Vaso-active peptides
Rakesh Bose
Student, B.Pharm
Bengal School of Technology
(A College of Pharmacy)
INTRODUCTION
Vasoactive peptides are one of the most important inflammatory signal mediators of human body coordinating a balance between sympathetic and parasympathetic nervous system. First vasoactive peptide got isolated and characterized when unknowingly a shot in the dark had been fired by scientists while discovering the mechanism of hypertension and by finding the renin angiotensin aldosterone pathway. Three separate vasoactive peptide got discovered subsequently in the form of renin, angiotensin I and ii .simultaneously during the development of anti-hypertensives particularly ace inhibitors two new vasoactive peptide emerged in the form of substance p and bradykinin via the discovery of kinin kalikerin pathway. since then a large number of vasoactive peptide have been isolated and characterized in recent years .first thought to be mediating only the vascular modelling and responses, later vasoactive peptide receptors were found in the CNS and PNS mediating multiple autocrine and paracrine cell signalling resulting in cellular differentiation and cell cycle .later with the finding of opioid peptides enkephalin and endorphin the multiparametric usage of vasoactive peptide got established. One of the primary functions of vasoactive peptide is to maintain homeostatic balance in the human body by activating the sympathetic and parasympathetic system. Vasoactive peptides and their agonists, partial agonists and antagonists are used for the therapeutic modalities regarding the diseases of cardiovascular such as left ventricular hypertrophy, st elevated myocardial infarction and essential hypertension regarding diabetic nephropathy and non-diabetic nephropathy. Similarly in the case of central nervous system diseases such as schizophrenia, depression and epilepsy the play a pivotal role. Classic example can be the activation of hypothalamic pituitary adrenal axis in case of anxiety and post-traumatic stress disorder where the activation or release of corticotrophin releasing hormone leads to the activation and release of ACTH or adrenocorticotropic stimulating hormone from the pituitary gland which induces a positive feedback loop and leads to the release of cortisol which is a prime marker in cases of anxiety and activation of catecholaminergic pathways exacerbating the condition. The discovery, identification and characterization of vasoactive peptide are of paramount importance primarily because of the fact that they can be used as biomarkers such as endothelin 1 and endothelin 2 in case of vascular remodelling in hypertensive patients and endothelin receptor antagonists can be used to treat the cases of primary pulmonary hypertension and right ventricular hypertrophy. The following project deals with the present discovered vasoactive peptide, their role in maintaining homeostasis and inflammatory mediation and development of therapeutic interventions regarding the non-communicable diseases. It also looks into the fact of emerging vasoactive peptides and their applications and tries to establish a framework for their usage.the outline of project is given below:
BOMBESIN
Bombesin (BBS, BB) is a 14-amino acid long polypeptide that has many physiological effects, including hormone control Bombesin is present in the brain, gastrointestinal tract, and lungs where it can release certain hormones and enzymes. Studies have shown that bombesin can be associated with many types of cancer cells. Studies have shown that several peptides are structurally related to bombesin. Two well-educated homologs are called neuromadin B and gastrin-releasing peptide (GRP). The gastrin-releasing peptide is biologically and immunologically equivalent to bombesin.
Receptor:-
Bombesin binds to a group of G protein-coupled receptors. It activates three different G-protein-coupled receptors known as –
BB1, previously known as Neuromedin B receptor NMBR
BB2, previously known as Gastrin-releasing peptide receptor GRPR
BB3, previously known as Bombesin-like receptor 3 BRS3
Physiological role:-
Neuropeptides that stimulate gastrin secretion and regulate fear.
Neuromedin C / gastrin releasing peptide acts as a chemoattract, acting to stimulate phagocytosis in phagocytic cells suppresses appetite, regulates stress.
Neuromedin also plays a role in the release of BB cytokines, reduces gastric motility and stimulates nociceptors.
Secreted by many tumor cells and promotes tumor growth.
Neuromedin B and gastrin release peptide / neuromedin C receptors improve tumor growth in tumours of the breast, CNS, colon, head and neck, lungs, pancreas and prostate.
Pathophysiology:-
Produced by many tumor cells, promotes tumor growth through epidermal growth factor receptors and HER2-mediated activation
Gastrin releases peptide / neuromedin C involved in duodenal ulcers and lung cancer
Neuromidin B is associated with obesity.
Neuromedin B and gastrin release peptide / neuromedin C receptors improve tumor growth in tumours of the breast, CNS, colon, head and neck, lungs, pancreas and prostate.
Targets and Therapeutic Properties:-
Bombesin is used to target these tumours directly to cytotoxic drugs. AN-152, a cytotoxic analogue of doxorubicin-bombasin, demonstrated disease stability during phase-1 clinical trials in ovarian and endometrial cancer. It is now undergoing phase I or phase II clinical trials on various cancers.
Demobasin 1 is a powerful new GRP-R-selective bombesin (BN) analogue that is an open-chain tetramine chelator for stable tectonium-1m binding used for GP receptor-targeted imaging.
VASOACTIVE INTESTINAL PEPTIDE
Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide, or VIP. VIP is a peptide of 28amino acid residues that contain glucagon / secretion, a ligand-linked receptor for class II G proteins. Vasoactive intestinal polypeptide (VIP) is a neuropeptide that acts as a neuromodulator and neurotransmitter. It is a potent vasodilator, which regulates smooth muscle activity, secretion of epithelial cells and blood flow in the gastrointestinal tract. As a chemical messenger, it acts as a neurohormone and paracrine mediator, acting locally on receptor-carrying cells released from nerve terminals. VIP has a half-life (t½) in about two minutes of blood.
Receptor:-
There are two known receptors for vasoactive intestinal peptide (VIP) called VPAC1 and VPAC2 .These receptors give some thickness to both VIP and pituitary adenylene cyclase-polypeptide (PACAP). Both receptors are members of the 7-transmembrane G protein-associated receptor family.
VPAC1 extends to the CNS, liver, lungs, intestines, and T-lymphocytes.
VPAC2 is found in the CNS, pancreas, skeletal muscle, heart, kidneys, adipose tissue, testes, and stomach.
Physiological role:-
VIP in the digestive system relaxes smooth muscles (lower oesophagus, sphincter, stomach, gall bladder).
VIP promotes the discharge of water into pancreatic juice and into the bile, and prevents the excretion of gastric acid and absorption from the intestinal lumen. It acts by stimulating the release of pepsinogen by the chief cells.
VIP appears to be an important neuropeptide during inflammatory bowel disease due to the interaction between mast cells and VIPs in colitis such as Crohn's disease.
It causes coronary vasodilation in the cardiovascular system
VIP stimulates vaginal lubrication in normal women, doubling the total amount of lubrication produced.
VIP in the pituitary helps in regulating prolactin secretion. It stimulates prolactin secretion in domestic turkeys.
In addition to strong vasodilatory effects, the peptide shows a high bronchodilatory potency.
Pathophysiology:-
VIP produces extra in VIPoma. Vasoactive intestinal peptide tumor (VIPoma) is a neuroendocrine tumor that secretes vasoactive intestinal peptide (VIP) in uncontrolled ways. Warner and Morrison first described it as a pancreatic tumor in 1955, resulting in watery diarrhoea and hypokalemia.it is also known as Verner-Morrison syndrome.
In addition to VIPoma, VIP also has a role for osteoarthritis (OA). The current contention, however, is that OA contributes to VIP's down-regulation or up-regulation.
An increased amount of VIP has been shown for inflammatory diseases of the upper and lower respiratory tract and peptides may also play a role in pulmonary hypertension.
Targets and Therapeutic Properties:-
Low doses of VIP in the sterile stable micelle (SSM) successfully reduce both inflammatory and autoimmune components of RA.
PB1046 is a sustained-release analogue of the domestic human peptide vasoactive intestinal peptide (VIP) by mixing the ELP biopolymer (injected subcutaneously) used in the treatment of DMD-related cardiomyopathy and cystic fibrosis.
VIP has been involved in the treatment of Alzheimer’s disease due to the neuroprotective properties of VIP. In a study by Delgado and colleagues, VIP was shown to effectively inhibit A-induced microglia activation of neurotoxins and subsequent expression of neurotoxins, such as tumor necrosis factor (TNF) -α, interleukin (IL-1), and nitric oxide (NO). Thus, VIP inhibits the death of malignant neuronal cells toward Alzheimer’s disease pathology in the brain.
