanuts, sweet potatoes, soybeans, pecans, and other crops, as well as having his assistants research and compile existing uses. This work, and especially his speaking to a national conference of the Peanut Growers Association in 1920 and in testimony before Congress in 1921 to support passage of a tariff on imported peanuts, brought him wide publicity and increasing renown. In these years, he became one of the most well-known African Americans of his time.

Rise to fame

"One of America's great scientists." U.S. World War II poster circa 1943

Carver developed techniques to improve soils depleted by repeated plantings of cotton. Together with other agricultural experts, he urged farmers to restore nitrogen to their soils by practicing systematic crop rotation: alternating cotton crops with plantings of sweet potatoes or legumes (such as peanuts, soybeans and cowpeas). These crops both restored nitrogen to the soil and were good for human consumption. Following the crop rotation practice resulted in improved cotton yields and gave farmers alternative cash crops. To train farmers to successfully rotate and cultivate the new crops, Carver developed an agricultural extension program for Alabama that was similar to the one at Iowa State. To encourage better nutrition in the South, he widely distributed recipes using the alternative crops.

Additionally, he founded an industrial research laboratory, where he and assistants worked to popularize the new crops by developing hundreds of applications for them. They did original research as well as promoting applications and recipes, which they collected from others. Carver distributed his information as agricultural bulletins.

Peanut specimen collected by Carver

Carver's work was known by officials in the national capital before he became a public figure. President Theodore Roosevelt publicly admired his work. Former professors of Carver's from Iowa State University were appointed to positions as Secretary of Agriculture: James Wilson, a former dean and professor of Carver's, served from 1897 to 1913. Henry Cantwell Wallace served from 1921 to 1924. He knew Carver personally because his son Henry A. Wallace and the researcher were friends. The younger Wallace served as U.S. Secretary of Agriculture from 1933 to 1940, and as Franklin Delano Roosevelt's vice president from 1941 to 1945.

The American industrialist, farmer, and inventor William Edenborn of Winn Parish, Louisiana, grew peanuts on his demonstration farm. He consulted with Carver.

In 1916, Carver was made a member of the Royal Society of Arts in England, one of only a handful of Americans at that time to receive this honor. Carver's promotion of peanuts gained him the most notice. In 1919, Carver wrote to a peanut company about the potential he saw for peanut milk. Both he and the peanut industry seemed unaware that in 1917 William Melhuish had secured US 1243855, issued 1917-10-23 for a milk substitute made from peanuts and soybeans.

The United Peanut Associations of America invited Carver to speak at their 1920 convention. He discussed "The Possibilities of the Peanut" and exhibited 145 peanut products. By 1920, the U.S. peanut farmers were being undercut by low prices on imported peanuts from the Republic of China

In 1921, peanut farmers and industry representatives planned to appear at Congressional hearings to ask for a tariff. Based on the quality of Carver's presentation at their convention, they asked the African-American professor to testify on the tariff issue before the Ways and Means Committee of the United States House of Representatives. Due to segregation, it was highly unusual for an African American to appear as an expert witness at Congress representing European-American industry and farmers. Southern congressmen, reportedly shocked at Carver's arriving to testify, were said to have mocked him. As he talked about the importance of the peanut and its uses for American agriculture, the committee members repeatedly extended the time for his testimony. The Fordney–McCumber Tariff of 1922 was passed including one on imported peanuts. Carver's testifying to Congress made him widely known as a public figure.

Life while famous

United States Farm Security Administration portrait, March 1942

During the last two decades of his life, Carver seemed to enjoy his celebrity status. He was often on the road promoting Tuskegee University, peanuts, and racial harmony. Although he only published six agricultural bulletins after 1922, he published articles in peanut industry journals and wrote a syndicated newspaper column, "Professor Carver's Advice". Business leaders came to seek his help, and he often responded with free advice. Three American presidents—Theodore Roosevelt, Calvin Coolidge and Franklin Roosevelt—met with him, and the Crown Prince of Sweden studied with him for three weeks. From 1923 to 1933, Carver toured white Southern colleges for the Commission on Interracial Cooperation.

With his increasing notability, Carver became the subject of biographies and articles. Raleigh H. Merritt contacted him for his biography published in 1929. Merritt wrote:
At present not a great deal has been done to utilize Dr. Carver's discoveries commercially. He says that he is merely scratching the surface of scientific investigations of the possibilities of the peanut and other Southern products.
In 1932, the writer James Saxon Childers wrote that Carver and his peanut products were almost solely responsible for the rise in U.S. peanut production after the boll weevil devastated the American cotton crop beginning about 1892. His article, "A Boy Who Was Traded for a Horse" (1932), in The American Magazine, and its 1937 reprint in Reader's Digest, contributed to this myth about Carver's influence. Other popular media tended to exaggerate Carver's impact on the peanut industry.

From 1933 to 1935, Carver worked to develop peanut oil massages to treat infantile paralysis (polio). Ultimately, researchers found that the massages, not the peanut oil, provided the benefits of maintaining some mobility to paralyzed limbs.

From 1935 to 1937, Carver participated in the USDA Disease Survey. Carver had specialized in plant diseases and mycology for his master's degree.

