Overview of Generic Peptide

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Amylin

Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin (in a roughly 100:1 ratio).

1. Function

Amylin functions as part of the endocrine pancreas and contributes to glycemic control. Although amylin's complete function may not yet be known, it has been shown to slow gastric emptying, promote satiety, inhibit secretion of glucagon during hyperglycemia, and therein reduce the total insulin demand.[1][2] As insulin lowers blood glucose and glucagon raises blood glucose, amylin supports the stability of blood glucose levels in effect by slowing the rate that digested glucose enters the bloodstream.

Rodent amylin knockouts are known to fail to achieve the normal anorexia following food consumption. Because it is an amidated peptide, like many neuropeptides, it is believed to be responsible for the anorectic effect.

2. Structure

The human form of IAPP has the amino acid sequence KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, with a disulfide bridge between cysteine residues 2 and 7. The peptide is secreted from the pancreas into the blood circulation and eventually excreted by the kidneys. IAPP is capable of forming amyloid fibrils in vitro. Within the fibrillization reaction, the early prefibrillar structures are extremely toxic to insuloma cells cultures. Later amyloid fibril structures also seem to have some cytotoxic effect on cell cultures. Rats and mice have proline residues that prevent the formation of amyloid fibrils.

3. History

IAPP was identified independently by two groups as the major component of diabetes-associated islet amyloid deposits in 1987.[3][4]

4. Receptors

There appears to be at least three distinct receptor complexes that bind with high affinity to amylin. All three complexes contain the calcitonin receptor at the core, plus one of three Receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3.[5]

5. References

1. Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG (2004). "Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial". Diabet Med 21 (11): 1204-12.
2. http://www.symlin.com
3. Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB (1987). "Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients". Proc Natl Acad Sci USA 84 (23): 8628-32.
4. Westermark P, Wernstedt C, Wilander E, Hayden DW, O'Brien TD, Johnson KH (1987). "Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells". Proc Natl Acad Sci USA 84 (11): 3881-3885.
5. Hay DL, Christopoulos G, Christopoulos A, Sexton PM (2004). "Amylin receptors: molecular composition and pharmacology". Biochem Soc Trans 32 (5): 865-7.

6. Notes

• Chronic Oxidative Stress as a Central Mechanism for Glucose Toxicity in Pancreatic Islet Beta Cells in Diabetes. JBC Vol. 279, Issue 41, 42351-42354, October 8, 2004

7. External links

• Amylin
• PDB entry 1KUW for amylin
• Shen et al. "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism." (substrates include amylin)

Angiotensin

Angiotensin is an oligopeptide in the blood that causes vasoconstriction, increased blood pressure, and release of aldosterone from the adrenal cortex. It is a powerful dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. It plays an important role in the renin-angiotensin system.

Contents

1. Precursor, and types of angiotensin
    1.1. Angiotensinogen
    1.2. Angiotensin I
    1.3. Angiotensin II
    1.4. Angiotensin III
    1.5. Angiotensin IV
2. Effects of angiotensin
    2.1. Cardiovascular effects
    2.2. Neural effects
    2.3. Adrenal effects
    2.4. Renal effects
3. References
4. External links

1. Precursor, and types of angiotensin

1.1. Angiotensinogen

Angiotensinogen is a α-2-globulin that is produced constitutively and released into the circulation mainly by the liver, although other sites are thought to be involved also. It is a member of the serpin family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma corticosteroid, estrogen, thyroid hormone, and angiotensin II levels.

Angiotensinogen consist of 453 amino acid residues.

1.2. Angiotensin I

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

Angiotensin I (CAS# 11128-99-7) is formed by the action of renin on angiotensinogen. Renin is produced in the kidneys in response to both decreased intra-renal blood pressure at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa. If more Na+ is sensed, renin release is decreased.

Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the ten amino acid peptide (des-Asp) angiotensin I (CAS# 9041-90-1).
Angiotensin I appears to have no biological activity and exists solely as a precursor to angiotensin II.

1.3. Angiotensin II

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe | His-Leu

Angiotensin I is converted to angiotensin II through removal of two terminal residues by the enzyme Angiotensin-converting enzyme (ACE, or kininase), which is found predominantly in the capillaries of the lung.[1]

ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of angiotensin II production. Other cleavage products, 7 or 9 amino acids long, are also known; they have differential affinity for angiotensin receptors, although their exact role is still unclear. The action of angiotensin II itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin II AT1 receptors.

Angiotensin II is degraded to angiotensin III by angiotensinases that are located in red blood cells and the vascular beds of most tissues. It has a half-life in circulation of around 30 seconds, while in tissue, it may be as long as 15-30 minutes.

1.4. Angiotensin III

Asp | Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin III has 40% of the pressor activity of Angiotensin II, but 100% of the aldosterone-producing activity.

1.5. Angiotensin IV

Arg | Val-Tyr-Ile-His-Pro-Phe

Angiotensin IV is a hexapeptide which, like angiotensin III, has some lesser activity.

2. Effects of angiotensin

Angiotensins II, III & IV have a number of effects throughout the body:

2.1. Cardiovascular effects

It is a potent direct vasoconstrictor, constricting arteries and veins and increasing blood pressure.

Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and production of PAI-1 and PAI-2.[2][3]

It has been proposed that angiotensin II could be a cause of vascular and cardiac muscle hypertrophy (enlargement of the heart).

2.2. Neural effects

Angiotensin II increases thirst sensation (dipsogen) through the subfornical organ (SFO) of the brain, decreases the response of the baroreceptor reflex, and increases the desire for salt. It increases secretion of ADH in the posterior pituitary and secretion of ACTH in the anterior pituitary. It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers.

