Endocrine Physiology PDF

ENDOCRINE PHYSIOLOGY Ahmed H. Arisha DVM. M.SC. Ph.D. Vice Dean for Education and Student Affairs Associate Professor of Physiology [email protected] Tel:01007857984  Syllabus Endocrine Physiology 2 Reproductive Phy...

ENDOCRINE PHYSIOLOGY Ahmed H. Arisha DVM. M.SC. Ph.D. Vice Dean for Education and Student Affairs Associate Professor of Physiology [email protected] Tel:01007857984  Syllabus Endocrine Physiology 2 Reproductive Physiology 3 Nervous System Physiology 3 Urinary Physiology 1 Digestive Physiology 2 Temperature and metabolism regulation & Avian and fish Physiology 1 Endocrine system definition ◼ The internal chemical communication system involving hormones ◼ Hormone ❑ Chemical signal secreted into body fluids (usually blood) ❑ Effective in minute amounts  Integration of Body Functions  Two regulatory systems coordinate internal body functions  Nervous system Rapid onset  Short duration  Endocrine system  Slow onset  Long duration  nervous and endocrine systems are similar Nervous and Endocrine Systems ◼ Act together to coordinate functions of all body systems ◼ Nervous system ❑ Nerve impulses/ Neurotransmitters ❑ Faster responses, briefer effects, acts on specific target ◼ Endocrine system ❑ Hormone – mediator molecule released in 1 part of the body but regulates activity of cells in other parts ❑ Slower responses, effects last longer, broader influence  Communication between cells in multicellular organisms For a multicellular organism to survive it must be able to respond to changes in the external and internal environment ----- individual cells must be able to communicate with one another Communication between cells occurs via 4 distinct mechanisms Cell-to-cell communication via gap junctions in the plasma membrane Paracrine control via locally acting chemical signals Electrical signals via the nervous system By chemical signals (hormones) released into the bloodstream Manipulation of the Endocrine System ◼Hormones can be used to regulate body functions ❑ growth (anabolic steroids) ❑ lactation (GH or STH) ❑ birth control (Estradiol, Progesterone) ❑ estrous cycle (PGF2) ❑ superovulation and embryo transplant (FSH,eCG) ❑ parturition (oxytocin) Endocrine Glands ◼ 2 kinds of glands ❑ Exocrine – ducted ❑ Endocrine – ductless ◼ Secrete products into interstitial fluid, diffuse into blood ◼ Endocrine glands include ❑ Pituitary, thyroid, parathyroid, adrenal and pineal glands ❑ Hypothalamus, thymus, pancreas, ovaries, testes, kidneys, stomach, liver, small intestine, skin, heart, adipose tissue, and placenta not exclusively endocrine glands Endocrine Gland A ductless gland Secretes substances (hormones) into blood or lymph that affect cells elsewhere in the body The secretion does not involve loss of tissue  Hormone ◼Substance produced by endocrine gland ◼Acts on cells, tissues or organs at a place other than where produced ◼Acts as a catalyst. ◼ Hormones are information transferring molecules which move from one cell to another for the benefit of the organism as a whole. Endocrine Cell H Target Cell ◼ General concepts ◼ 1. Hormones are chemicals produced by specific tissues that are transported by the vascular system to affect other tissues at low concentrations. ◼ 2. The endocrine and nervous systems are integrated in their control of physiological processes. ◼ Synthesis of hormones ◼ 1. Protein hormones are initially synthesized as preprohormones and then cleaved in the rough endoplasmic reticulum to form prohormones and in the Golgi apparatus to form the active hormones, which are stored in granules before being released by exocytosis. ◼ 2. Steroids are synthesized from cholesterol, which is synthesized by the liver; steroids are not stored but are released as they are synthesized. ◼ Transport of hormones in the blood ◼ 1. Protein hormones are hydrophilic and carried in the plasma in dissolved form. ◼ 2. Steroids and thyroid hormones are lipophilic and carried in plasma in association with both specific and nonspecific binding