In 1937, Carver attended two chemurgy conferences, an emerging field in the 1930s, during the Great Depression and the Dust Bowl, concerned with developing new products from crops. He was invited by Henry Ford to speak at the conference held in Dearborn, Michigan, and they developed a friendship. That year Carver's health declined, and Ford later installed an elevator at the Tuskegee dormitory where Carver lived, so that the elderly man would not have to climb stairs.

Carver had been frugal in his life, and in his seventies he established a legacy by creating a museum of his work, as well as the George Washington Carver Foundation at Tuskegee in 1938 to continue agricultural research. He donated nearly US$60,000 (equivalent to $1,089,787 in 2019) in his savings to create the foundation.

Relationships

"Austin Curtis - Scientist successor to Dr. Carver", cartoon by C.H. Alston

Carver never married. At age 40, he began a courtship with Sarah L. Hunt, an elementary school teacher and the sister-in-law of Warren Logan, Treasurer of Tuskegee Institute. This lasted three years until she took a teaching job in California. In her 2015 biography, Christina Vella reviews his relationships and suggests that Carver was bisexual and constrained by mores of his historic period.

When he was 70, Carver established a friendship and research partnership with the scientist Austin W. Curtis, Jr. This young black man, a graduate of Cornell University, had some teaching experience before coming to Tuskegee. Carver bequeathed to Curtis his royalties from an authorized 1943 biography by Rackham Holt. After Carver died in 1943, Curtis was fired from Tuskegee Institute. He left Alabama and resettled in Detroit. There he manufactured and sold peanut-based personal care products.

Death


Upon returning home one day, Carver took a bad fall down a flight of stairs; he was found unconscious by a maid who took him to a hospital. Carver died January 5, 1943, at the age of 78 from complications (anemia) resulting from this fall. He was buried next to Booker T. Washington at Tuskegee University. Due to his frugality, Carver's life savings totaled $60,000, all of which he donated in his last years and at his death to the Carver Museum and to the George Washington Carver Foundation.

On his grave was written, He could have added fortune to fame, but caring for neither, he found happiness and honor in being helpful to the world.

Personal life

Voice pitch

Even as an adult Carver spoke with a high pitch. Historian Linda O. McMurry noted that he "was a frail and sickly child" who suffered "from a severe case of whooping cough and frequent bouts of what was called croup." McMurry contested the diagnosis of croup, holding rather that "His stunted growth and apparently impaired vocal cords suggest instead tubercular or pneumococcal infection. Frequent infections of that nature could have caused the growth of polyps on the larynx and may have resulted from a gamma globulin deficiency. ... until his death the high pitch of his voice startled all who met him, and he suffered from frequent chest congestion and loss of voice."

There are some rumors that Carver was castrated. Harley Flack and Edmund Pellegrino's book African-American Perspectives on Biomedical Ethics (1992) reports that Carver was castrated by a physician at age 11 at the request of his white master. A friend of Carver's was told by the autopsy doctors — according to Carver's biographer Peter Burchard, who told this to Iowa Public Radio in 2010 — that Carver had only scar tissue instead of testicles. If it is true that he was castrated before puberty, it would explain his high voice, but it would also suggest that he should not have been able to grow his beard.

Christianity

Carver believed he could have faith both in God and science and integrated them into his life. He testified on many occasions that his faith in Jesus was the only mechanism by which he could effectively pursue and perform the art of science. Carver became a Christian when he was still a young boy, as he wrote in connection to his conversion in 1931:
I was just a mere boy when converted, hardly ten years old. There isn't much of a story to it. God just came into my heart one afternoon while I was alone in the 'loft' of our big barn while I was shelling corn to carry to the mill to be ground into meal.
A dear little white boy, one of our neighbors, about my age came by one Saturday morning, and in talking and playing he told me he was going to Sunday school tomorrow morning. I was eager to know what a Sunday school was. He said they sang hymns and prayed. I asked him what prayer was and what they said. I do not remember what he said; only remember that as soon as he left I climbed up into the 'loft,' knelt down by the barrel of corn and prayed as best I could. I do not remember what I said. I only recall that I felt so good that I prayed several times before I quit.
My brother and myself were the only colored children in that neighborhood and of course, we could not go to church or Sunday school, or school of any kind.
That was my simple conversion, and I have tried to keep the faith.
— G. W. Carver; Letter to Isabelle Coleman; July 24, 1931
He was not expected to live past his 21st birthday due to failing health. He lived well past the age of 21, and his belief deepened as a result. Throughout his career, he always found friendship with other Christians. He relied on them especially when criticized by the scientific community and media regarding his research methodology.

Carver viewed faith in Jesus Christ as a means of destroying both barriers of racial disharmony and social stratification. He was as concerned with his students' character development as he was with their intellectual development. He compiled a list of eight cardinal virtues for his students to strive toward: 

A monument to Carver at the Missouri Botanical Garden in St. Louis
  • Be clean both inside and out.
  • Neither look up to the rich nor down on the poor.
  • Lose, if need be, without squealing.
  • Win without bragging.
  • Always be considerate of women, children, and older people.
  • Be too brave to lie.
  • Be too generous to cheat.
  • Take your share of the world and let others take theirs.
Beginning in 1906 at Tuskegee, Carver led a Bible class on Sundays for several students at their request. He regularly portrayed stories by acting them out. He responded to critics with this: "When you do the common things in life in an uncommon way, you will command the attention of the world."