It has been suggested as a viable therapeutic option for Parkinson's disease. In a 2003 study, Delgado and Ganea showed that VIPs could protect dopaminergic cells from LPS induce inflammation caused by endotoxin in mouse embryonic neurons.
SUBSTANCE P
Substance P (SP) is an undecapeptide (a peptide consisting of a chain of 11 amino acid residues), a member of the tachykinin neuronal peptide family. It is a neuronal peptide that acts as a neurotransmitter and as a neuromodulator. The closely related substance P and neurokinin A (NKA) are produced by the polyprotein precursor after differential distribution of the preprotachichinin a gene. The substance P is released from the terminals of certain sensory nerves. It is found in the brain and spinal cord and is associated with inflammatory processes and pain.
Receptor:-
The endocrine receptor of substance P is the neurokinin 1 receptor (NK1-receptor, NK1R). It belongs to the tachykinin receptor sub-family of GPCRs. substance P and NK1 receptor expand into the brain and are found in regions of the brain that specialize in controlling emotions (hypothalamus, amygdala, and periaqueductal grey). They are found in close search with serotonin (5-HT) and norepinephrine neurons that are currently targeted by the used antidepressants.
Physiological role:-
Substance P is a powerful vasodilator. Substance P-induced vasodilation is dependent on nitric oxide elution. Substance P is involved in axonal reflex-mediated vasodilation with local heating and wheel and flame and flare reactions. In contrast to other neuropeptides studied in human skin, P-induced vasodilatation decreased during continuous infusion.
Substance P has been linked to mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity.
SP initiates the expression of almost all known immune chemical messengers (cytokines). Also, most cytokines induce SP and NK1 receptors instead. Substances P and other sensitive neuropeptides can be released from the peripheral terminals of the sensory nerve fibres of the skin, muscles, and joints. It is suggested that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infections or injuries.
The vomiting center in the medulla is called region postrema, with a high concentration of substance P and its receptors. Their activation stimulates vomiting reflex.
Preclinical data support the idea that substance P is an important component of pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P uses co-experimental neurotransmitter glutamate in primary circles that respond to painful stimuli.
Pathophysiology:-
Substance P plays a role in inducing inflammation in response to various types of irritants, and may be part of the CNS pathways involved in stress.
Substance P induces anxiety-like behaviour, which is done by inhibiting the neurokinin receptor type 1 (NK1), which binds the neuropeptide.
Targets and Therapeutic Properties:-
NK1 receptor antagonists appear to be detectable at one stage of the animal test and able to block behavioural responses to other stressor-sensitive stimuli, but it fails to provide a level of sensitive blockade to induce clinical analgesia in humans.
The non-peptide NK-1R antagonist CP-96,345 has been reported to downregulate constitutive substance P mRNA expression in human mononuclear cells and the ability of such NK-1R antagonists to treat a range of gastrointestinal, respiratory and urogenital, and sensory disorders has been explored.
The radioactively labelled NK-1R antagonist casopitant has been shown to be rapidly absorbed into the bloodstream and subsequently found in the brain. This antagonist has completed Phase II and III clinical trials and has similar success as aprepitant in the treatment of chemotherapy-induced nausea and vomiting, but the drug has not yet been approved by the US Food and Drug Administration.
UROTENSIN II
Urotensin II (UII) is a cyclic peptide initially isolated from goby uropeye (Gillichthys mirabilis) based on its potent vasoconstrictor effect. The UII (11 to 15 amino acids) has a cyclic structure of 6 residues flanked by two Cys residues, which are completely conserved. UII is present in all vertebrate species, from lampreys to mammals. A paralogic UII called UII-related peptide (URP) also exists in tetrapods and teleosts. Due to the involvement of the UII system in various biological systems such as cardiovascular, nervous, endocrine and renal, represents a promising target for the development of new drugs.
Receptor:-
The urotensin-2 receptor (UR-II), also known as GPR14, is a G protein coupled-receptor of the rhodopsin a family with 138 amino acid, which binds mainly to the neuropeptide of urotensin II. When it is discovered that, when activated by urotensin II, it induces the most potent vasoconstriction effect ever observed. Although the precise function of the urotensin II receptor is not completely known, it has been linked to cardiovascular effects, stress and REM sleep.
Physiological role:-
The urotensin II was soon released as a powerful vasoconstrictor. Although previous studies have shown that the U II removes the effects of contraction on most smooth muscle tissue in fish, these effects have been demonstrated in mammalian tissues up until the mid-1980s.
Heart is one of the main urotensin II release sites. Many hemodynamic and cardiac effects of the urotensin II have been evaluated in various animal and human experiments. Low doses of HUII (<30 pmol · kg · 10-11) in rats have been shown to increase cardiac output, reduce regional vascular resistance and maintain systemic blood pressure unchanged. At high doses (pm10 pmol kg · 10-11), however, HUII causes a dose-dependent reduction in cardiac output and a severe obstructive stroke, myocardial contraction and systemic vasoconstriction.
The urotensin II is believed to play a role in maintaining renal vascular tone and tubular function. HUII has been shown to produce NO-mediated endothelial vasodilation in rat renal arteries. Prolonged invasion of HUII causes a dose-dependent increase in renal blood flow as well as an increase in urine in water and excretion of sodium.
There is also structural and functional evidence that the UI plays a role in the regulation of normal adrenal function.
Oxygenic behavior that increases appetite and thirst is also observed after ICV injection of U-II in rats.
Pathophysiology:-
The role that the urotensin II plays in the progression of atherosclerosis is an important and urgent area of current research. Plasma UII levels is found to be elevated in patients with confirmed atherosclerosis.
The urotensin II can play an important role in the etiology of essential hypertension. The UII reflects plasma levels and systolic blood pressure. Immunity concentrations similar to the user interface were higher in patients with hypertension and in those with hypertensive renal disease.
The cumulative effects of UIIs on glucose metabolism and insulin resistance can be combined with pressure, lipogenic and inflammatory effects in a positive feedback mechanism.
There is widespread evidence of changes in the expression of UII and in the circulation of UII levels in various renal diseases, including renal failure, nephrotic disorder and end-stage renal disease.
The basal endogenous expression supports the role of the UII in various tumours in renal carcinoma of the UII and UT receptor and in certain rhabdomyosarcoma cell lines, respectively.
There has been direct evidence for the pathological role of the UII in chronic liver disease. In patients with chronic liver disease, the serum UII is increased compared to controls.
Targets and Therapeutic Properties:-
Urantide is a potent antagonist of the UT receptor peptide, able to mediate the pathological effects of the UII in a variety of diseases. In relation to hypertension, the urantide inhibits UII-mediated vasoconstriction in the cerebral artery of the rat.
Palosuran is another potent non-peptide UT receptor antagonist with therapeutic potential. When infused intravenously at a dose of 10 mg/ (kg·h), palosuran provided protection to a rat model of renal ischemia-reperfusion via improved renal blood flow and significantly decreased tubulointerstitial lesions.
SB-611812 is a non-peptide receptor antagonist that has also been tested in various model pathologies of different animals. SB-611812 has been shown to improve cardiac function and prevent cardiac remodelling in a rat model of congestive heart failure.
ENDOTHELIN
Endothelin is a vasoconstrictor peptide of 21 amino acids originally produced in the endothelium, which plays a key role in vascular homeostasis. Endothelin is involved in vascular diseases of various organ systems, including the heart, lungs, kidneys and brain. Since the beginning of 2018, endothelin has been under extensive clinical and basic research to define their role in various organ systems.
Receptor:-
There are at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC, all G protein-linked receptors whose activation causes high levels intracellular-free calcium, which shrinks the smooth muscle of the arteries, raises blood pressure or relaxes the smooth muscles of the blood vessels, lowering blood pressure, among other functions.
Physiological role:-
Endothelin is the most potent vasoconstrictor known. Excessive production of endothelin in the lungs can cause pulmonary hypertension.
Endothelin receptors are present in three pituitary lobes. Indeed, exposure to endothelin-1 in the blood or ventricular system actually increases metabolism.
ET-1 contributes to vascular dysfunction associated with cardiovascular disease, especially in atherosclerosis and hypertension.
The binding of platelets to the Lox-1 endothelial cell receptor causes the release of endothelin, which induces endothelial dysfunction.
