Bradykinin
Encyclopedia
Bradykinin is a peptide
that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to lower. A class of drugs called ACE inhibitor
s, which are used to lower blood pressure, increase bradykinin (by inhibiting its degradation) further lowering blood pressure. Bradykinin works on blood vessels through the release of prostacyclin
, nitric oxide
, and Endothelium-Derived Hyperpolarizing Factor.
Bradykinin is a physiologically and pharmacologically active peptide
of the kinin
group of protein
s, consisting of nine amino acid
s.
. The amino acid
sequence of bradykinin is: Arg
- Pro
- Pro
- Gly
- Phe
- Ser
- Pro
- Phe
- Arg
. Its empirical formula is therefore C50H73N15O11.
makes bradykinin by proteolytic cleavage
of its kininogen precursor, high-molecular-weight kininogen (HMWK or HK), by the enzyme kallikrein
.
(ACE), aminopeptidase P (APP), and carboxypeptidase
N (CPN), which cleave the 7-8, 1-2, and 8-9 positions, respectively.
-dependent vasodilator
, causes contraction of non-vascular smooth muscle
, increases vascular permeability
and also is involved in the mechanism of pain
. Bradykinin also causes natriuresis
, contributing to a drop in blood pressure.
Bradykinin raises internal calcium
levels in neocortical
astrocyte
s causing them to release glutamate
.
Bradykinin is also thought to be the cause of the dry cough in some patients on angiotensin converting enzyme (ACE) inhibitor drugs. This refractory cough is a common cause for stopping ACE inhibitor
therapy. In which case Angiotensin II Receptor Antagonists are the next line of treatment.
Overactivation of bradykinin is thought to play a role in a rare disease called Hereditary Angioedema
, formerly known as Hereditary Angio-Neurotic Edema.
Initial secretion of Bradykinin post-natally causes constriction and eventual atrophy of the ductus arteriosus
, forming the ligamentum artertiosum between the pulmonary trunk and aortic arch.
The kinin B1 and B2 receptors belong to G protein coupled receptor (GPCR) family.
ian physiologists and pharmacologists working at the Instituto Biológico
, in São Paulo, Brazil
, led by Dr. Maurício Rocha e Silva
. Together with colleagues Wilson Teixeira Beraldo
and Gastão Rosenfeld
, they discovered the powerful hypotensive
effects of bradykinin in animal preparations
. Bradykinin was detected in the blood plasma
of animals after the addition of venom extracted from the Bothrops jararaca
(Brazilian lancehead snake
), brought by Rosenfeld from the Butantan Institute
. The discovery was part of a continuing study on circulatory shock and proteolytic
enzyme
s related to the toxicology
of snake bites, started by Rocha e Silva as early as 1939. Bradykinin was to prove a new autopharmacological principle, i.e., a substance that is released in the body by a metabolic modification from precursors, which are pharmacologically active. According to B.J. Hagwood, Rocha e Silva's biographer, "The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins." Etymology: brady [Gk] slow, kinin [Gk ] kīn(eîn) to move, set in motion, ? from the effect of snake venom on intestinal smooth muscle, which was noted to slowly contract
at the University of São Paulo, Dr. Sérgio Henrique Ferreira
, discovered a bradykinin potentiating factor (BPF) in the bothropic venom which increases powerfully both the duration and magnitude of its effects on vasodilation and the consequent fall in blood pressure
. On the basis of this finding, Squibb
scientists developed the first of a new generation of highly-effective anti-hypertensive drugs, the so-called ACE inhibitor
s, such as captopril
(trademarked Capoten).
Currently, bradykinin inhibitors (antagonists
) are being developed as potential therapies for hereditary angioedema. Icatibant
is one such inhibitor. Additional bradykinin inhibitors exist. It has long been known in animal studies that bromelain
, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues. Other substances that act as bradykinin inhibitors include aloe
and polyphenol
s, substances found in red wine and green tea.
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to lower. A class of drugs called ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s, which are used to lower blood pressure, increase bradykinin (by inhibiting its degradation) further lowering blood pressure. Bradykinin works on blood vessels through the release of prostacyclin
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
, nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, and Endothelium-Derived Hyperpolarizing Factor.
Bradykinin is a physiologically and pharmacologically active peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
of the kinin
Kinin
A kinin is any of various structurally related polypeptides, such as bradykinin and kallikrein. They are members of the autacoid family.They act locally to induce vasodilation and contraction of smooth muscle.It is a component of the kinin-kallikrein system....
group of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, consisting of nine amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s.