Honors

Legacy

A movement to establish a U.S. national monument to Carver began before his death. Because of World War II, such non-war expenditures had been banned by presidential order. Missouri senator Harry S. Truman sponsored a bill in favor of a monument. In a committee hearing on the bill, one supporter said:
The bill is not simply a momentary pause on the part of busy men engaged in the conduct of the war, to do honor to one of the truly great Americans of this country, but it is in essence a blow against the Axis, it is in essence a war measure in the sense that it will further unleash and release the energies of roughly 15,000,000 Negro people in this country for full support of our war effort.
The bill passed unanimously in both houses. 

On July 14, 1943, President Franklin D. Roosevelt dedicated $30,000 for the George Washington Carver National Monument west-southwest of Diamond, Missouri, the area where Carver had spent time in his childhood. This was the first national monument dedicated to an African American and the first to honor someone other than a president. The 210-acre (0.8 km2) national monument complex includes a bust of Carver, a ¾-mile nature trail, a museum, the 1881 Moses Carver house, and the Carver cemetery. The national monument opened in July 1953.

In December 1947, a fire broke out in the Carver Museum, and much of the collection was damaged. Time magazine reported that all but three of the 48 Carver paintings at the museum were destroyed. His best-known painting, displayed at the World's Columbian Exposition of 1893 in Chicago, depicts a yucca and cactus. This canvas survived and has undergone conservation. It is displayed together with several of his other paintings.

1948 US postage stamp

Carver was featured on U.S. 1948 commemorative stamps. From 1951 to 1954, he was depicted on the commemorative Carver-Washington half dollar coin along with Booker T. Washington. A second stamp honoring Carver, of face value 32¢, was issued on 3 February 1998 as part of the Celebrate the Century stamp sheet series. Two ships, the Liberty ship SS George Washington Carver and the nuclear submarine USS George Washington Carver (SSBN-656), were named in his honor.

In 1977, Carver was elected to the Hall of Fame for Great Americans. In 1990, he was inducted into the National Inventors Hall of Fame. In 1994, Iowa State University awarded Carver a Doctor of Humane Letters. In 2000, Carver was a charter inductee in the USDA Hall of Heroes as the "Father of Chemurgy".

In 2002, scholar Molefi Kete Asante listed George Washington Carver as one of 100 Greatest African Americans.

In 2005, Carver's research at the Tuskegee Institute was designated a National Historic Chemical Landmark by the American Chemical Society. On February 15, 2005, an episode of Modern Marvels included scenes from within Iowa State University's Food Sciences Building and about Carver's work. In 2005, the Missouri Botanical Garden in St. Louis, Missouri, opened a George Washington Carver garden in his honor, which includes a life-size statue of him.

Many institutions continue to honor George Washington Carver. Dozens of elementary schools and high schools are named after him. National Basketball Association star David Robinson and his wife, Valerie, founded an academy named after Carver; it opened on September 17, 2001, in San Antonio, Texas. The Carver Community Cultural Center, a historic center located in San Antonio, is named for him.

Reputed inventions

Carver was given credit in popular folklore for many inventions that did not come out of his lab. Three patents (one for cosmetics; US 1522176, issued January 6, 1925, and two for paints and stains; US 1541478, issued June 9, 1925 and US 1632365, issued June 14, 1927) were issued to Carver in 1925 to 1927; however, they were not commercially successful. Aside from these patents and some recipes for food, Carver left no records of formulae or procedures for making his products. He did not keep a laboratory notebook. Mackintosh notes that, "Carver did not explicitly claim that he had personally discovered all the peanut attributes and uses he cited, but he said nothing to prevent his audiences from drawing the inference." Carver's research was intended to produce replacements from common crops for commercial products, which were generally beyond the budget of the small one-horse farmer. A misconception grew that his research on products for subsistence farmers were developed by others commercially to change Southern agriculture. Carver's work to provide small farmers with resources for more independence from the cash economy foreshadowed the "appropriate technology" work of E. F. Schumacher.

Peanut products

Dennis Keeney, director of the Leopold Center for Sustainable Agriculture at Iowa State University, wrote in the Leopold Letter (newsletter):
Carver worked on improving soils, growing crops with low inputs, and using species that fixed nitrogen (hence, the work on the cowpea and the peanut). Carver wrote in 'The Need of Scientific Agriculture in the South': "The virgin fertility of our soils and the vast amount of unskilled labor have been more of a curse than a blessing to agriculture. This exhaustive system for cultivation, the destruction of forest, the rapid and almost constant decomposition of organic matter, have made our agricultural problem one requiring more brains than of the North, East or West."
Carver worked for years to create a company to market his products. The most important was the Carver Penol Company, which sold a mixture of creosote and peanuts as a patent medicine for respiratory diseases such as tuberculosis. Sales were lackluster and the product was ineffective according to the Food and Drug Administration. Other ventures were The Carver Products Company and the Carvoline Company. Carvoline Antiseptic Hair Dressing was a mix of peanut oil and lanolin. Carvoline Rubbing Oil was a peanut oil for massages. 