2.3. Adrenal effects

Angiotensin II acts on the adrenal cortex, causing it to release aldosterone, a hormone that causes the kidneys to retain sodium and lose potassium. Elevated plasma angiotensin II levels are responsible for the elevated aldosterone levels present during the luteal phase of the menstrual cycle.

2.4. Renal effects

Angiotensin II has a direct effect on the proximal tubules to increase Na+ resorption. Although it slightly inhibits glomerular filtration by indirectly (through sympathetic effects) and directly stimulating mesangial cell constriction, its overall effect is to increase the glomerular filtration rate by increasing the renal perfusion pressure via efferent renal arteriole constriction. Angiotensin II causes the release of prostaglandins from the kidneys.

3. References

1. Physiology at MCG
2. Skurk T, Lee YM,Hauner H. "Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture." Hypertension. 2001 May; 37(5):1336-40.
3. Gesualdo L, et al. "Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells." Kidney Int. 1999 Aug; 56(2):461-70.
• Brenner & Rector's The Kidney, 7th ed., Saunders, 2004.
• Mosby's Medical Dictionary, 3rd Ed., CV Mosby Company, 1990.
• Review of Medical Physiology, 20th Ed., William F. Ganong, McGraw-Hill, 2001.

4. External links

• Angiotensins

Argipressin

Arginine vasopressin (AVP is the official symbol [1]), also known as argipressin or antidiuretic hormone (ADH), is a human hormone that is released when the body is low on water; it causes the kidneys to conserve water, but not salt, by concentrating the urine and reducing urine volume. It also raises blood pressure by inducing moderate vasoconstriction. It has various effects in the brain.

A very similar substance, lysine vasopressin (LVP) or lypressin, has the same function in pigs and is often used in human therapy.

Vasopressin is a peptide hormone. It is derived from a preprohormone precursor that is synthesized in the hypothalamus, from which it is liberated during transport to the posterior pituitary. Most of it is stored in the posterior part of the pituitary gland to be released into the blood stream; some of it is also released directly into the brain.

Contents

1. Physiology
    1.1. Action
    1.2. Control
    1.3. Sources
    1.4. Effects on the Central Nervous System (CNS)
    1.5. Summary Table
2. Structure and relation to oxytocin
3. Role in disease
4. Pharmacology
    4.1. Vasopressin analogues
    4.2. Vasopressin receptor inhibition
5. References
6. Further Reading

1. Physiology

1.1. Action

AVP allows water reabsorption by the introduction of additional water channels in cortical and inner medullary collecting ducts.

1.2. Control

Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume and in response to increases in the plasma osmolality:

• Secretion in response to reduced plasma volume is activated by pressure receptors in the veins, atria, and carotids.

• Secretion in response to increases in plasma osmotic pressure is mediated by osmoreceptors in the hypothalamus.

The neurons that make vasopressin, in the supraoptic nucleus and paraventricular nucleus, are themselves osmoreceptors, but they also receive synaptic input from other osmoreceptors located in regions adjacent to the anterior wall of the third ventricle. These regions include the organum vasculosum of the lamina terminalis and the subfornical organ.

Many factors influence the secretion of vasopressin:

• Ethanol and caffeine reduce vasopressin secretion. The resulting decrease in water reabsorption by the kidneys leads to a higher urine output. Coffee is an example of a food product that supresses the body's release of antidiuretic hormones, due to its level of caffeine. This intake of caffeine causes the body to lose more water and may lead to dehydration if consumed excessively.

• Angiotensin II stimulates the secretion of vasopressin.[1]

1.3. Sources

The vasopressin that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of vasopressin-secreting tumours). However there are two other sources of vasopressin with important local effects:

• Vasopressin is secreted from parvocellular neurons of the paraventricular nucleus at the median eminence into the short portal vessels of the pituitary stalk. These vessels carry the peptide directly to the anterior pituitary gland, where it is an important releasing factor for ACTH, acting in conjunction with CRH.

• Vasopressin is also released into the brain by several different populations of neurons (see below).

1.4. Effects on the Central Nervous System (CNS)

Vasopressin released within the brain has many actions:

• It has been implicated in memory formation, including delayed reflexes, image, short- and long-term memory, though the mechanism remains unknown, and these findings are controversial. However, the synthetic vasopressin analogue desmopressin has come to interest as a likely nootropic.

• Vasopressin is released into the brain in a circadian rhythm by neurons of the suprachiasmatic nucleus of the hypothalamus.

• Vasopressin released from centrally-projecting hypothalamic neurons is involved in aggression, blood pressure regulation and temperature regulation.

In recent years there has been particular interest in the role of vasopressin in social behavior. It is thought that vasopressin, released into the brain during sexual activity, initiates and sustains patterns of activity that support the pair-bond between the sexual partners; in particular, vasopressin seems to induce the male to become aggressive towards other males.

Evidence for this comes from experimental studies in several species, which indicate that the precise distribution of vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In particular, there are consistent differences between monogamous species and promiscuous species in the distribution of vasopressin receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely-related species are compared. Moreover, studies involving either injecting vasopressin agonists into the brain, or blocking the actions of vasopressin, support the hypothesis that vasopressin is involved in aggression towards other males. There is also evidence that differences in the vasopressin receptor gene between individual members of a species might be predictive of differences in social behavior.

1.5. Summary Table

Here is a table summarizing some of the actions of Avp at its three receptors, differently expressed in different tissues and exerting different actions:

2. Structure and relation to oxytocin

The vasopressins are peptides consisting of nine amino acids (nonapeptides). (NB: the value in the table above of 164 amino acids is that obtained before the hormone is activated by cleavage). The amino acid sequence of arginine vasopressin is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly, with the cysteine residues forming a sulfur bridge. Lysine vasopressin has a lysine in place of the arginine.