Pathophysiology:-
Endothelin (ET) -1, a potent endogenous vasoconstrictor, can play an important role both in the induction of fibrosis and the proliferation of vascular smooth muscle cells, in the development of CNI-induced nephrotoxicity and in the rejection of chronic allograft. ET-1 levels increase after isograft implantation and ET-1 levels play an important role in CNI-induced renal vasoconstriction, sodium retention, and hypertension.
ET-1 inhibits glucose uptake in skeletal muscle of insulin-resistant subjects, which in turn worsens insulin resistance.
The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among different organ systems. Among numerous diseases potentially occurring from endothelin dysregulation are:
arterial hypertension, pulmonary hypertension, and other cardiovascular disorders
cardiac hypertrophy and heart failure
several types of cancer
pain mediation
Targets and Therapeutic Properties:-
Bosentan, a non-selective ET-1 receptor antagonist (ETA and ETB receptor blocker) is currently used in the treatment of pulmonary hypertension. Another drug used for pulmonary hypertension is amberatin, a selective antagonist of the ETA receptor.
Preclinical data obtained with the double ETAR and the ETBR antagonist macitentan indicate that this molecule, which targets tumor cells and tumor micro environmental elements, could be a therapeutic option for cancer.
Atrasentan is a novel and selective inhibitor of ET-1 and ET-A. In vitro and in vivo data show that this oral agent is capable of inhibiting tumor cells in vitro. The second and third clinical trials that evaluated Atrasentan in patients with hormone refractory prostate cancer suggest that targeting this pathway could be a new therapeutic strategy, particularly in the treatment of prostate cancer.
ANGIOTENSIN II
Angiotensin II is a peptide hormone that increases vasoconstriction and blood pressure. It is part of the renin-angiotensin system, which regulates blood pressure. Angiotensin also promotes aldosterone excretion from the adrenal cortex to promote sodium retention by the kidneys. An oligopeptide, angiotensin hormone and dipsogen. It is derived from the precursor molecule of a serum globulin angiotensinogen produced in the liver.
Receptor:-
Angiotensin II receptors, (AGTR1) and (AGTR2), are a class of G protein-coupled receptors with angiotensin II as their ligands. These are important in the renin-angiotensin system: they are responsible for signal transduction to the hormone vasoconstrictor stimulation, the main effector of angiotensin II.
Physiological role:-
Angiotensin II is a powerful direct vasoconstrictors, which increase blood pressure by narrowing the arteries and veins. This effect is found through the activation of GPCR AT1, which signals through a GQ protein to activate phospholipase C and subsequently increase intracellular calcium.
Angiotensin II increases the sensation of thirst (dipsogen) through the posterior region and the subfornical organs of the brain, decreases the response to baroreceptor reflex, increases the salivary aspiration, increases the secretion of ADH from the posterior pituitary and increases the ACTH from the anterior pituitary.
Angiotensin II works in the adrenal cortex, releasing a hormone called aldosterone that causes the kidneys to hold sodium and lose potassium.
Angiotensin II has a direct effect on the proximal tubule to increase Na + reabsorption. It has a complex and variable effect on glomerular filtration and renal blood flow.
Angiotensin II is the most important Gq stimulant in the heart during hypertrophy, compared to endothelin-1 and α1 adrenoreceptors.
Pathophysiology:-
Angiotensin II activates nuclear factor-Kb and boost the inflammatory process of atherosclerosis.
Angiotensin II (Ang II) increases blood pressure (BP) through various activities, most importantly increasing vasoconstriction, sympathetic nerve stimulation, aldosterone biosynthesis and renal activities.
Ang II action involves increased synthesis of type I and III collagen in fibroblasts that lead to dense vascular and myocardial walls and fibrosis.
The increase of Ang II is an important component of neurohumoural activation in heart failure.
Targets and Therapeutic Properties:-
Angiotensin II type 1 receptor blockers (ARBs), specific antagonists of the angiotensin II type 1 (AT1) receptor subtype, are the newest therapeutic agents to counter effects of the RAS. In patients with hypertension, ARBs are generally as effective as ACE inhibitors.
Vaccines against angiotensin II, for example CYT006-AngQb, have been investigated.
OXYTOCIN
Oxytocin (Oxt) is a peptide hormone and neuropeptide. Oxytocin is usually produced in the hypothalamus and released by the pituitary. It plays a role in social bonding, sexual reproduction, childbirth and postpartum periods. Oxytocin is excreted as a hormone in the bloodstream in response to the uterus and uterus expanding during labour, and with stimulating the nipple of the breast during lactation. It helps in birth, bonding with the baby and producing milk.(
Receptor:-
Oxytocin receptor, also known as OXTR, is a protein that acts for hormone and neurotransmitter named oxytocin. In humans, the oxytocin receptor is encoded by the OXTR gene that is located on the human chromosome 3p25. The OXTR protein belongs to the G-protein coupled receptor family.
Physiological role:-
Oxytocin is important for uterine formation before birth, oxytocin causes contraction in the second and third stages of labour.
In breastfeeding mothers, oxytocin acts on the mammary glands, causing "release" of milk into the milk vessels, from which it can pass through the breast.
In combination with vasopressin, it can reduce urinary excretion somewhat. In several species, oxytocin can stimulate the excretion of sodium from the kidney (necrosis).
Oxytocin and oxytocin receptors are also found in some rat hearts and may play a role in the foetal development of the heart by promoting differentiation of hormone cardio myocytes.
Oxytocin, in certain circumstances, indirectly inhibits adrenocorticotropic hormone and cortisol excretion, and in such circumstances, Oxytocin may be considered as an antidote of vasopressin.
When oxytocin enters the bloodstream it affects the uterus and lactation, but it can affect emotional, cognitive, and social behavior when released into certain parts of the brain.
Oxytocin may also play a role in anger management. Studies indicate that some polymorphisms in the oxytocin receptor (OXTR) gene are associated with a larger tendency to respond angrily to situations.
Pathophysiology:-
Low levels of oxytocin have been associated with autism and autism spectrum disorders.
Low oxytocin is associated with depressive symptoms and has been proposed as a treatment for depressive disorders.
The hypersensitive trigger of high levels of oxytocin in the feelings of others is commonly referred to as the "love hormone". It plays an important role in social bonding, and recent research has shown that hormone can help people with autism and schizophrenia interact better with others.
Targets and Therapeutic Properties:-
Oxytocin has been suggested as a potential treatment for social phobia, autism and postpartum depression.
Oxytocin promotes prostaglandin E2 (PGE2) secretion in intestinal line cells. It helps repair intestinal lesions and protect against such injuries.
It is particularly effective in inducing labour to women with gestational diabetes and preeclampsia.
Oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin. As a medication, it is used to cause contraction of the uterus to start labour, increase the speed of labour, and to stop bleeding following delivery. For this purpose, it is given by injection either into a muscle or into a vein.
Oxytocin can also be used to treat incomplete abortion or miscarriage.
VASOPRESSIN
Vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP), or vasopressin, is a hormone synthesized as peptide prohormone in neurons of the hypothalamus and converted to AVP. It then travels along the axon of the cell, which ends in the posterior pituitary and is excreted by the vasculature of the circulation in response to the hypertonicity of the extracellular fluid (hyperosmolarity).
Receptor:-
Vasopressin initiates its physiological actions by combining with a specific receptor. These are two major types of vasopressin receptors: V1 & V2.
The V1 receptors are located on blood vessels and are responsible for the vasopressor action.
The V2 receptors are in the basolateral membrane of the collecting tubule cells in the kidney.
Physiological role:-
The primary function of AVP in the body is to control the amount of extracellular fluid that regulates the renal manipulation of water, although it is also a vasoconstrictor and a pressure agent (hence the name "vasopressin"). AVP acts on the renal collecting drains through the V2 receptor to increase water permeability (cAMP-dependent mechanism), which reduces urine depletion (hence, the antidiuretic action of the "antidiuretic hormone"). It increases blood volume, cardiac output and blood pressure.
Vasoconstriction is a secondary function of AVP. AVP binds to V1 receptors on vascular smooth muscle to generate vasoconstriction through the IP3 signal transduction pathway and the Rho-kinase pathway, which increases blood pressure; However, the normal physiological concentration of AVP is below its vasoactive range.
Pathophysiology:-
A decrease in the release of AVP (neurogenic - due to alcohol or intoxication) or a renal sensitivity to AVP (nephrogenic, that is to say by mutation of the V2 receptor or AQP) leads to diabetes insipidus, a condition that presents a hypernatremia concentration of sodium in the blood), polyuria (excessive production of urine) and polydipsia (thirst).