Carver is often mistakenly credited with the invention of peanut butter. By the time Carver published "How to Grow the Peanut and 105 Ways of Preparing it For Human Consumption" in 1916, many methods of preparation of peanut butter had been developed or patented by various pharmacists, doctors and food scientists working in the US and Canada. The Aztec were known to have made peanut butter from ground peanuts as early as the 15th century. Canadian pharmacist Marcellus Gilmore Edson was awarded U.S. Patent 306,727 (for its manufacture) in 1884, 12 years before Carver began his work at Tuskegee.

Sweet potato products

Carver is also associated with developing sweet potato products. In his 1922 sweet potato bulletin, Carver listed a few dozen recipes, "many of which I have copied verbatim from Bulletin No. 129, U. S. Department of Agriculture". Carver's records included the following sweet potato products: 73 dyes, 17 wood fillers, 14 candies, 5 library pastes, 5 breakfast foods, 4 starches, 4 flours, and 3 molasses. He also had listings for vinegars, dry coffee and instant coffee, candy, after-dinner mints, orange drops, and lemon drops.

Carver bulletins

During his more than four decades at Tuskegee, Carver's official published work consisted mainly of 44 practical bulletins for farmers. His first bulletin in 1898 was on feeding acorns to farm animals. His final bulletin in 1943 was about the peanut. He also published six bulletins on sweet potatoes, five on cotton, and four on cowpeas. Some other individual bulletins dealt with alfalfa, wild plum, tomato, ornamental plants, corn, poultry, dairying, hogs, preserving meats in hot weather, and nature study in schools.

His most popular bulletin, How to Grow the Peanut and 105 Ways of Preparing it for Human Consumption, was first published in 1916 and was reprinted many times. It gave a short overview of peanut crop production and contained a list of recipes from other agricultural bulletins, cookbooks, magazines, and newspapers, such as the Peerless Cookbook, Good Housekeeping, and Berry's Fruit Recipes. Carver's was far from the first American agricultural bulletin devoted to peanuts, but his bulletins did seem to be more popular and widespread than previous ones.

ACE inhibitor

From Wikipedia, the free encyclopedia

Angiotensin-converting-enzyme inhibitor
Captopril skeletal.svg
Captopril, the first synthetic ACE inhibitor
Class identifiers
UseHypertension
ATC codeC09A
Biological targetAngiotensin-converting enzyme
Clinical data
Drugs.comDrug Classes
Consumer ReportsBest Buy Drugs
WebMDMedicineNet  RxList
External links
MeSHD000806
In Wikidata

Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an important component of the renin–angiotensin system liable to convert angiotensin I to angiotensin II, and hydrolyse bradykinin Thereby, ACE inhibitors in turn decrease the formation of angiotensin II, a vasopressin, but increase the level of bradykinin, a peptide vasodilator. This combination, thereby, is synergistic in increasing ACE inhibitors' blood pressure-lowering effect.

Frequently prescribed ACE inhibitors include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.

Medical use

ACE inhibitors were initially approved for the treatment of hypertension and can be used alone or in combination with other anti-hypertensive medications. Later, they were found useful for other cardiovascular and kidney diseases including:
In treating high blood pressure, ACE inhibitors are often the first drug choice, particularly when diabetes is present, but age can lead to different choices and it is common to need more than one drug to obtain the desired improvement. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. ACE inhibitors have also been used in chronic kidney failure and kidney involvement in systemic sclerosis (hardening of tissues, as scleroderma renal crisis). In those with stable coronary artery disease, but no heart failure, benefits are similar to other usual treatments.

In 2012, there was a meta-analysis published in the BMJ that described the protective role of ACE inhibitors in reducing the risk of pneumonia when compared to ARBs (Angiotensin II Receptor Blockers). The authors found a decreased risk in patients with previous stroke (54% risk reduction), with heart failure (37% risk reduction), and of Asian descent (43% risk reduction vs 54% risk reduction in non-Asian population). However, no reduced pneumonia related mortality was observed.

Other

ACE inhibitors may also be used to help decrease excessive water consumption in people with schizophrenia resulting in psychogenic polydipsia. A double-blind, placebo-controlled trial showed that when used for this purpose, enalapril led to decreased consumption (determined by urine output and osmality) in 60% of people; the same effect has been demonstrated in other ACE inhibitors.

Adverse effects

Common side effects include: low blood pressure, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and kidney impairment.

The main adverse effects of ACE inhibition can be understood from their pharmacological action. The other reported adverse effects are liver problems and effect on the fetus. Kidney problems may occur with all ACE inhibitors that directly follows from their mechanism of action. Patients starting on an ACE inhibitor usually have a modest reduction in glomerular filtration rate (GFR). However, the decrease may be significant in conditions of pre-existing decreased renal perfusion, such as renal artery stenosis, heart failure, polycystic kidney disease, or volume depletion. In these patients, the maintenance of GFR depends on angiotensin-II-dependent efferent vasomotor tone. Therefore, renal function should be closely monitored over the first few days after initiation of treatment with ACE inhibitor in patients with decreased renal perfusion. A moderate reduction in renal function, no greater than 30% rise in serum creatinine, that is stabilized after a week of treatment is deemed acceptable as part of the therapeutic effect, providing the residual renal function is sufficient. 