The structure of oxytocin is very similar to that of the vasopressins: it is also a nonapeptide with a sulfur bridge and its amino acid sequence differs at only two positions (see table below). The two genes are located on the same chromosome separated by a relatively small distance of less than 15,000 bases in various species. The magnocellular neurons that make vasopressin are adjacent to magnocellular neurons that make oxytocin, and are similar in many respects. The similarity of the two peptides can cause some cross-reactions: oxytocin has a slight antidiuretic function, and high levels of vasopressin can cause uterine contractions.

Here is a table showing the superfamily of vasopressin and oxytocin neuropeptides:

3. Role in disease

Decreased vasopressin release or decreased renal sensitivity to vasopressin leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium content), polyuria (excess urine production), and polydipsia (thirst).

High levels of vasopressin secretion (syndrome of inappropriate antidiuretic hormone, SIADH) and resultant hyponatremia (low blood sodium levels) occurs in brain diseases and conditions of the lungs. In the perioperative period, the effects of surgical stress and some commonly used medications (e.g., opiates, syntocinon, anti-emetics) lead to a similar state of excess vasopressin secretion. This may cause mild hyponatraemia for several days.

4. Pharmacology

4.1. Vasopressin analogues

Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some forms of von Willebrand disease) and in extreme cases of bedwetting by children. Terlipressin and related analogues are used as vasocontrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970.[6]

Vasopressin infusion has been used as a second line of management in septic shock patients not responding to high dose of inotropes (e.g., dopamine or epinephrine). It had been shown to be more effective than epinephrine in asystolic cardiac arrest.[7] While not all studies are in agreement, a 2006 study of out-of hospital cardiac arrests has added to the evidence for the superiority of vasopressin in this situation.[8]

4.2. Vasopressin receptor inhibition

Demeclocycline, a tetracycline antibiotic, is sometimes used to block the action of vasopressin in the kidney in hyponatremia due to inappropriately high secretion of vasopressin (SIADH, see above), when fluid restriction has failed. A new class of medication (conivaptan, tolvaptan, relcovaptan, lixivaptan) acts by inhibiting the action of vasopressin on its receptors (V1 and V2), with tolvaptan acting on V1a and V2 and the remainder mainly on V1a receptors. The same class of drugs is also being studied in congestive heart failure.

5. References

1. Vander, A.J., Renal Physiology, McGraw-Hill, 1991.
2. Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice.Neuropsychopharmacology. 2004; 29:483-93.
3. Wersinger SR, Caldwell HK, Martinez L, Gold P, Hu SB, Young WS 3rd. Vasopressin 1a receptor knockout mice have a subtle olfactory deficit but normal aggression. Genes Brain Behav. 2006 Nov 3.
4. Lolait SJ, Stewart LQ, Jessop DS, Young WS 3rd, O'Carroll AM. The hypothalamic-pituitary-adrenal axis response to stress in mice lacking functional vasopressin V1b receptors. Endocrinology. 2007;148:849-56.
5. Wersinger SR, Kelliher KR, Zufall F, Lolait SJ, O'Carroll AM, Young WS 3rd. Social motivation is reduced in vasopressin 1b receptor null mice despite normal performance in an olfactory discrimination task. Horm Behav. 2004;46:638-45.
6. Baum S, Nusbaum M, Tumen HJ. The control of gastrointestinal hemorrhage by selective mesenteric infusion of pitressin. Gastroenterology 1970;58:926.
7. Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH; European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350:105-13.
8. Grmec S, Mally S. Vasopressin improves outcome in out-of-hospital cardiopulmonary resuscitation of ventricular fibrillation and pulseless ventricular tachycardia: an observational cohort study. Crit Care. 2006 Feb;10(1):R13.

6. Further Reading

• Brenner & Rector's The Kidney, 7th ed., Saunders, 2004.
• Caldwell, H.K. and Young, W.S., III. Oxytocin and Vasopressin: Genetics and Behavioral Implications in Lim, R. (ed.) Handbook of Neurochemistry and Molecular Neurobiology, 3rd edition, Springer, New York, pp. 573-607, 2006.

Bivalirudin

Bivalirudin is a drug that belongs to the anticoagulant class and acts as a direct thrombin inhibitor.

Chemically it constitutes a synthetic congener of the naturally occurring drug hirudin (found in the saliva of the medicinal leech Hirudo medicinalis).

Both bivalirudin and hirudin directly inhibit thrombin by specifically binding as well to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine protease that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release.

The pharmacological difference between both drugs is that Hirudin is an irreversible inhibitor of thrombin while Bivalirudin is a reversible one. This leads to a relatively small rate of severe bleedings under Bivalirudin compared to standard therapy (see below under section comparative results).

When delivered by i.v.-infusion with a rate of 2.5 mg/kg/hr, the mean steady-state-concentration is 12.4 µg/ml. 80% of the drug is proteolytically cleaved, and the remaining 20% is renally metabolized. The half-life of Bivalirudin is 25 minutes.

The clinical onset of action is almost immediate after i.v.-bolus. Bivalirudin prolongs a number of coagulation parameters due to its mode of action. These are the activated clotting time (ACT), the activated partial thromboplastin time (aPPT), the thrombin time (TT), and the prothrombin time (PTT). After termination of treatment the coagulation parameters return to normal within 1 to 2 hours indicating a short action of Bivalirudin resulting in a good controllability of therapy.

Calcitonin

Calcitonin is a 32 amino acid polypeptide hormone that is produced in humans primarily by the Parafollicular (also known as C) cells of the thyroid, and in many other animals in the ultimobranchial body.[1] It acts to reduce blood calcium Ca2+, opposing the effects of parathyroid hormone (PTH).