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) can in turn be caused by a series of problems. Some forms of cancer can cause SIADH, particularly small cell lung cancer but also a number of other cancers. A series of diseases that affect the brain or lungs (infections, bleeding) can be the driving force behind SIADH.
Targets and Therapeutic Properties:-
Several non-peptide AVP antagonists (vasopressin receptor antagonists [VRAs]), also called "vaptans", have been developed and are studied vigorously, mainly for the treatment of conditions characterized by hyponatremia and fluid overload. Conivaptan is a combined V (1A) / V (2) receptor antagonist that induces diuresis and hemodynamic improvement.
Tolvaptan, a selective V (2) receptor antagonist, has been extensively tested in the treatment of hyponatremia and heart failure. It has been shown to effectively reduce volume-overloaded fluids in patients with heart failure and to correct hyponatremia.
Lixivaptan and satavaptan (SR-121463) are other selective V (2) receptor antagonists evaluated for the treatment of hyponatremia.
Desmopressin (DDAVP), a selective V (2) receptor agonist, can reduce polyuria, nocturia and polydypsia. It is administered nasally, sublingually, i.m.
Vasopressin infusions are also used as second-line therapy in patients with septic shock who do not respond to fluid resuscitation or catecholamine infusions (e.g. dopamine or norepinephrine) to increase blood pressure while sparing use of catecholamines.
BRADYKININ
Bradykinin is an inflammatory mediator. It is a peptide that causes dilation (enlargement) of the blood vessels by the release of prostacyclin, nitric oxide and hyperpolarizing factor derived from the endothelium. Bradykinin is a physiologically and pharmacologically active peptide of the kinin protein group consisting of nine amino acids. A class of drugs called angiotensin converting enzyme (ACE) inhibitors increases bradykinin levels by inhibiting their degradation, thereby increasing the lowering effect of blood pressure. ACE inhibitors are FDA approved for the treatment of hypertension and heart failure.
Receptor:-
There are two receptors for bradykinin: the B1 receptor and the B2 receptor. The family of the bradykinin receptors is a group of G-protein coupled receptors whose main ligand is the bradykinin protein.
The B1 receptor (also called the bradykinin B1 receptor) is expressed only after tissue injury and is thought to play a role in chronic pain. It has also been described that this receptor plays a role in inflammation.
The B2 receptor is constitutively expressed and participates in the vasodilator role of bradykinin.
Physiological role:-
Bradykinin plays a major role in inflammation. Bradykinin, along with prostaglandins and histamine, mediates vasodilatation, in which arteriolar smooth muscle relaxes and, in turn, increases blood flow.
Bradykinin, along with Prostaglandin E2 (PGE2), also plays a role in the sensitization of sensory nerve endings, which causes pain or pain, a component of the inflammatory process.
Pathophysiology:-
Bradykinin plays a major role in the pathophysiology of C1 esterase inhibitor deficiency. It is an inherited autosomal dominant disorder that presents recurrent episodes of angioedema without hives of the face, extremities, oropharynx and abdomen.
It can also cause angioedema in the gastrointestinal tract that manifests with severe abdominal pain and gastrointestinal disturbances. These episodes of angioedema are often preceded by a period of fatigue and flu-like symptoms.
Angioedema is due to the unregulated activation of kallikrein. This activation of kallikrein increases the levels of bradykinin because kallikrein activates bradykinin. This excessive bradykinin induces an increase in permeability, an increase in vasodilation and an increase in pain.
Increased levels of bradykinins resulting from the use of ACE inhibitors have been associated with an increased risk of lung cancer.
Targets and Therapeutic Properties:-
Inhibitors of bradykinin (antagonists) are developed as potential treatments for hereditary angioedema. Icatibant is one of these inhibitors.
A bradykinin-potentiating factor (BPF) increasing the duration and magnitude of the effects of bradykinin on vasodilation and the resulting blood pressure drop was found in Bothrops' Jararaca venom. Based on this finding, a non-protein, oral, effective BPF analogue was developed: the first inhibitor of the captopril converting enzyme, angiotensin.
A substance obtained from the stems and leaves of the pineapple, suppresses the swelling induced by the trauma caused by the release of bradykinin into the bloodstream and into the tissues.(60)
SOMATOSTATIN
Somatostatin, also known as growth hormone inhibitory hormone (GHIH) or many other names, is a peptide hormone that regulates the endocrine system and influences neurotransmission and cell proliferation through an interaction with G protein somatostatin receptors and inhibition of the release of many secondary hormones. Somatostatin inhibits the secretion of insulin and glucagon. Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one composed of 14 amino acids, the other composed of 28 amino acids.
Receptor:-
Somatostatin receptors are receptors of the somatostatin ligand, a small neuropeptide associated with neural signaling, particularly in the post-synaptic response to co-stimulation / activation of NMDA receptors. Somatostatin is encoded by CRE and is highly susceptible to activation of the promoter region of the gene by the transcription factor CREB. There are five known somatostatin receptors: SST1, SST2, SST3, SST4, and SST5. All are seven transmembrane receptors coupled to G proteins.
Physiological role:-
Somatostatin Inhibit the release of growth hormone (GH) (thus neutralizing the effects of growth hormone and growth hormone (GHRH))
Inhibit the release of thyroid-stimulating hormone & prolactin.
Inhibit adenylyl cyclase in parietal cells.
Decreases the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine.
Somatostatin is homologous with cortistatin and suppresses the release of gastrointestinal hormones.
Suppresses the exocrine secretory action of the pancreas.
Pathophysiology:-
Somatostatinoma is a delta-pancreatic cell tumor that produces somatostatin. Increased levels of somatostatin inhibit pancreatic hormones and gastrointestinal hormones. Therefore, somatostatinomas are associated with mild diabetes mellitus (due to inhibition of insulin release), steatorrhea and gallstones (due to inhibition of cholecystokinin release) and with achlorhydria (due to inhibition of gastrin release). Somatostatinomas are common in the pancreas head.
Somatostatin regulates many physiological processes. Inadequate production of somatostatin causes a number of problems, including excessive secretion of growth hormone. However, very few cases of somatostatin deficiency have been reported.
Targets and Therapeutic Properties:-
Somatostatin analogues are used to treat tumours secreting a vasoactive intestinal peptide, carcinoid tumours, glucagonomers and various pituitary adenomas. It is also used to treat acromegaly (a condition characterized by excessive secretion of growth hormone in adults).
Short synthetic analogues of somatostatin (octreotide, lanreotide) used clinically (e.g. for the treatment of cancer, gastrointestinal disorders) interact primarily with sst2.
JR11 is an antagonist whose selectivity for sstr subtype 2 is under clinical development as a PET imaging agent when labelled with 68Ga and as a therapeutic agent if labelled with 177Lu.
Conclusion
The development of vasoactive peptide resulted in a landmark development when it comes to drug discovery and biomarker identification. The first vasoactive peptide angiotensin which got discovered in early part of this century resulted in an active development of angiotensin converting enzyme inhibitor .at the same time bradykinin got discovered which acts as a vasodilator from then onwards 30 odd vasoactive peptide got discovered resulting in an plethora of advancements with regards to therapeutic modalities. The above dissertation tries to shed some light into the evolving dynamic of vasoactive peptides and their role in drug discovery and biomarker development with the impending omics revolution and availability of large scale human genome, proteome, metabolome , microbiome, epigenome and transcriptome the process will only get expedited from now onwards at an exponential rate the complexity of human biological system and the advancement in molecular diagnostic tools would lead to development of thousands of advanced and precise biomarkers in the coming decade. The project aims to highlight only a few of them and thus tries to start a conversation regarding the potential of vasoactive peptides. Vasoactive peptides present a paradigm shift in understanding the diseases and their biomarkers and possible therapeutic interventions. Every technological development Vis a Vis medical progress takes off when three simultaneous events take place Technological feasibility, commercial viability and a push from the government. With the first two pieces of the puzzle getting solved in the next decade because of the rapid advancement in computational architecture, massive data storage capabilities and the impending insurance related revolution with regards to penetration of the products, the technology is at a prime when it comes to deploying the tech on a grand scale and only requires a significant amount of government spending. The coming together of all three will truly herald in the biomarkers and molecular diagnostics development over the next decade and truly enable the move towards the personalised medicine from the present one size fits all.