Reduced GFR is especially a problem if the patient is concomitantly taking an NSAID and a diuretic. When the three drugs are taken together, the risk of developing renal failure is significantly increased.

High blood potassium is another possible complication of treatment with an ACE inhibitor due to its effect on aldosterone. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium. Some people, however, can continue to lose potassium while on an ACE inhibitor. Hyperkalemia may decrease the velocity of impulse conduction in the nerves and muscles, including cardiac tissues. This leads to cardiac dysfunction and neuromuscular consequences, such as muscle weakness, paresthesia, nausea, diarrhea, and others. Close monitoring of potassium levels is required in patients receiving treatment with ACE inhibitors who are at risk of hyperkalemia.

Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in bradykinin level.

A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms has been disputed. Many cases of cough in people on ACE inhibitors may not be from the medication itself, however. People who experience this cough are often switched to angiotensin II receptor antagonists

Some (0.7%) develop angioedema due to increased bradykinin levels. A genetic predisposition may exist.

A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.

Blood

Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.

Pregnancy

In pregnant women, ACE inhibitors taken during all the trimesters have been reported to cause congenital malformations, stillbirths, and neonatal deaths. Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria, oligohydramnios, intrauterine growth retardation, pulmonary hypoplasia, patent ductus arteriosus, and incomplete ossification of the skull. Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading to birth defects.

ACE inhibitors are ADEC pregnancy category D, and should be avoided in women who are likely to become pregnant. In the U.S., ACE inhibitors must be labeled with a boxed warning concerning the risk of birth defects when taken during the second and third trimester. Their use in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems.

Overdose

Symptoms and Treatment: There are few reports of ACE inhibitor overdose in the literature. The most likely manifestations are hypotension, which may be severe, hyperkalemia, hyponatremia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive, with volume expansion using normal saline to correct hypotension and improve renal function, and gastric lavage followed by activated charcoal and a cathartic to prevent further absorption of the drug. Captopril, enalapril, lisinopril and perindopril are known to be removable by hemodialysis.

Contraindications and precautions

The ACE inhibitors are contraindicated in people with:
  • Pregnancy or breastfeeding
  • Previous angioedema associated with ACE inhibitor therapy
  • Bilateral renal artery stenosis
  • Hypersensitivity to ACE inhibitors
ACE inhibitors should be used with caution in people with:
A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects. The commonly reported adverse effects of drug combination with ACE are acute renal failure, hypotension, and hyperkalemia. The drugs interacting with ACE inhibitor should be prescribed with caution. Special attention should be given to combinations of ACE inhibitor with other RAAS blockers, diuretics (especially potassium-sparing diuretics), NSAIDs, anticoagulants, cyclosporine, DPP-4 inhibitors, and potassium supplements.

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.

Concomitant use with cyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.

Mechanism of action

ACE inhibitors reduce the activity of the renin–angiotensin–aldosterone system (RAAS) as the primary etiologic (causal) event in the development of hypertension in people with diabetes mellitus, as part of the insulin-resistance syndrome or as a manifestation of renal disease.

Renin–angiotensin–aldosterone system


Renin–angiotensin–aldosterone system is a major blood pressure regulating mechanism. Markers of electrolyte and water imbalance in the body such as hypotension, low distal tubule sodium concentration, decreased blood volume and high sympathetic tone trigger the release of the enzyme renin from the cells of juxtaglomerular apparatus in the kidney. Renin activates a circulating liver derived prohormone angiotensinogen by proteolytic cleavage of all but its first ten amino acid residues known as angiotensin I. ACE (Angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into angiotensin II. ACE is found in the pulmonary circulation and in the endothelium of many blood vessels. The system increases blood pressure by increasing the amount of salt and water the body retains, although angiotensin is also very good at causing the blood vessels to tighten (a potent vasoconstrictor).

Effects

ACE inhibitors block the conversion of Angiotensin I (ATI) to Angiotensin II (ATII).[37] They thereby lower arteriolar resistance and increase venous capacity; decrease cardiac output, cardiac index, stroke work, and volume; lower resistance in blood vessels in the kidneys; and lead to increased natriuresis (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of ATI to ATII. ATI increases for the same reason; ATII and aldosterone decrease. Bradykinin increases because of less inactivation by ACE.
Under normal conditions, angiotensin II has these effects:
  • Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by ATII may lead to increased blood pressure and hypertension. Further, constriction of the efferent arterioles of the kidney leads to increased perfusion pressure in the glomeruli.
  • It contributes to ventricular remodeling and ventricular hypertrophy of the heart through stimulation of the proto-oncogenes c-fos, c-jun, c-myc, transforming growth factor beta (TGF-B), through fibrogenesis and apoptosis (programmed cell death).
  • Stimulation by ATII of the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules, causes sodium and chloride ions retention and potassium excretion. Sodium is a "water-holding" ion, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.
  • Stimulation of the posterior pituitary to release vasopressin (antidiuretic hormone, ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in heart failure, Na+ level in the plasma may fall (hyponatremia), and this is a sign of increased risk of death in heart failure patients.
  • A decrease renal protein kinase C
During the course of ACE inhibitor use, the production of ATII is decreased, which prevents aldosterone release from the adrenal cortex. This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure. 