Structure
Bradykinin is a 9 amino acid peptide chainTranslation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
. The amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence of bradykinin is: Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
- Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
- Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
- Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
- Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
- Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
- Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
- Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
- Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
. Its empirical formula is therefore C50H73N15O11.
Synthesis
The kinin-kallikrein systemKinin-kallikrein system
The kinin-kallikrein system or simply kinin system is a poorly understood system of blood proteins that plays a role in inflammation, blood pressure control, coagulation and pain...
makes bradykinin by proteolytic cleavage
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
of its kininogen precursor, high-molecular-weight kininogen (HMWK or HK), by the enzyme kallikrein
Kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known homologue, while tissue kallikrein-related peptidases encode a family of fifteen closely related serine proteases...
.
Metabolism
In humans, bradykinin is broken down by three kininases: angiotensin-converting enzymeAngiotensin-converting enzyme
Angiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...
(ACE), aminopeptidase P (APP), and carboxypeptidase
Carboxypeptidase
A carboxypeptidase is a protease enzyme that hydrolyzes the peptide bond of an amino acid residue at the carboxy-terminal end...
N (CPN), which cleave the 7-8, 1-2, and 8-9 positions, respectively.
Effects
Bradykinin is a potent endotheliumEndothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
-dependent vasodilator
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
, causes contraction of non-vascular smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
, increases vascular permeability
Vascular permeability
Vascular permeability, often in the form of capillary permeability, characterizes the capacity of a blood vessel wall to allow for the flow of small molecules or even whole cells in and out of the vessel. Blood vessel walls are lined by a single layer of endothelial cells...
and also is involved in the mechanism of pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
. Bradykinin also causes natriuresis
Natriuresis
Natriuresis is the process of excretion of sodium in the urine via action of the kidneys. Natriuresis is promoted by Brain and Atrial natriuretic peptides, and it is inhibited by chemicals such as aldosterone...
, contributing to a drop in blood pressure.
Bradykinin raises internal calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
levels in neocortical
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s causing them to release glutamate
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
.
Bradykinin is also thought to be the cause of the dry cough in some patients on angiotensin converting enzyme (ACE) inhibitor drugs. This refractory cough is a common cause for stopping ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
therapy. In which case Angiotensin II Receptor Antagonists are the next line of treatment.
Overactivation of bradykinin is thought to play a role in a rare disease called Hereditary Angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
, formerly known as Hereditary Angio-Neurotic Edema.
Initial secretion of Bradykinin post-natally causes constriction and eventual atrophy of the ductus arteriosus
Ductus arteriosus
In the developing fetus, the ductus arteriosus , also called the ductus Botalli, is a shunt connecting the pulmonary artery to the aortic arch. It allows most of the blood from the right ventricle to bypass the fetus's fluid-filled lungs. Upon closure at birth, it becomes the ligamentum arteriosum...
, forming the ligamentum artertiosum between the pulmonary trunk and aortic arch.
Receptors
- The B1 receptor (also called bradykinin receptor B1Bradykinin receptor B1Bradykinin receptor B1 is a G-protein coupled receptor encoded by the BDKRB1 gene in humans. Its principal ligand is bradykinin, a 9 amino acid peptide generated in pathophysiologic conditions such as inflammation, trauma, burns, shock, and allergy...
) is expressed only as a result of tissue injury, and is presumed to play a role in chronic pain. This receptor has been also described to play a role in inflammationInflammationInflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. Most recently, it has been shown that the kinin B1 receptor recruits neutrophil via the chemokine CXCL5CXCL5C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.- Function :The protein encoded by this gene, CXCL5 is a small cytokine belonging to the CXC chemokine family that is also known as epithelial-derived neutrophil-activating peptide 78...
production. Moreover, endothelial cells have been described as a potential source for this B1 receptor-CXCL5 pathway.
- The B2 receptor is constitutively expressed and participates in bradykinin's vasodilatory role.
The kinin B1 and B2 receptors belong to G protein coupled receptor (GPCR) family.
History
Bradykinin was discovered in 1948 by three BrazilBrazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
ian physiologists and pharmacologists working at the Instituto Biológico
Instituto Biológico
Biological Institute is an applied research center organised in 1924 in São Paulo, Brazil. It is a governmental organisation concerned with the prevention of zoonoses and foodborne animal pathogens such as rabies and tuberculosis, sanitary advertisement campaigns, alternatives to the chemical...