Student, B.Pharm
Bengal School of Technology
(A College of Pharmacy)
INTRODUCTION
Vasoactive peptides are one of the most important inflammatory signal mediators of human body coordinating a balance between sympathetic and parasympathetic nervous system. First vasoactive peptide got isolated and characterized when unknowingly a shot in the dark had been fired by scientists while discovering the mechanism of hypertension and by finding the renin angiotensin aldosterone pathway. Three separate vasoactive peptide got discovered subsequently in the form of renin, angiotensin I and ii .simultaneously during the development of anti-hypertensives particularly ace inhibitors two new vasoactive peptide emerged in the form of substance p and bradykinin via the discovery of kinin kalikerin pathway. since then a large number of vasoactive peptide have been isolated and characterized in recent years .first thought to be mediating only the vascular modelling and responses, later vasoactive peptide receptors were found in the CNS and PNS mediating multiple autocrine and paracrine cell signalling resulting in cellular differentiation and cell cycle .later with the finding of opioid peptides enkephalin and endorphin the multiparametric usage of vasoactive peptide got established. One of the primary functions of vasoactive peptide is to maintain homeostatic balance in the human body by activating the sympathetic and parasympathetic system. Vasoactive peptides and their agonists, partial agonists and antagonists are used for the therapeutic modalities regarding the diseases of cardiovascular such as left ventricular hypertrophy, st elevated myocardial infarction and essential hypertension regarding diabetic nephropathy and non-diabetic nephropathy. Similarly in the case of central nervous system diseases such as schizophrenia, depression and epilepsy the play a pivotal role. Classic example can be the activation of hypothalamic pituitary adrenal axis in case of anxiety and post-traumatic stress disorder where the activation or release of corticotrophin releasing hormone leads to the activation and release of ACTH or adrenocorticotropic stimulating hormone from the pituitary gland which induces a positive feedback loop and leads to the release of cortisol which is a prime marker in cases of anxiety and activation of catecholaminergic pathways exacerbating the condition. The discovery, identification and characterization of vasoactive peptide are of paramount importance primarily because of the fact that they can be used as biomarkers such as endothelin 1 and endothelin 2 in case of vascular remodelling in hypertensive patients and endothelin receptor antagonists can be used to treat the cases of primary pulmonary hypertension and right ventricular hypertrophy. The following project deals with the present discovered vasoactive peptide, their role in maintaining homeostasis and inflammatory mediation and development of therapeutic interventions regarding the non-communicable diseases. It also looks into the fact of emerging vasoactive peptides and their applications and tries to establish a framework for their usage.the outline of project is given below:
BOMBESIN
Bombesin (BBS, BB) is a 14-amino acid long polypeptide that has many physiological effects, including hormone control Bombesin is present in the brain, gastrointestinal tract, and lungs where it can release certain hormones and enzymes. Studies have shown that bombesin can be associated with many types of cancer cells. Studies have shown that several peptides are structurally related to bombesin. Two well-educated homologs are called neuromadin B and gastrin-releasing peptide (GRP). The gastrin-releasing peptide is biologically and immunologically equivalent to bombesin.
Receptor:-
Bombesin binds to a group of G protein-coupled receptors. It activates three different G-protein-coupled receptors known as –
BB1, previously known as Neuromedin B receptor NMBR
BB2, previously known as Gastrin-releasing peptide receptor GRPR
BB3, previously known as Bombesin-like receptor 3 BRS3
Physiological role:-
Neuropeptides that stimulate gastrin secretion and regulate fear.
Neuromedin C / gastrin releasing peptide acts as a chemoattract, acting to stimulate phagocytosis in phagocytic cells suppresses appetite, regulates stress.
Neuromedin also plays a role in the release of BB cytokines, reduces gastric motility and stimulates nociceptors.
Secreted by many tumor cells and promotes tumor growth.
Neuromedin B and gastrin release peptide / neuromedin C receptors improve tumor growth in tumours of the breast, CNS, colon, head and neck, lungs, pancreas and prostate.
Pathophysiology:-
Produced by many tumor cells, promotes tumor growth through epidermal growth factor receptors and HER2-mediated activation
Gastrin releases peptide / neuromedin C involved in duodenal ulcers and lung cancer
Neuromidin B is associated with obesity.
Neuromedin B and gastrin release peptide / neuromedin C receptors improve tumor growth in tumours of the breast, CNS, colon, head and neck, lungs, pancreas and prostate.
Targets and Therapeutic Properties:-
Bombesin is used to target these tumours directly to cytotoxic drugs. AN-152, a cytotoxic analogue of doxorubicin-bombasin, demonstrated disease stability during phase-1 clinical trials in ovarian and endometrial cancer. It is now undergoing phase I or phase II clinical trials on various cancers.
Demobasin 1 is a powerful new GRP-R-selective bombesin (BN) analogue that is an open-chain tetramine chelator for stable tectonium-1m binding used for GP receptor-targeted imaging.
VASOACTIVE INTESTINAL PEPTIDE
Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide, or VIP. VIP is a peptide of 28amino acid residues that contain glucagon / secretion, a ligand-linked receptor for class II G proteins. Vasoactive intestinal polypeptide (VIP) is a neuropeptide that acts as a neuromodulator and neurotransmitter. It is a potent vasodilator, which regulates smooth muscle activity, secretion of epithelial cells and blood flow in the gastrointestinal tract. As a chemical messenger, it acts as a neurohormone and paracrine mediator, acting locally on receptor-carrying cells released from nerve terminals. VIP has a half-life (t½) in about two minutes of blood.
Receptor:-
There are two known receptors for vasoactive intestinal peptide (VIP) called VPAC1 and VPAC2 .These receptors give some thickness to both VIP and pituitary adenylene cyclase-polypeptide (PACAP). Both receptors are members of the 7-transmembrane G protein-associated receptor family.
VPAC1 extends to the CNS, liver, lungs, intestines, and T-lymphocytes.
VPAC2 is found in the CNS, pancreas, skeletal muscle, heart, kidneys, adipose tissue, testes, and stomach.
Physiological role:-
VIP in the digestive system relaxes smooth muscles (lower oesophagus, sphincter, stomach, gall bladder).
VIP promotes the discharge of water into pancreatic juice and into the bile, and prevents the excretion of gastric acid and absorption from the intestinal lumen. It acts by stimulating the release of pepsinogen by the chief cells.
VIP appears to be an important neuropeptide during inflammatory bowel disease due to the interaction between mast cells and VIPs in colitis such as Crohn's disease.
It causes coronary vasodilation in the cardiovascular system
VIP stimulates vaginal lubrication in normal women, doubling the total amount of lubrication produced.
VIP in the pituitary helps in regulating prolactin secretion. It stimulates prolactin secretion in domestic turkeys.
In addition to strong vasodilatory effects, the peptide shows a high bronchodilatory potency.
Pathophysiology:-
VIP produces extra in VIPoma. Vasoactive intestinal peptide tumor (VIPoma) is a neuroendocrine tumor that secretes vasoactive intestinal peptide (VIP) in uncontrolled ways. Warner and Morrison first described it as a pancreatic tumor in 1955, resulting in watery diarrhoea and hypokalemia.it is also known as Verner-Morrison syndrome.
In addition to VIPoma, VIP also has a role for osteoarthritis (OA). The current contention, however, is that OA contributes to VIP's down-regulation or up-regulation.
An increased amount of VIP has been shown for inflammatory diseases of the upper and lower respiratory tract and peptides may also play a role in pulmonary hypertension.
Targets and Therapeutic Properties:-
Low doses of VIP in the sterile stable micelle (SSM) successfully reduce both inflammatory and autoimmune components of RA.
PB1046 is a sustained-release analogue of the domestic human peptide vasoactive intestinal peptide (VIP) by mixing the ELP biopolymer (injected subcutaneously) used in the treatment of DMD-related cardiomyopathy and cystic fibrosis.
VIP has been involved in the treatment of Alzheimer’s disease due to the neuroprotective properties of VIP. In a study by Delgado and colleagues, VIP was shown to effectively inhibit A-induced microglia activation of neurotoxins and subsequent expression of neurotoxins, such as tumor necrosis factor (TNF) -α, interleukin (IL-1), and nitric oxide (NO). Thus, VIP inhibits the death of malignant neuronal cells toward Alzheimer’s disease pathology in the brain.