Epidemiological and clinical studies have shown ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect. This action of ACE inhibitors is used in the prevention of diabetic renal failure.

ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, and prophylaxis of cardiovascular events) is justified, because it improves clinical outcomes independently of the blood pressure-lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the effects of rapidly decreasing blood pressure (dizziness, fainting, etc.).

ACE inhibitors have also been shown to cause a central enhancement of parasympathetic nervous system activity in healthy volunteers and patients with heart failure. This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials. ACE Inhibitors also reduce plasma norepinephrine levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles of sympathetic and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure.

The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure. ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.

Examples

ACE inhibitors are easily identifiable by their common suffix, '-pril'. ACE inhibitors can be divided into three groups based on their molecular structure of the enzyme binding sites (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE:

Sulfhydryl-containing agents

These agents appear to show antioxidative properties but may be involved in adverse events such as skin eruptions.

Dicarboxylate-containing agents

This is the largest group, including:

Phosphonate-containing agents

  • Fosinopril (Fositen/Monopril) is the only member of this group

Naturally occurring

  • A comprehensive resource on anti-hypertensive peptides is available in form of a database. It contains around 1700 unique antihypertensive peptides.
  • Arfalasin (HOE 409) is angiotensin antagonist. 

Dairy products

  • Casokinins and lactokinins, breakdown products of casein and whey, occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain.
  • The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein have been shown to have ACE-inhibiting and antihypertensive functions. In one study, L. helveticus PR4 was isolated from Italian cheeses.

Comparative information

All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie with captopril, the first ACE inhibitor. Captopril has a shorter duration of action and an increased incidence of adverse effects. It is also the only ACE inhibitor capable of passing through the blood–brain barrier, although the significance of this characteristic has not been shown to have any positive clinical effects.

In a large clinical study, one of the agents in the ACE inhibitor class, ramipril (Altace), demonstrated an ability to reduce the mortality rates of patients suffering from a myocardial infarction, and to slow the subsequent development of heart failure. This finding was made after it was discovered that regular use of ramipril reduced mortality rates even in test subjects not having suffered from hypertension.

Some believe ramipril's additional benefits may be shared by some or all drugs in the ACE-inhibitor class. However, ramipril currently remains the only ACE inhibitor for which such effects are actually evidence-based.

A meta-analysis confirmed that ACE inhibitors are effective and certainly the first-line choice in hypertension treatment. This meta-analysis was based on 20 trials and a cohort of 158,998 patients, of whom 91% were hypertensive. ACE inhibitors were used as the active treatment in seven trials (n=76,615) and angiotensin receptor blocker (ARB) in 13 trials (n=82,383). ACE inhibitors were associated with a statistically significant 10% mortality reduction: (HR 0.90; 95% CI, 0.84–0.97; P=0.004). In contrast, no significant mortality reduction was observed with ARB treatment (HR 0.99; 95% CI, 0.94–1.04; P=0.683). Analysis of mortality reduction by different ACE inhibitors showed that perindopril-based regimens are associated with a statistically significant 13% all-cause mortality reduction. Taking into account the broad spectrum of the hypertensive population, one might expect that an effective treatment with ACE inhibitors, in particular with perindopril, would result in an important gain of lives saved.

Equivalent doses in hypertension

The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.

ACE inhibitors dosages for hypertension
Dosage
Dosage
Note: bid = two times a day, tid = three times a day, d = daily
Drug dosages from Drug Lookup, Epocrates Online.
Name Equivalent daily dose
Start Usual Maximum
Benazepril 10 mg
10 mg 20–40 mg 80 mg
Captopril 50 mg (25 mg bid)
12.5–25 mg bid-tid 25–50 mg bid-tid 450 mg/d
Enalapril 5 mg
5 mg 10–40 mg 40 mg
Fosinopril 10 mg
10 mg 20–40 mg 80 mg
Lisinopril 10 mg
10 mg 10–40 mg 80 mg
Moexipril 7.5 mg
7.5 mg 7.5–30 mg 30 mg
Perindopril 4 mg
4 mg 4–8 mg 16 mg
Quinapril 10 mg
10 mg 20–80 mg 80 mg
Ramipril 2.5 mg
2.5 mg 2.5–20 mg 20 mg
Trandolapril 2 mg
1 mg 2–4 mg 8 mg

Angiotensin II receptor antagonists

ACE inhibitors possess many common characteristics with another class of cardiovascular drugs, angiotensin II receptor antagonists, which are often used when patients are intolerant of the adverse effects produced by ACE inhibitors. ACE inhibitors do not completely prevent the formation of angiotensin II, as blockage is dose-dependent, so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT1 receptor, leaving AT2 receptor unblocked; the latter may have consequences needing further study.