, in São Paulo, Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
, led by Dr. Maurício Rocha e Silva
Maurício Rocha e Silva
Maurício Oscar da Rocha e Silva was a Brazilian physician, biomedical scientist and pharmacologist...
. Together with colleagues Wilson Teixeira Beraldo
Wilson Teixeira Beraldo
Wilson Teixeira Beraldo was a Brazilian physician and physiologist, a co-discoverer of bradykinin....
and Gastão Rosenfeld
Gastão Rosenfeld
Gastão Rosenfeld , was a Brazilian physician and biomedical scientist, one of the co-discoverers of bradykinin, together with Maurício Rocha e Silva and Wilson Teixeira Beraldo, in 1949....
, they discovered the powerful hypotensive
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
effects of bradykinin in animal preparations
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
. Bradykinin was detected in the blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
of animals after the addition of venom extracted from the Bothrops jararaca
Bothrops jararaca
Bothrops jararaca is a venomous pit viper species found in southern Brazil, Paraguay and northern Argentina. The species name is derived from the Tupi words yarará and ca, which means "large snake." Within its range it is often abundant and is an important cause of snakebite...
(Brazilian lancehead snake
Snake
Snakes are elongate, legless, carnivorous reptiles of the suborder Serpentes that can be distinguished from legless lizards by their lack of eyelids and external ears. Like all squamates, snakes are ectothermic, amniote vertebrates covered in overlapping scales...
), brought by Rosenfeld from the Butantan Institute
Instituto Butantan
Instituto Butantan is a Brazilian biomedical research center affiliated to the São Paulo State Secretary of Health. It is located near the campus of the University of São Paulo, in the city of the same name.-History:...
. The discovery was part of a continuing study on circulatory shock and proteolytic
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s related to the toxicology
Toxicology
Toxicology is a branch of biology, chemistry, and medicine concerned with the study of the adverse effects of chemicals on living organisms...
of snake bites, started by Rocha e Silva as early as 1939. Bradykinin was to prove a new autopharmacological principle, i.e., a substance that is released in the body by a metabolic modification from precursors, which are pharmacologically active. According to B.J. Hagwood, Rocha e Silva's biographer, "The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins." Etymology: brady [Gk] slow, kinin [Gk ] kīn(eîn) to move, set in motion, ? from the effect of snake venom on intestinal smooth muscle, which was noted to slowly contract
Therapeutic Implications
The practical importance of the discovery of bradykinin became apparent when one of his collaborators at the Medical School of Ribeirão PretoFaculdade de Medicina de Ribeirão Preto
Faculdade de Medicina de Ribeirão Preto is a medical school of the University of São Paulo located in the city of Ribeirão Preto, state of São Paulo, Brazil, founded 1952...
at the University of São Paulo, Dr. Sérgio Henrique Ferreira
Sérgio Henrique Ferreira
Sérgio Henrique Ferreira , Brazil, Brazilian physician and pharmacologist, noted for his discovery of Bradykinin potentiating factor, which led to better anti-hypertension drugs.Ferreira received his M.D...
, discovered a bradykinin potentiating factor (BPF) in the bothropic venom which increases powerfully both the duration and magnitude of its effects on vasodilation and the consequent fall in blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
. On the basis of this finding, Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
scientists developed the first of a new generation of highly-effective anti-hypertensive drugs, the so-called ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s, such as captopril
Captopril
Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...
(trademarked Capoten).
Currently, bradykinin inhibitors (antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
) are being developed as potential therapies for hereditary angioedema. Icatibant
Icatibant
Icatibant is a peptidomimetic drug consisting of ten amino acids, which is a selective and specific antagonist of bradykinin B2 receptors...
is one such inhibitor. Additional bradykinin inhibitors exist. It has long been known in animal studies that bromelain
Bromelain
Bromelain is a pineapple extract thought to be effective for reducing swelling , especially of the nose and sinuses, after surgery or injury. It may also be used for a variety of other effects that remain scientifically unconfirmed and not authorized by regulatory authorities like the Food and Drug...
, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues. Other substances that act as bradykinin inhibitors include aloe
Aloe
Aloe , also Aloë, is a genus containing about 500 species of flowering succulent plants. The most common and well known of these is Aloe vera, or "true aloe"....
and polyphenol
Polyphenol
Polyphenols are a structural class of natural, synthetic, and semisynthetic organic chemicals characterized by the presence of large multiples of phenol structural units...
s, substances found in red wine and green tea.