It has been suggested as a viable therapeutic option for Parkinson's disease. In a 2003 study, Delgado and Ganea showed that VIPs could protect dopaminergic cells from LPS induce inflammation caused by endotoxin in mouse embryonic neurons.
SUBSTANCE P
Substance P (SP) is an undecapeptide (a peptide consisting of a chain of 11 amino acid residues), a member of the tachykinin neuronal peptide family. It is a neuronal peptide that acts as a neurotransmitter and as a neuromodulator. The closely related substance P and neurokinin A (NKA) are produced by the polyprotein precursor after differential distribution of the preprotachichinin a gene. The substance P is released from the terminals of certain sensory nerves. It is found in the brain and spinal cord and is associated with inflammatory processes and pain.
Receptor:-
The endocrine receptor of substance P is the neurokinin 1 receptor (NK1-receptor, NK1R). It belongs to the tachykinin receptor sub-family of GPCRs. substance P and NK1 receptor expand into the brain and are found in regions of the brain that specialize in controlling emotions (hypothalamus, amygdala, and periaqueductal grey). They are found in close search with serotonin (5-HT) and norepinephrine neurons that are currently targeted by the used antidepressants.
Physiological role:-
Substance P is a powerful vasodilator. Substance P-induced vasodilation is dependent on nitric oxide elution. Substance P is involved in axonal reflex-mediated vasodilation with local heating and wheel and flame and flare reactions. In contrast to other neuropeptides studied in human skin, P-induced vasodilatation decreased during continuous infusion.
Substance P has been linked to mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity.
SP initiates the expression of almost all known immune chemical messengers (cytokines). Also, most cytokines induce SP and NK1 receptors instead. Substances P and other sensitive neuropeptides can be released from the peripheral terminals of the sensory nerve fibres of the skin, muscles, and joints. It is suggested that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infections or injuries.
The vomiting center in the medulla is called region postrema, with a high concentration of substance P and its receptors. Their activation stimulates vomiting reflex.
Preclinical data support the idea that substance P is an important component of pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P uses co-experimental neurotransmitter glutamate in primary circles that respond to painful stimuli.
Pathophysiology:-
Substance P plays a role in inducing inflammation in response to various types of irritants, and may be part of the CNS pathways involved in stress.
Substance P induces anxiety-like behaviour, which is done by inhibiting the neurokinin receptor type 1 (NK1), which binds the neuropeptide.
Targets and Therapeutic Properties:-
NK1 receptor antagonists appear to be detectable at one stage of the animal test and able to block behavioural responses to other stressor-sensitive stimuli, but it fails to provide a level of sensitive blockade to induce clinical analgesia in humans.
The non-peptide NK-1R antagonist CP-96,345 has been reported to downregulate constitutive substance P mRNA expression in human mononuclear cells and the ability of such NK-1R antagonists to treat a range of gastrointestinal, respiratory and urogenital, and sensory disorders has been explored.
The radioactively labelled NK-1R antagonist casopitant has been shown to be rapidly absorbed into the bloodstream and subsequently found in the brain. This antagonist has completed Phase II and III clinical trials and has similar success as aprepitant in the treatment of chemotherapy-induced nausea and vomiting, but the drug has not yet been approved by the US Food and Drug Administration.
UROTENSIN II
Urotensin II (UII) is a cyclic peptide initially isolated from goby uropeye (Gillichthys mirabilis) based on its potent vasoconstrictor effect. The UII (11 to 15 amino acids) has a cyclic structure of 6 residues flanked by two Cys residues, which are completely conserved. UII is present in all vertebrate species, from lampreys to mammals. A paralogic UII called UII-related peptide (URP) also exists in tetrapods and teleosts. Due to the involvement of the UII system in various biological systems such as cardiovascular, nervous, endocrine and renal, represents a promising target for the development of new drugs.
Receptor:-
The urotensin-2 receptor (UR-II), also known as GPR14, is a G protein coupled-receptor of the rhodopsin a family with 138 amino acid, which binds mainly to the neuropeptide of urotensin II. When it is discovered that, when activated by urotensin II, it induces the most potent vasoconstriction effect ever observed. Although the precise function of the urotensin II receptor is not completely known, it has been linked to cardiovascular effects, stress and REM sleep.
Physiological role:-
The urotensin II was soon released as a powerful vasoconstrictor. Although previous studies have shown that the U II removes the effects of contraction on most smooth muscle tissue in fish, these effects have been demonstrated in mammalian tissues up until the mid-1980s.
Heart is one of the main urotensin II release sites. Many hemodynamic and cardiac effects of the urotensin II have been evaluated in various animal and human experiments. Low doses of HUII (<30 pmol · kg · 10-11) in rats have been shown to increase cardiac output, reduce regional vascular resistance and maintain systemic blood pressure unchanged. At high doses (pm10 pmol kg · 10-11), however, HUII causes a dose-dependent reduction in cardiac output and a severe obstructive stroke, myocardial contraction and systemic vasoconstriction.
The urotensin II is believed to play a role in maintaining renal vascular tone and tubular function. HUII has been shown to produce NO-mediated endothelial vasodilation in rat renal arteries. Prolonged invasion of HUII causes a dose-dependent increase in renal blood flow as well as an increase in urine in water and excretion of sodium.
There is also structural and functional evidence that the UI plays a role in the regulation of normal adrenal function.
Oxygenic behavior that increases appetite and thirst is also observed after ICV injection of U-II in rats.
Pathophysiology:-
The role that the urotensin II plays in the progression of atherosclerosis is an important and urgent area of current research. Plasma UII levels is found to be elevated in patients with confirmed atherosclerosis.
The urotensin II can play an important role in the etiology of essential hypertension. The UII reflects plasma levels and systolic blood pressure. Immunity concentrations similar to the user interface were higher in patients with hypertension and in those with hypertensive renal disease.
The cumulative effects of UIIs on glucose metabolism and insulin resistance can be combined with pressure, lipogenic and inflammatory effects in a positive feedback mechanism.
There is widespread evidence of changes in the expression of UII and in the circulation of UII levels in various renal diseases, including renal failure, nephrotic disorder and end-stage renal disease.
The basal endogenous expression supports the role of the UII in various tumours in renal carcinoma of the UII and UT receptor and in certain rhabdomyosarcoma cell lines, respectively.
There has been direct evidence for the pathological role of the UII in chronic liver disease. In patients with chronic liver disease, the serum UII is increased compared to controls.
Targets and Therapeutic Properties:-
Urantide is a potent antagonist of the UT receptor peptide, able to mediate the pathological effects of the UII in a variety of diseases. In relation to hypertension, the urantide inhibits UII-mediated vasoconstriction in the cerebral artery of the rat.
Palosuran is another potent non-peptide UT receptor antagonist with therapeutic potential. When infused intravenously at a dose of 10 mg/ (kg·h), palosuran provided protection to a rat model of renal ischemia-reperfusion via improved renal blood flow and significantly decreased tubulointerstitial lesions.
SB-611812 is a non-peptide receptor antagonist that has also been tested in various model pathologies of different animals. SB-611812 has been shown to improve cardiac function and prevent cardiac remodelling in a rat model of congestive heart failure.
ENDOTHELIN
Endothelin is a vasoconstrictor peptide of 21 amino acids originally produced in the endothelium, which plays a key role in vascular homeostasis. Endothelin is involved in vascular diseases of various organ systems, including the heart, lungs, kidneys and brain. Since the beginning of 2018, endothelin has been under extensive clinical and basic research to define their role in various organ systems.
Receptor:-
There are at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC, all G protein-linked receptors whose activation causes high levels intracellular-free calcium, which shrinks the smooth muscle of the arteries, raises blood pressure or relaxes the smooth muscles of the blood vessels, lowering blood pressure, among other functions.
Physiological role:-
Endothelin is the most potent vasoconstrictor known. Excessive production of endothelin in the lungs can cause pulmonary hypertension.
Endothelin receptors are present in three pituitary lobes. Indeed, exposure to endothelin-1 in the blood or ventricular system actually increases metabolism.
ET-1 contributes to vascular dysfunction associated with cardiovascular disease, especially in atherosclerosis and hypertension.
The binding of platelets to the Lox-1 endothelial cell receptor causes the release of endothelin, which induces endothelial dysfunction.