Use in combination

The combination therapy of angiotensin II receptor antagonists with ACE inhibitors may be superior to either agent alone. This combination may increase levels of bradykinin while blocking the generation of angiotensin II and its activity at the AT1 receptor. This 'dual blockade' may be more effective than using an ACE inhibitor alone, because angiotensin II can be generated via non-ACE-dependent pathways. Preliminary studies suggest this combination of pharmacologic agents may be advantageous in the treatment of essential hypertension, chronic heart failure, and nephropathy. However, the more recent ONTARGET study showed no benefit of combining the agents and more adverse events. While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking. There are warnings about the combination of ACE inhibitors with ARBs.

Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling.

The most compelling evidence for the treatment of nephropathy has been found: This combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients afflicted with diabetic nephropathy, and pediatric IgA nephropathy.

History

The first step in the development of ACE inhibitors was the discovery of ACE in plasma by Leonard T. Skeggs and his colleagues in 1956. Brazilian scientist Sérgio Henrique Ferreira reported a bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca, a South American pit viper, in 1965. Ferreira then went to John Vane's laboratory as a postdoctoral fellow with his already-isolated BPF. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967, Kevin K. F. Ng and John R. Vane showed plasma ACE is too slow to account for the conversion of angiotensin I to angiotensin II in vivo. Subsequent investigation showed rapid conversion occurs during its passage through the pulmonary circulation.

Bradykinin is rapidly inactivated in the circulating blood, and it disappears completely in a single pass through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation because of its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme. In 1970, Ng and Vane, using BPF provided by Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.

BPFs are members of a family of peptides whose potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF teprotide (SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effect in vivo. Teprotide had limited clinical value as a result of its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing. David Cushman, Miguel Ondetti and colleagues used peptide analogues to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor, in 1975.

Captopril was approved by the United States Food and Drug Administration in 1981. The first nonsulfhydryl-containing ACE inhibitor, enalapril, was marketed two years later. At least 12 other ACE inhibitors have since been marketed. 

In 1991, Japanese scientists created the first milk-based ACE inhibitor, in the form of a fermented milk drink, using specific cultures to liberate the tripeptide isoleucine-proline-proline (IPP) from the dairy protein. Valine-proline-proline (VPP) is also liberated in this process—another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as lactotripeptides. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk. Although twice the amount of VPP is needed to achieve the same ACE-inhibiting activity as the originally discovered IPP, VPP also is assumed to add to the total blood pressure lowering effect. Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.

Renin–angiotensin system

From Wikipedia, the free encyclopedia
 
Anatomical diagram of RAS
 
The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates blood pressure and fluid and electrolyte balance, as well as systemic vascular resistance.

When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the precursor prorenin (already present in the blood) into renin and secrete it directly into circulation. Plasma renin then carries out the conversion of angiotensinogen, released by the liver, to angiotensin I. Angiotensin I is subsequently converted to angiotensin II by the angiotensin-converting enzyme (ACE) found on the surface of vascular endothelial cells, predominantly those of the lungs. Angiotensin II is a potent vasoconstrictive peptide that causes blood vessels to narrow, resulting in increased blood pressure. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the renal tubules to increase the reabsorption of sodium and water into the blood, while at the same time causing the excretion of potassium (to maintain electrolyte balance). This increases the volume of extracellular fluid in the body, which also increases blood pressure.

If the RAS is abnormally active, blood pressure will be too high. There are many drugs that interrupt different steps in this system to lower blood pressure. These drugs are one of the primary ways to control high blood pressure, heart failure, kidney failure, and harmful effects of diabetes.[6][7] Renin activates the renin–angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin–converting enzyme primarily within the capillaries of the lungs.

Activation


RAAS schematic

The system can be activated when there is a loss of blood volume or a drop in blood pressure (such as in hemorrhage or dehydration). This loss of pressure is interpreted by baroreceptors in the carotid sinus. It can also be activated by a decrease in the filtrate sodium chloride (NaCl) concentration or a decreased filtrate flow rate that will stimulate the macula densa to signal the juxtaglomerular cells to release renin.
  1. If the perfusion of the juxtaglomerular apparatus in the kidney's macula densa decreases, then the juxtaglomerular cells (granular cells, modified pericytes in the glomerular capillary) release the enzyme renin.
  2. Renin cleaves a decapeptide from angiotensinogen, a globular protein. The decapeptide is known as angiotensin I.
  3. Angiotensin I is then converted to an octapeptide, angiotensin II by angiotensin-converting enzyme (ACE), which is thought to be found mainly in endothelial cells of the capillaries throughout the body, within the lungs and the epithelial cells of the kidneys. One study in 1992 found ACE in all blood vessel endothelial cells.
  4. Angiotensin II is the major bioactive product of the renin–angiotensin system, binding to receptors on intraglomerular mesangial cells, causing these cells to contract along with the blood vessels surrounding them and causing the release of aldosterone from the zona glomerulosa in the adrenal cortex. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine hormone.