It has been found in fish, reptiles, birds and mammals. Its importance in humans has not been as well established as its importance in other animals.[2]

Contents

1. Biosynthesis
2. Physiology
3. Actions
4. Receptor
5. History
6. Pharmacology
    6.1. General characteristics of the active substance
    6.2. Characteristics in patients
    6.3. Preclinical safety data
7. Pharmaceutical manufacture
8. References

1. Biosynthesis

Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide which is the product of the CALC1 gene (CALCA). The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.

2. Physiology

The hormone participates in calcium (Ca2+) and phosphorus metabolism. In many ways, calcitonin has the counter effects of parathyroid hormone (PTH).

Specifically, calcitonin reduces blood Ca2+ levels in three ways:

• Decreasing Ca2+ absorption by the intestines[3]
• Decreasing osteoclast activity in bones[4]
• Decreasing Ca2+ and phosphate reabsorption by the kidney tubules[5]

3. Actions

Its actions, broadly, are:

• Bone mineral metabolism:
- Prevent postprandial hypercalcemia resulting from absorption of Ca2+ from foods during a meal
- Promote mineralization of skeletal bone
- Protect against Ca2+ loss from skeleton during periods of Ca2+ stress such as pregnancy and lactation

• Vitamin D regulation

• A satiety hormone:
- Inhibit food intake in rats and monkeys
- May have CNS action involving the regulation of feeding and appetite

4. Receptor

The calcitonin receptor is a G protein-coupled receptor which is coupled by Gs to adenylyl cyclase and thereby to the generation of cAMP in target cells.

5. History

Calcitonin was purified in 1962 by Copp and Cheney.[6] While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cells of the thyroid gland.

6. Pharmacology

Salmon calcitonin is used for the treatment of:

• Postmenopausal osteoporosis
• Hypercalcaemia
• Paget's disease
• Bone metastases
• Phantom limb pain [7]

The following information is from the UK Electronic Medicines Compendium [8]

6.1. General characteristics of the active substance

Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.

Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).

Calcitonin has short absorption and elimination half-lives of 10-15 minutes and 50-80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30 to 40%.

6.2. Characteristics in patients

There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea and vomiting.

6.3. Preclinical safety data

Conventional long term toxicity, reproduction, mutagenicity and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic and mutagenic potential.

An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.
In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.

7. Pharmaceutical manufacture

Historically, it was extracted from the Ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. Currently it is produced either by recombinant DNA technology or by chemical peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.[8]

8. References

1. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_21.htm
2. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_23.htm
3. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_26.htm
4. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_24.htm
5. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_25.htm
6. Copp DH, Cheney B. Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood. Nature 1962; 193: 381-2.
7. "Calcitonin in phantom limb pain": Ann Pharmacother. 1999 Apr; 33(4): 499-501
8. http://emc.medicines.org.uk/UK Electronic Medicines Compendium

Cetrorelix

Cetrorelix acetate is a gonadotropin-releasing hormone antagonist (GnRH antagonist). A synthetic decapeptide, it is used to treat hormone-sensitive cancers of the prostate and breast (in pre-/perimenopausal women) and some benign gynaecological disorders (endometriosis, uterine fibroids and endometrial thinning). In addition, cetrorelix is used in assisted reproduction. The drug works by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of LH and FSH.

Desmopressin

Desmopressin is a synthetic drug that mimics the action of antidiuretic hormone.

1. Chemistry

Desmopressin (1-desamino-8-d-arginine vasopressin) is a modified form of the normal human hormone arginine vasopressin, a peptide containing nine amino acids.

Compared to vasopressin, desmopressin's first amino acid has been deaminated, and the arginine at the eighth position is in the dextro rather than the levo form.

2. Method of action

Desmopressin binds to V2 receptors in renal collecting ducts, increasing water resorption. It also stimulates release of factor VIII from endothelial cells due to stimulation of the V1a receptor.

Desmopressin is degraded more slowly than recombinant vasopressin, and requires less frequent administration. In addition, it has little effect on blood pressure, while vasopressin may cause arterial hypertension.

3. Uses

Desmopressin is used to reduce urine production in central diabetes insipidus patients and to promote the release of von Willebrand factor and factor VIII in patients with coagulation disorders such as type I von Willebrand disease, mild hemophilia A, and thrombocytopenia. Desmopressin is not effective in the treatment of hemophilia B or severe hemophilia A.

It may also be prescribed to reduce frequent bedwetting episodes in children and adults with Enuresis by decreasing nocturnal urine production.
It has also seen interest as a possible nootropic.

4. References

Leissinger C, Becton D, Cornell C Jr, Cox Gill J. High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A. Haemophilia 2001;7:258-66.

Enfuvirtide

Enfuvirtide (INN) is an HIV fusion inhibitor, the first of a novel class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection.

1. Pharmacology

1.1. Mechanism of action

Enfuvirtide works by disrupting the HIV-1 molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected. A biomimetic peptide, enfuvirtide was rationally designed to mimic components of the HIV-1 fusion machinery and displace them, preventing normal fusion. Drugs that disrupt fusion of virus and target cell are termed entry inhibitors or Fusion inhibitors. HIV binds to host cell receptor CD4+ by the protein GP120; upon binding, GP120 deforms allowing the viral protein GP41 to inbed itself into the host cell's plasma membrane, entry inhibitors bind to GP41 preventing the creation of an entry pore for the capsid of the virus keeping it out of the cell. [1]

1.2. Microbiology

Enfuvirtide is considered to be active against HIV-1 only. Low activity against HIV-2 isolates has been demonstrated in vitro.[1]
Variable susceptibility to enfuvirtide has been observed in clinical isolates, with acquired resistance the result of a mutated 10 amino acid motif in viral gp41. Primary resistance, however, has yet to be observed.[2]

2. References

1. Roche Products Pty Ltd. Fuzeon (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.

2. Greenberg ML, Cammack N. Resistance to enfuvirtide, the first HIV fusion inhibitor. J Antimicrob Chemother 2004;54(2):333-40.

Glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) is derived from the transcription product of the proglucagon gene. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. The biologically active forms of GLP-1 are: GLP-1-(7-37) and GLP-1-(7-36)NH2.

GLP-1 secretion by L cells is dependent on the presence of nutrients in the lumen of the small intestine. The secretagogues (agents that causes or stimulates secretion) of this hormone include major nutrients like carbohydrate, protein and lipid. Once in the circulation, GLP-1 has a half life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4.

1. Physiological functions

GLP-1 possesses several physiological properties that make it a subject of intensive investigation as a potential treatment of diabetes mellitus.[1][2][3]. The known physiological functions of GLP-1 include:

• increases insulin secretion from the pancreas in a glucose-dependent manner.
• decreases glucagon secretion from the pancreas.
• increases beta cells mass and insulin gene expression.
• inhibits acid secretion and gastric emptying in the stomach.
• decreases food intake by increasing satiety.

2. References

1. "Diabetes and Intestinal Incretin Hormones: A New Therapeutic Paradigm" at medscape.com
2. Toft-Nielsen M, Madsbad S, Holst J (2001). "Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes.". J Clin Endocrinol Metab 86 (8): 3853-60.
3. Meier J, Weyhe D, Michaely M, Senkal M, Zumtobel V, Nauck M, Holst J, Schmidt W, Gallwitz B (2004). "Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes.". Crit Care Med 32 (3): 848-51.

3. External links

• GLP-1
• Glucagon-Like+Peptide+1

Glucagon

Glucagon is an important hormone involved in carbohydrate metabolism. Produced by the pancreas, it is released when the glucose level in the blood is low (starvation), causing the liver to convert stored glycogen into glucose and release it into the bloodstream. The action of glucagon is thus opposite to that of insulin, which instructs the body's cells to take in glucose from the blood in times of satiation.

Contents

1. History
2. Structure
3. Physiology
    3.1. Production
    3.2. Regulatory mechanism
    3.3. Function.
    3.4. Mechanism of action
4. Pathology 
5. References

1. History

In the 1920s, Kimball and Murlin studied pancreatic extracts and found an additional substance with hyperglycemic properties. They described glucagon in 1923.[1] The amino acid sequence of glucagon was described in the late-1950s.[2] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.

2. Structure

Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-Phe- Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser- Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu- Met-Asn-Thr-COOH.

The polypeptide has a molecular weight of 3485 daltons.

3. Physiology

3.1 Production

The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. The alpha cells are located in the outer rim of the islet.

3.2. Regulatory mechanism

Increased secretion of glucagon is caused by:

• Decreased plasma glucose

• Increased catecholamines - norepinephrine and epinephrine

• Increased plasma amino acids (to protect from hypoglycemia if an all protein meal consumed)

• Sympathetic nervous system

• Acetylcholine

• Cholecystokinin

Decreased secretion of glucagon (inhibition) is caused by:

• Somatostatin

• Insulin

3.3. Function

Glucagon helps maintain the level of glucose in the blood by binding to glucagon receptors on hepatocytes, causing the liver to release glucose - stored in the form of glycogen - through a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by gluconeogenesis. This glucose is released into the bloodstream. Both of these mechanisms lead to glucose release by the liver, preventing the development of hypoglycemia.

• Increased free fatty acids and ketoacids into the blood

• Increased urea production

3.4. Mechanism of action

Glucagon binds to the glucagon receptor, a G protein-coupled receptor located in the plasma membrane. The conformation change in the receptor activates G proteins, a heterotrimeric protein with alpha, beta and gamma subunits. The subunits breakup under GTP hydrolysis and the alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cAMP (cyclical AMP) which activates protein kinase A (cAMP-dependent protein kinase). This enzyme in turn activates phosphorylase B kinase, which in turn, phosphorylates phosphorylase B. Phosphorylase B is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.

4. Pathology

Abnormally-elevated levels of glucagon may be caused by pancreatic tumors such as glucagonoma, symptoms of which include necrolytic migratory erythema (NME), elevated amino acids and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1.

5. References

1.  Kimball C, Murlin J. Aqueous extracts of pancreas III. Some precipitation reactions of insulin. J Biol Chem 1923; 58:337-348.

2.  Bromer W, Winn L, Behrens O. The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence. J Am Chem Soc 1957; 79:2807-2810.

Gonadorelin

Gonadotropin-releasing hormone 1 (GNRH1), also known as Luteinising-hormone releasing hormone (LHRH), is a peptide hormone responsible for the release of FSH and LH from the anterior pituitary. GNRH1 is synthesized and released by the hypothalamus.

Contents

1. Gene
2. Structure
3. GNRH1 as a neurohormone
4. Control of FSH and LH
5. Activity
6. GNRH1 in other organs
7. Agonists and antagonists
8. References

1. Gene

The gene, GNRH1, for the GNRH1 precursor is located on chromosome 8. This precursor contains 92 amino acids and is processed to GNRH1, a decapeptide (10 amino acids) in mammals. This chain is represented by: pGlu-His-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

GnRH was previously called LHRH.

2. Structure

The identity of GNRH1 was clarified by the 1977 Nobel Laureates Roger Guillemin and Andrew V. Schally: pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly CONH2.