Pathophysiology:-
Endothelin (ET) -1, a potent endogenous vasoconstrictor, can play an important role both in the induction of fibrosis and the proliferation of vascular smooth muscle cells, in the development of CNI-induced nephrotoxicity and in the rejection of chronic allograft. ET-1 levels increase after isograft implantation and ET-1 levels play an important role in CNI-induced renal vasoconstriction, sodium retention, and hypertension.
ET-1 inhibits glucose uptake in skeletal muscle of insulin-resistant subjects, which in turn worsens insulin resistance.
The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among different organ systems. Among numerous diseases potentially occurring from endothelin dysregulation are:
arterial hypertension, pulmonary hypertension, and other cardiovascular disorders
cardiac hypertrophy and heart failure
several types of cancer
pain mediation
Targets and Therapeutic Properties:-
Bosentan, a non-selective ET-1 receptor antagonist (ETA and ETB receptor blocker) is currently used in the treatment of pulmonary hypertension. Another drug used for pulmonary hypertension is amberatin, a selective antagonist of the ETA receptor.
Preclinical data obtained with the double ETAR and the ETBR antagonist macitentan indicate that this molecule, which targets tumor cells and tumor micro environmental elements, could be a therapeutic option for cancer.
Atrasentan is a novel and selective inhibitor of ET-1 and ET-A. In vitro and in vivo data show that this oral agent is capable of inhibiting tumor cells in vitro. The second and third clinical trials that evaluated Atrasentan in patients with hormone refractory prostate cancer suggest that targeting this pathway could be a new therapeutic strategy, particularly in the treatment of prostate cancer.
ANGIOTENSIN II
Angiotensin II is a peptide hormone that increases vasoconstriction and blood pressure. It is part of the renin-angiotensin system, which regulates blood pressure. Angiotensin also promotes aldosterone excretion from the adrenal cortex to promote sodium retention by the kidneys. An oligopeptide, angiotensin hormone and dipsogen. It is derived from the precursor molecule of a serum globulin angiotensinogen produced in the liver.
Receptor:-
Angiotensin II receptors, (AGTR1) and (AGTR2), are a class of G protein-coupled receptors with angiotensin II as their ligands. These are important in the renin-angiotensin system: they are responsible for signal transduction to the hormone vasoconstrictor stimulation, the main effector of angiotensin II.
Physiological role:-
Angiotensin II is a powerful direct vasoconstrictors, which increase blood pressure by narrowing the arteries and veins. This effect is found through the activation of GPCR AT1, which signals through a GQ protein to activate phospholipase C and subsequently increase intracellular calcium.
Angiotensin II increases the sensation of thirst (dipsogen) through the posterior region and the subfornical organs of the brain, decreases the response to baroreceptor reflex, increases the salivary aspiration, increases the secretion of ADH from the posterior pituitary and increases the ACTH from the anterior pituitary.
Angiotensin II works in the adrenal cortex, releasing a hormone called aldosterone that causes the kidneys to hold sodium and lose potassium.
Angiotensin II has a direct effect on the proximal tubule to increase Na + reabsorption. It has a complex and variable effect on glomerular filtration and renal blood flow.
Angiotensin II is the most important Gq stimulant in the heart during hypertrophy, compared to endothelin-1 and α1 adrenoreceptors.
Pathophysiology:-
Angiotensin II activates nuclear factor-Kb and boost the inflammatory process of atherosclerosis.
Angiotensin II (Ang II) increases blood pressure (BP) through various activities, most importantly increasing vasoconstriction, sympathetic nerve stimulation, aldosterone biosynthesis and renal activities.
Ang II action involves increased synthesis of type I and III collagen in fibroblasts that lead to dense vascular and myocardial walls and fibrosis.
The increase of Ang II is an important component of neurohumoural activation in heart failure.
Targets and Therapeutic Properties:-
Angiotensin II type 1 receptor blockers (ARBs), specific antagonists of the angiotensin II type 1 (AT1) receptor subtype, are the newest therapeutic agents to counter effects of the RAS. In patients with hypertension, ARBs are generally as effective as ACE inhibitors.
Vaccines against angiotensin II, for example CYT006-AngQb, have been investigated.
OXYTOCIN
Oxytocin (Oxt) is a peptide hormone and neuropeptide. Oxytocin is usually produced in the hypothalamus and released by the pituitary. It plays a role in social bonding, sexual reproduction, childbirth and postpartum periods. Oxytocin is excreted as a hormone in the bloodstream in response to the uterus and uterus expanding during labour, and with stimulating the nipple of the breast during lactation. It helps in birth, bonding with the baby and producing milk.(
Receptor:-
Oxytocin receptor, also known as OXTR, is a protein that acts for hormone and neurotransmitter named oxytocin. In humans, the oxytocin receptor is encoded by the OXTR gene that is located on the human chromosome 3p25. The OXTR protein belongs to the G-protein coupled receptor family.
Physiological role:-
Oxytocin is important for uterine formation before birth, oxytocin causes contraction in the second and third stages of labour.
In breastfeeding mothers, oxytocin acts on the mammary glands, causing "release" of milk into the milk vessels, from which it can pass through the breast.
In combination with vasopressin, it can reduce urinary excretion somewhat. In several species, oxytocin can stimulate the excretion of sodium from the kidney (necrosis).
Oxytocin and oxytocin receptors are also found in some rat hearts and may play a role in the foetal development of the heart by promoting differentiation of hormone cardio myocytes.
Oxytocin, in certain circumstances, indirectly inhibits adrenocorticotropic hormone and cortisol excretion, and in such circumstances, Oxytocin may be considered as an antidote of vasopressin.
When oxytocin enters the bloodstream it affects the uterus and lactation, but it can affect emotional, cognitive, and social behavior when released into certain parts of the brain.
Oxytocin may also play a role in anger management. Studies indicate that some polymorphisms in the oxytocin receptor (OXTR) gene are associated with a larger tendency to respond angrily to situations.
Pathophysiology:-
Low levels of oxytocin have been associated with autism and autism spectrum disorders.
Low oxytocin is associated with depressive symptoms and has been proposed as a treatment for depressive disorders.
The hypersensitive trigger of high levels of oxytocin in the feelings of others is commonly referred to as the "love hormone". It plays an important role in social bonding, and recent research has shown that hormone can help people with autism and schizophrenia interact better with others.
Targets and Therapeutic Properties:-
Oxytocin has been suggested as a potential treatment for social phobia, autism and postpartum depression.
Oxytocin promotes prostaglandin E2 (PGE2) secretion in intestinal line cells. It helps repair intestinal lesions and protect against such injuries.
It is particularly effective in inducing labour to women with gestational diabetes and preeclampsia.
Oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin. As a medication, it is used to cause contraction of the uterus to start labour, increase the speed of labour, and to stop bleeding following delivery. For this purpose, it is given by injection either into a muscle or into a vein.
Oxytocin can also be used to treat incomplete abortion or miscarriage.
VASOPRESSIN
Vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP), or vasopressin, is a hormone synthesized as peptide prohormone in neurons of the hypothalamus and converted to AVP. It then travels along the axon of the cell, which ends in the posterior pituitary and is excreted by the vasculature of the circulation in response to the hypertonicity of the extracellular fluid (hyperosmolarity).
Receptor:-
Vasopressin initiates its physiological actions by combining with a specific receptor. These are two major types of vasopressin receptors: V1 & V2.
The V1 receptors are located on blood vessels and are responsible for the vasopressor action.
The V2 receptors are in the basolateral membrane of the collecting tubule cells in the kidney.
Physiological role:-
The primary function of AVP in the body is to control the amount of extracellular fluid that regulates the renal manipulation of water, although it is also a vasoconstrictor and a pressure agent (hence the name "vasopressin"). AVP acts on the renal collecting drains through the V2 receptor to increase water permeability (cAMP-dependent mechanism), which reduces urine depletion (hence, the antidiuretic action of the "antidiuretic hormone"). It increases blood volume, cardiac output and blood pressure.
Vasoconstriction is a secondary function of AVP. AVP binds to V1 receptors on vascular smooth muscle to generate vasoconstriction through the IP3 signal transduction pathway and the Rho-kinase pathway, which increases blood pressure; However, the normal physiological concentration of AVP is below its vasoactive range.
Pathophysiology:-
A decrease in the release of AVP (neurogenic - due to alcohol or intoxication) or a renal sensitivity to AVP (nephrogenic, that is to say by mutation of the V2 receptor or AQP) leads to diabetes insipidus, a condition that presents a hypernatremia concentration of sodium in the blood), polyuria (excessive production of urine) and polydipsia (thirst).