Cardiovascular effects

Renal hormone regulation schematic

It is believed that angiotensin I may have some minor activity, but angiotensin II is the major bio-active product. Angiotensin II has a variety of effects on the body:
  • Throughout the body, angiotensin II is a potent vasoconstrictor of arterioles.
  • In the kidneys, angiotensin II constricts glomerular arterioles, having a greater effect on efferent arterioles than afferent. As with most other capillary beds in the body, the constriction of afferent arterioles increases the arteriolar resistance, raising systemic arterial blood pressure and decreasing the blood flow. However, the kidneys must continue to filter enough blood despite this drop in blood flow, necessitating mechanisms to keep glomerular blood pressure up. To do this, angiotensin II constricts efferent arterioles, which forces blood to build up in the glomerulus, increasing glomerular pressure. The glomerular filtration rate (GFR) is thus maintained, and blood filtration can continue despite lowered overall kidney blood flow. Because the filtration fraction, which is the ratio of the glomerular filtration rate (GFR) to the renal plasma flow (RPF), has increased, there is less plasma fluid in the downstream peritubular capillaries. This in turn leads to a decreased hydrostatic pressure and increased oncotic pressure (due to unfiltered plasma proteins) in the peritubular capillaries. The effect of decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries will facilitate increased reabsorption of tubular fluid.
  • Angiotensin II decreases medullary blood flow through the vasa recta. This decreases the washout of NaCl and urea in the kidney medullary space. Thus, higher concentrations of NaCl and urea in the medulla facilitate increased absorption of tubular fluid. Furthermore, increased reabsorption of fluid into the medulla will increase passive reabsorption of sodium along the thick ascending limb of the Loop of Henle.
  • Angiotensin II stimulates Na+/H+ exchangers located on the apical membranes (faces the tubular lumen) of cells in the proximal tubule and thick ascending limb of the loop of Henle in addition to Na+ channels in the collecting ducts. This will ultimately lead to increased sodium reabsorption.
  • Angiotensin II stimulates the hypertrophy of renal tubule cells, leading to further sodium reabsorption.
  • In the adrenal cortex, angiotensin II acts to cause the release of aldosterone. Aldosterone acts on the tubules (e.g., the distal convoluted tubules and the cortical collecting ducts) in the kidneys, causing them to reabsorb more sodium and water from the urine. This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium to blood, potassium is secreted into the tubules, becomes part of urine and is excreted.
  • Angiotensin II causes the release of anti-diuretic hormone (ADH), also called vasopressin – ADH is made in the hypothalamus and released from the posterior pituitary gland. As its name suggests, it also exhibits vaso-constrictive properties, but its main course of action is to stimulate reabsorption of water in the kidneys. ADH also acts on the central nervous system to increase an individual's appetite for salt, and to stimulate the sensation of thirst.
These effects directly act together to increase blood pressure and are opposed by atrial natriuretic peptide (ANP).

Local renin–angiotensin systems

Locally expressed renin–angiotensin systems have been found in a number of tissues, including the kidneys, adrenal glands, the heart, vasculature and nervous system, and have a variety of functions, including local cardiovascular regulation, in association or independently of the systemic renin–angiotensin system, as well as non-cardiovascular functions. Outside the kidneys, renin is predominantly picked up from the circulation but may be secreted locally in some tissues; its precursor prorenin is highly expressed in tissues and more than half of circulating prorenin is of extrarenal origin, but its physiological role besides serving as precursor to renin is still unclear. Outside the liver, angiotensinogen is picked up from the circulation or expressed locally in some tissues; with renin they form angiotensin I, and locally expressed angiotensin-converting enzyme, chymase or other enzymes can transform it into angiotensin II. This process can be intracellular or interstitial.

In the adrenal glands, it is likely involved in the paracrine regulation of aldosterone secretion; in the heart and vasculature, it may be involved in remodeling or vascular tone; and in the brain, where it is largely independent of the circulatory RAS, it may be involved in local blood pressure regulation. In addition, both the central and peripheral nervous systems can use angiotensin for sympathetic neurotransmission. Other places of expression include the reproductive system, the skin and digestive organs. Medications aimed at the systemic system may affect the expression of those local systems, beneficially or adversely.

Fetal renin–angiotensin system

In the fetus, the renin–angiotensin system is predominantly a sodium-losing system, as angiotensin II has little or no effect on aldosterone levels. Renin levels are high in the fetus, while angiotensin II levels are significantly lower; this is due to the limited pulmonary blood flow, preventing ACE (found predominantly in the pulmonary circulation) from having its maximum effect.

Clinical significance

Flowchart showing the clinical effects of RAAS activity and the sites of action of ACE inhibitors and angiotensin receptor blockers.
  • ACEIs–inhibitors of angiotensin-converting enzyme are often used to reduce the formation of the more potent angiotensin II. Captopril is an example of an ACE inhibitor. ACE cleaves a number of other peptides, and in this capacity is an important regulator of the kinin–kallikrein system, as such blocking ACE can lead to side effects.
  • Angiotensin II receptor antagonists, also known as angiotensin receptor blockers, can be used to prevent angiotensin II from acting on its receptors.
  • Direct renin inhibitors can also be used for hypertension. The drugs that inhibit renin are aliskiren and the investigational remikiren.
  • Vaccines against angiotensin II, for example CYT006-AngQb, have been investigated.

Inequality (mathematics)

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Inequality...