3. GNRH1 as a neurohormone

GNRH1 is considered a neurohormone, a hormone produced in a specific neural cell and released at its neural terminal. A key area for production of GNRH1 is the preoptic area of the hypothalamus, that contains most of the GNRH1-secreting neurons. GNRH1 is secreted in the hypophysial portal bloodstream at the median eminence. The portal blood carries the GNRH1 to the pituitary gland, which contains the gonadotrope cells, where GNRH1 activates its own receptor, gonadotropin-releasing hormone receptor (GNRHR), located in the cell membrane.

GNRH1 is degraded by proteolysis within a few minutes.

4. Control of FSH and LH

At the pituitary, GNRH1 stimulates the synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These processes are controlled by the size and frequency of GNRH1 pulses, as well as by feedback from androgens and estrogens. Low frequency GNRH1 pulses lead to FSH release, whereas high frequency GNRH1 pulses stimulate LH release.

There are differences in GNRH1 secretion between males and females. In males, GNRH1 is secreted in pulses at a constant frequency, but in females the frequency of the pulses varies during the menstrual cycle and there is a large surge of GNRH1 just before ovulation.

GNRH1 secretion is pulsatile in all vertebrates, and is necessary for correct reproductive function. Thus, a single hormone, GNRH1, controls a complex process of follicular growth, ovulation, and corpus luteum maintenance in the female, and spermatogenesis in the male.

5. Activity

GNRH1 activity is very low during childhood, and is activated at puberty. During the reproductive years, pulse activity is critical for successful reproductive function as controlled by feedback loops. However, once a pregnancy is established, GNRH1 activity is not required. Pulsatile activity can be disrupted by hypothalamic-pituitary disease, either dysfunction (i.e., hypothalamic suppression) or organic lesions (trauma, tumor). Elevated prolactin levels decrease GNRH1 activity. In contrast, hyperinsulinemia increases pulse activity leading to disorderly LH and FSH activity, as seen in Polycystic ovary syndrome (PCOS). GNRH1 formation is congenitally absent in Kallmann syndrome.

The GNRH1 neurons are regulated by many different afferent neurons, using several different transmitters (including norepinephrine, GABA, glutamate). For instance, dopamine appears to stimulate LH release (through GnRH) in estrogen-progesterone primed females; dopamine may inhibit LH release in ovariectomized females.[1] Kisspeptin appears to be an important regulator of GNRH release.[2] GNRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.[3]

6. GNRH1 in other organs

GNRH1 is found in organs outside of the hypothalamus and pituitary and its role in other life processes is poorly understood. For instance, there is likely to be a role for GNRH1 in the placenta and in the gonads.

7. Agonists and antagonists

While GNRH1 has been synthesized and become available, its short half-life requires infusion pumps for its clinical use. Modifications of the decapeptide structure of GNRH1 have led to GNRH1 analog medications that either stimulate (GNRH1 agonists) or suppress (GNRH1 antagonists) the gonadotropins. It is important to note that, through downregulation, agonists are also able to exert a prolonged suppression effect.

8. References

1. R.E. Brown. An Introduction to Neuroenocrinology; Cambridge University Press 1994.
2. H. M. Dungan, D. K. Clifton and R. A. Steiner (2006) "Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion" in Endocrinology Volume 147, pages 1154-1158
3. I. Franceschini, D. Lomet, M. Cateau, G. Delsol, Y. Tillet and A. Caraty (2006) "Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha" in Neurosci Lett. 2 Volume 401, pages 225-230.

Goserelin

Goserelin is a GnRH analogue. It is chemically similar to the body's natural GnRH though it has a greatly extended half-life. After administration, peak serum concentrations are reached in about two hours. It rapidly binds to the GnRH receptor cells in the pituitary gland thus leading to an initial increase in production of luteinizing hormone and thus leading to an initial increase in the production of corresponding sex hormones. Eventually, after a period of about 14-21 days, production of LH is greatly reduced due to receptor downregulation, and sex hormones are generally reduced to castrate levels.

References

Kotake, Toshihiko; Michiyuki Usami, Hideyuki Akaza et al. (August 1999). "Goserelin Acetate with or without Antiandrogen or Estrogen in the Treatment of Patients with Advanced Prostate Cancer: a Multicenter, Randomized, Controlled Trial in Japan". Japanese Journal of Clin. Oncol. 29 (11): 562-570.

Leuprorelin

Leuprorelin or leuprolide acetate is a gonadotropin-releasing hormone agonist (GnRH agonist).

1. Mode of action

By causing constant stimulation of the pituitary GnRH receptors, it initially causes stimulation (flare), but thereafter decreases pituitary secretion (downregulation) of gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

2. Clinical usage

Like other GnRH agonists, leuprolide may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), to treat precocious puberty, and to control ovarian stimulation in IVF. It is considered a possible treatment for paraphilias.[1] Recently, it has been suggested as a possible treatment for autism where testosterone may have a synergistic effect on mercury toxicity,[2] although this is currently regarded as medical hypothesis.

3. References

1.  Saleh F, Niel T, Fishman M (2004). "Treatment of paraphilia in young adults with leuprolide acetate: a preliminary case report series.“ J Forensic Sci 49 (6): 1343-8.
2.  Geier M, Geier D (2005). "The potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity.” Med Hypotheses 64 (5): 946-54.

Nafarelin

Nafarelin is a gonadotropin-releasing hormone agonist (GnRH agonist). By causing constant stimulation of the pituitary, it decreases pituitary secretion of gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). Nafarelin may be used in the treatment of estrogen-dependent conditions (such as endometriosis or uterine fibroids), to treat central precocious puberty, and to control ovarian stimulation in IVF.