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) can in turn be caused by a series of problems. Some forms of cancer can cause SIADH, particularly small cell lung cancer but also a number of other cancers. A series of diseases that affect the brain or lungs (infections, bleeding) can be the driving force behind SIADH.
Targets and Therapeutic Properties:-
Several non-peptide AVP antagonists (vasopressin receptor antagonists [VRAs]), also called "vaptans", have been developed and are studied vigorously, mainly for the treatment of conditions characterized by hyponatremia and fluid overload. Conivaptan is a combined V (1A) / V (2) receptor antagonist that induces diuresis and hemodynamic improvement.
Tolvaptan, a selective V (2) receptor antagonist, has been extensively tested in the treatment of hyponatremia and heart failure. It has been shown to effectively reduce volume-overloaded fluids in patients with heart failure and to correct hyponatremia.
Lixivaptan and satavaptan (SR-121463) are other selective V (2) receptor antagonists evaluated for the treatment of hyponatremia.
Desmopressin (DDAVP), a selective V (2) receptor agonist, can reduce polyuria, nocturia and polydypsia. It is administered nasally, sublingually, i.m.
Vasopressin infusions are also used as second-line therapy in patients with septic shock who do not respond to fluid resuscitation or catecholamine infusions (e.g. dopamine or norepinephrine) to increase blood pressure while sparing use of catecholamines.
BRADYKININ
Bradykinin is an inflammatory mediator. It is a peptide that causes dilation (enlargement) of the blood vessels by the release of prostacyclin, nitric oxide and hyperpolarizing factor derived from the endothelium. Bradykinin is a physiologically and pharmacologically active peptide of the kinin protein group consisting of nine amino acids. A class of drugs called angiotensin converting enzyme (ACE) inhibitors increases bradykinin levels by inhibiting their degradation, thereby increasing the lowering effect of blood pressure. ACE inhibitors are FDA approved for the treatment of hypertension and heart failure.
Receptor:-
There are two receptors for bradykinin: the B1 receptor and the B2 receptor. The family of the bradykinin receptors is a group of G-protein coupled receptors whose main ligand is the bradykinin protein.
The B1 receptor (also called the bradykinin B1 receptor) is expressed only after tissue injury and is thought to play a role in chronic pain. It has also been described that this receptor plays a role in inflammation.
The B2 receptor is constitutively expressed and participates in the vasodilator role of bradykinin.
Physiological role:-
Bradykinin plays a major role in inflammation. Bradykinin, along with prostaglandins and histamine, mediates vasodilatation, in which arteriolar smooth muscle relaxes and, in turn, increases blood flow.
Bradykinin, along with Prostaglandin E2 (PGE2), also plays a role in the sensitization of sensory nerve endings, which causes pain or pain, a component of the inflammatory process.
Pathophysiology:-
Bradykinin plays a major role in the pathophysiology of C1 esterase inhibitor deficiency. It is an inherited autosomal dominant disorder that presents recurrent episodes of angioedema without hives of the face, extremities, oropharynx and abdomen.
It can also cause angioedema in the gastrointestinal tract that manifests with severe abdominal pain and gastrointestinal disturbances. These episodes of angioedema are often preceded by a period of fatigue and flu-like symptoms.
Angioedema is due to the unregulated activation of kallikrein. This activation of kallikrein increases the levels of bradykinin because kallikrein activates bradykinin. This excessive bradykinin induces an increase in permeability, an increase in vasodilation and an increase in pain.
Increased levels of bradykinins resulting from the use of ACE inhibitors have been associated with an increased risk of lung cancer.
Targets and Therapeutic Properties:-
Inhibitors of bradykinin (antagonists) are developed as potential treatments for hereditary angioedema. Icatibant is one of these inhibitors.
A bradykinin-potentiating factor (BPF) increasing the duration and magnitude of the effects of bradykinin on vasodilation and the resulting blood pressure drop was found in Bothrops' Jararaca venom. Based on this finding, a non-protein, oral, effective BPF analogue was developed: the first inhibitor of the captopril converting enzyme, angiotensin.
A substance obtained from the stems and leaves of the pineapple, suppresses the swelling induced by the trauma caused by the release of bradykinin into the bloodstream and into the tissues.(60)
SOMATOSTATIN
Somatostatin, also known as growth hormone inhibitory hormone (GHIH) or many other names, is a peptide hormone that regulates the endocrine system and influences neurotransmission and cell proliferation through an interaction with G protein somatostatin receptors and inhibition of the release of many secondary hormones. Somatostatin inhibits the secretion of insulin and glucagon. Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one composed of 14 amino acids, the other composed of 28 amino acids.
Receptor:-
Somatostatin receptors are receptors of the somatostatin ligand, a small neuropeptide associated with neural signaling, particularly in the post-synaptic response to co-stimulation / activation of NMDA receptors. Somatostatin is encoded by CRE and is highly susceptible to activation of the promoter region of the gene by the transcription factor CREB. There are five known somatostatin receptors: SST1, SST2, SST3, SST4, and SST5. All are seven transmembrane receptors coupled to G proteins.
Physiological role:-
Somatostatin Inhibit the release of growth hormone (GH) (thus neutralizing the effects of growth hormone and growth hormone (GHRH))
Inhibit the release of thyroid-stimulating hormone & prolactin.
Inhibit adenylyl cyclase in parietal cells.
Decreases the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine.
Somatostatin is homologous with cortistatin and suppresses the release of gastrointestinal hormones.
Suppresses the exocrine secretory action of the pancreas.
Pathophysiology:-
Somatostatinoma is a delta-pancreatic cell tumor that produces somatostatin. Increased levels of somatostatin inhibit pancreatic hormones and gastrointestinal hormones. Therefore, somatostatinomas are associated with mild diabetes mellitus (due to inhibition of insulin release), steatorrhea and gallstones (due to inhibition of cholecystokinin release) and with achlorhydria (due to inhibition of gastrin release). Somatostatinomas are common in the pancreas head.
Somatostatin regulates many physiological processes. Inadequate production of somatostatin causes a number of problems, including excessive secretion of growth hormone. However, very few cases of somatostatin deficiency have been reported.
Targets and Therapeutic Properties:-
Somatostatin analogues are used to treat tumours secreting a vasoactive intestinal peptide, carcinoid tumours, glucagonomers and various pituitary adenomas. It is also used to treat acromegaly (a condition characterized by excessive secretion of growth hormone in adults).
Short synthetic analogues of somatostatin (octreotide, lanreotide) used clinically (e.g. for the treatment of cancer, gastrointestinal disorders) interact primarily with sst2.
JR11 is an antagonist whose selectivity for sstr subtype 2 is under clinical development as a PET imaging agent when labelled with 68Ga and as a therapeutic agent if labelled with 177Lu.
Conclusion
The development of vasoactive peptide resulted in a landmark development when it comes to drug discovery and biomarker identification. The first vasoactive peptide angiotensin which got discovered in early part of this century resulted in an active development of angiotensin converting enzyme inhibitor .at the same time bradykinin got discovered which acts as a vasodilator from then onwards 30 odd vasoactive peptide got discovered resulting in an plethora of advancements with regards to therapeutic modalities. The above dissertation tries to shed some light into the evolving dynamic of vasoactive peptides and their role in drug discovery and biomarker development with the impending omics revolution and availability of large scale human genome, proteome, metabolome , microbiome, epigenome and transcriptome the process will only get expedited from now onwards at an exponential rate the complexity of human biological system and the advancement in molecular diagnostic tools would lead to development of thousands of advanced and precise biomarkers in the coming decade. The project aims to highlight only a few of them and thus tries to start a conversation regarding the potential of vasoactive peptides. Vasoactive peptides present a paradigm shift in understanding the diseases and their biomarkers and possible therapeutic interventions. Every technological development Vis a Vis medical progress takes off when three simultaneous events take place Technological feasibility, commercial viability and a push from the government. With the first two pieces of the puzzle getting solved in the next decade because of the rapid advancement in computational architecture, massive data storage capabilities and the impending insurance related revolution with regards to penetration of the products, the technology is at a prime when it comes to deploying the tech on a grand scale and only requires a significant amount of government spending. The coming together of all three will truly herald in the biomarkers and molecular diagnostics development over the next decade and truly enable the move towards the personalised medicine from the present one size fits all.
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