Oxytocin

Oxytocin is a mammalian hormone that also acts as a neurotransmitter in the brain. In women, it is released mainly after distension of the cervix and vagina during labor, and after stimulation of the nipples, facilitating birth and breastfeeding, respectively. Oxytocin is released during orgasm in both sexes. In the brain, oxytocin is involved in social recognition and bonding, and might be involved in the formation of trust between people.

Contents

1. Synthesis, storage and release
    1.1. Structure and relation to vasopressin
2. Actions
    2.1. Peripheral (hormonal) actions
    2.2. Actions of oxytocin within the brain 
3. Evolution
4. References

1. Synthesis, storage and release

Oxytocin is made in magnocellular neurosecretory cells in the supraoptic nucleus and paraventricular nucleus of the hypothalamus and is released into the blood from the posterior lobe of the pituitary gland. Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.

In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I as shown in the inset of the figure; neurophysin is a large peptide fragment of the giant precursor protein molecule from which oxytocin is derived by enzymatic cleavage.

Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.

1.1. Structure and relation to vasopressin

Oxytocin is a peptide of nine amino acids (a nonapeptide). The sequence is cysteine - tyrosine - isoleucine - glutamine - asparagine - cysteine - proline - leucine - glycine (CYIQNCPLG). The cysteine residues form a sulfur bridge. Oxytocin has a molecular mass of 1007 daltons. One international unit (IU) of oxytocin is the equivalent of about 2 micrograms of pure peptide.

The structure of oxytocin is very similar to that of vasopressin (cysteine - tyrosine - phenylalanine - glutamine - asparagine - cysteine - proline - arginine - glycine), also a nonapeptide with a sulfur bridge, whose sequence differs from oxytocin by 2 amino acids. A table showing the sequences of members of the vasopressin/oxytocin superfamily and the species expressing them is present in the vasopressin article. Oxytocin and vasopressin were discovered, isolated and synthesized by Vincent du Vigneaud in 1953, work for which he received the Nobel Prize in Chemistry in 1955.

Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other peptides, including corticotropin-releasing hormone (CRH) and dynorphin, for example, that act locally. The magnocellular neurons that make oxytocin are adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.

2. Actions

Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. The actions of oxytocin are mediated by specific, high affinity oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor which requires Mg2+ and cholesterol. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.

2.1. Peripheral (hormonal) actions

The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. (See oxytocin receptor for more detail on its action.)

• Letdown reflex – in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be 'let down' into a collecting chamber, from where it can be extracted by sucking at the nipple. Sucking by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituitary gland.

• Uterine contraction – important for cervical dilation before birth and causes contractions during the second and third stages of labor. Oxytocin release during breastfeeding causes mild but often painful uterine contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition is normal.[1]

• Oxytocin is secreted into the blood at orgasm – in both males and females.[2] In males, oxytocin may facilitate sperm transport in ejaculation.

• Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. More important, in several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and in humans, high doses of oxytocin can result in hyponatremia.

• Oxytocin and oxytocin receptors are also found in the heart in some rodents, and the hormone may play a role in the embryonal development of the heart by promoting cardiomyocyte differentiation. [3][4] However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.[1]

2.2. Actions of oxytocin within the brain

Oxytocin secreted from the pituitary gland cannot re-enter the brain because of the blood-brain barrier. Instead, the behavioral effects of oxytocin are thought to reflect release from centrally-projecting oxytocin neurons, different from those that project to the pituitary gland. Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum and brainstem.

• Sexual arousal. Oxytocin injected into the cerebrospinal fluid causes spontaneous erections in rats,[5] reflecting actions in the hypothalamus and spinal cord.

• Bonding. In the Prairie Vole, oxytocin released into the brain of the female during sexual activity is important for forming a monogamous pair bond with her sexual partner. Vasopressin appears to have a similar effect in males [6]. In people, plasma concentrations of oxytocin have been reported to be higher amongst people who claim to be falling in love. Oxytocin has a role in social behaviors in many species, and so it seems likely that it has similar roles in humans.

• Autism. It has been suggested that deficiencies in oxytocin pathways in the brain might be a feature of autism. A recent study found a decrease in autism spectrum repetitive behaviors when oxytocin was administered intravenously[7].

• Maternal behavior. Sheep and rat females given oxytocin antagonists after giving birth do not exhibit typical maternal behavior. By contrast, virgin sheep females show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. [8]

• Various anti-stress functions. Oxytocin reduces blood pressure and cortisol levels, increasing tolerance to pain, and reducing anxiety. Oxytocin may play a role in encouraging "tend and befriend", as opposed to "fight or flight", behavior, in response to stress.

• Increasing trust and reducing fear. In a risky investment game, experimental subjects given nasally administered oxytocin displayed "the highest level of trust" twice as often as the control group. Subjects who were told that they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk-aversion.[9] Nasally-administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses).[10] There is no conclusive evidence for access of oxytocin to the brain through intranasal administration, however.

• According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms.[11]

• Preparing fetal neurons for delivery. Crossing the placenta, maternal oxytocin reaches the fetal brain and induces a switch in the action of neurotransmitter GABA from excitatory to inhibitory on fetal cortical neurons. This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage.[12]

• Certain learning and memory functions are impaired by centrally-administered oxytocin.[5]

3. Evolution

Virtually all vertebrates have an oxytocin-like nonapeptide hormone that supports reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are always located close to each other (less than 15,000 bases apart) on the same chromosome and are transcribed in opposite directions. It is thought that the two genes resulted from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomes (modern members of the Agnatha).[5]

4. References

1. Takayanagi Y et al. (2005) Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci USA 102:16096-101
2. Carmichael MS, Humbert R, Dixen J, Palmisano G, Greenleaf W, Davidson JM. (1987) Plasma oxytocin increases in the human sexual response. J Clin Endocrinol Metab 64:27-31
3. Paquin J et al.(2002) Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes. Proc Natl Acad Sci USA 99:9550-5
4. Jankowski et al. (2004) Oxytocin in cardiac ontogeny. Proc Natl Acad Sci USA 101:13074-9
5. Gimpl G, Fahrenholz F. (2001) The oxytocin receptor system: structure, function, and regulation. Physiological Reviews 81
6. Vacek M, High on Fidelity. What can voles teach us about monogamy?
7. Hollander E, Oxytocin Infusion Reduces Repetitive Behaviors in Adults with Autistic and Asperger’s Disorders
8. Kendrick KM, The Neurobiology of Social Bonds
9. Kosfeld M et al. (2005) Oxytocin increases trust in humans. Nature 435:673-676.
10. Kirsch P et al. (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489-93
11. Kovacs GL, Sarnyai Z, Szabo G. (1998) Oxytocin and addiction: a review. Psychoneuroendocrinology 23:945-62
12. Tyzio R et al.(2006) Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain During Delivery. Science 314: 1788-1792

Secretin

Secretin is a peptide hormone produced in the S cells of the duodenum in the crypts of Lieberkühn. Its primary effect is to regulate the pH of the duodenal contents via the control of gastric acid secretion and buffering with bicarbonate. It was the first hormone ever discovered.

1. Stimulus

Secretin is secreted in response to low duodenal pH due to chyme, which contains hydrochloric acid, entering from the stomach.

2. Function

Secretin stimulates the secretion of bicarbonate (base) from the liver, pancreas, and duodenal Brunner's glands in order to buffer the incoming protons of the acidic chyme. It also enhances the effects of cholecystokinin. It is known to promote the normal growth and maintenance of the pancreas.

It counteracts blood glucose concentration spikes by triggering increased insulin release, following oral glucose intake.[1]

It also reduces acid secretion from the stomach by inhibiting gastrin release from G cells. This helps neutralize the pH of the digestive products entering the duodenum from the stomach, as digestive enzymes from the pancreas (eg, pancreatic amylase and pancreatic lipase) function optimally at neutral pH.

3. Structure

Secretin is a peptide hormone, comprised of 27 amino acids, of which 14 amino acids are homologous to the sequence of glucagon.

4. History

In 1902, William Bayliss and Ernest Starling were studying how the nervous system controls the process of digestion. It was known that the pancreas secreted digestive juices in response to the passage of food into the duodenum. They discovered (by cutting all the nerves to the pancreas in their experimental animals) that this process was not, in fact, governed by the nervous system. They determined that a substance secreted by the intestinal lining stimulates the pancreas after being transported via the bloodstream. They named this intestinal secretion secretin. Secretin was the first such "chemical messenger" identified. This type of substance is now called a hormone, a term coined by Bayliss in 1905.

5. References

1.  Kraegen EW, Chisholm DJ, Young JD, Lazarus L (1970). "The gastrointestinal stimulus to insulin release. II. A dual action of secretin". J. Clin. Invest. 49 (3): 524-9.  

6. External links

• Overview at colostate.edu
• Secretin
• Physiology at MCG

Somatostatin

Somatostatin (also known as growth hormone inhibiting hormone (GHIH) or somatotropin release-inhibiting hormone (SRIF)) is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.

Somatostatin has two active forms produced by alternative cleavage of a single preproprotein: one of 14 amino acids, the other of 28 amino acids.[1]

Contents

1. Production
   1.1. Digestive system
   1.2. Brain
2. Actions
3. Synthetic substitutes
4. References

1. Production

1.1. Digestive system

Somatostatin is secreted in several locations in the digestive system:

• stomach
• intestine
• delta cells of the pancreas[2]

1.2. Brain

Somatostatin is produced by neuroendocrine neurons of the periventricular nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamo-hypophysial portal circulation. These blood vessels carry somatostatin to the anterior pituitary gland, where somatostatin inhibits the secretion of growth hormone from somatotrope cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatin neurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone.

Somatostatin is also produced by several other populations that project centrally - i.e. to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, there are populations of somatostatin neurons in the arcuate nucleus, the hippocampus and the brainstem nucleus of the solitary tract.

2. Actions

Somatostatin is classified as an inhibitory hormone,[1] whose main actions are to:

• Inhibit the release of growth hormone (GH)[3] (thus opposing the effects of Growth Hormone-Releasing Hormone (GHRH))

• Inhibit the release of thyroid-stimulating hormone (TSH)

• Suppress the release of gastrointestinal hormones

• Gastrin
• Cholecystokinin (CCK)
• Secretin
• Motilin
• Vasoactive intestinal peptide (VIP)
• Gastric inhibitory polypeptide (GIP)
• Enteroglucagon (GIP)

• Lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine [3]

• Suppress the release of pancreatic hormones

• Inhibit the release of insulin[4]
• Inhibit the release of glucagon[4]

• Suppress the exocrine secretory action of pancreas.

3. Synthetic substitutes

Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octopeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone.

4. References

1. Physiology at MCG 5/5ch4/s5ch4_16
2. Costanzo, LS. Board Review Series: Physiology 3rd Ed. Lippincott, Williams & Wilkins. 2003. p. 280.
3. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/otherendo/somatostatin.html
4. Physiology at MCG 5/5ch4/s5ch4_17

Triptorelin

Triptorelin (acetate or palmoate) is a gonadotropin releasing hormone agonist (GnRH agonist). By causing constant stimulation of the pituitary, it decreases pituitary secretion of gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). Like other GnRH agonists, triptorelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, precocious puberty, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction.

References

• Pharmacokinetics and pharmacodynamics of GnRH agonists: clinical implications in pediatrics. J Pediatr Endocrinol Metab. 2000 Jul;13 Suppl 1:723-37.