proteins; the amount of unbound, active hormone is relatively small. ◼ Hormone-cell interaction ◼ 1. Protein hormones have specific receptors on target tissue plasma membranes ◼ 2. steroids have specific receptors within the cytoplasm or nucleus. ◼ Postreceptor cell responses ◼ 1. Steroids interact directly with the cell nucleus through the formation of a complex with its cytosolic receptor, ◼ 2. protein hormones need a messenger because they cannot enter the cell. ◼ Feedback control mechanisms ◼ 1. The most important feedback control for hormones is the negative feedback system, in which increased hormone concentrations result in less production of the hormone, usually through an interaction with the hypothalamus or pituitary gland. ◼ 2. Endocrine secretory patterns can be influenced by factors such as sleep or light and can produce circadian rhythms. General features of hormones 1) A specific chemical substance 2) Secreted by ductless gland 3) In a catalytic amount (very small amounts) 4) Transported by the blood (directly or through lymphatics), To a specific target cells (which have a specific hormone receptors), 5) Where it produces: ▪ physiologic, ▪ morphologic and ▪ biochemical responses Physiological effects of hormones are proportional to hormone concentration The magnitude of the response to a hormone is determined by: The concentration of the hormone at the surface of the target cell, which in turn depends 100% on the rate of production (under the control of positive and negative feedback loops); the rate of delivery (dependent on blood flow); and the 50% rate of metabolism, degradation and elimination. The sensitivity of the target cell. The number of functional target cells. The availability of cell membrane receptors on target cells The plasma half-life of a hormone (time needed for the concentration of the hormone to decrease to its half) Hormones: ◼ do not initiate reactions but rather they effect the rate of pre-existing metabolic functions in a positive or negative fashion ◼ some hormones have specific effects on a single cell type, others a more general effect ◼ hormones are effective at minute concentrations - range 10-12 to 10-8 M ◼ hormones have a very short half-life in circulation ( ranging from minutes to hours)  Hormone concentration ◼ Hormones are inactivated or degraded to an inactive form (H*)at a constant rate ◼ It follows that the level of hormone in circulation is dependent on the rate of secretion Endocrine Cell [H] Target Cell H*  Physiological effects of hormones are timed responses ◼ The effects of hormones Hormone occur in a regulated and and Physiological Response Physiol. timed manner Hormone Concentration Response ◼ Hormone levels increase in response to a physiological signal which results in an increased secretion of hormone ◼ hormone levels decrease when secretion ceases Time Hormone Activity ◼ Hormones affect only specific target tissues with specific receptors ◼ Receptors constantly synthesized and broken down ❑ Up-regulation: stimulation of receptor synthesis; ❑ Down-regulation: internalisation of receptors by endocytosis; suppression of receptor synthesis. ◼ Hormone types ❑ Circulating – circulate in blood throughout body ❑ Local hormones – act locally ◼ Paracrine – act on neighboring cells ◼ Autocrine – act on the same cell that secreted them Classification and Properties of Hormone A. Site of Production B. Type of action 1. Primary hormone of reproduction (FSH, LH, estradiol, progesterone) 2. Metabolic hormone (thyroxin, insulin, TSH) C. Chemical Structure 1. General structure ◼ Proteins and polypeptides ◼ Steroids ◼ Fatty acids ◼ Modified amino acid 2. Size A. Site of Production Hypothalamus: releasing peptide hormone acting on the anterior pituitary : GHRH, CRH, TRH GnRH Anterior Pituitary: Growth Hormone (GH), Corticotrophin (ACTH), Thyroid Stimulating hormone (TSH), Luteinizing hormone (LH), Follicle stimulating hormone (FSH) Posterior Pituitary: oxytocin, vasopressin (ADH) Pancreatic Islets of Langerhans: insulin and glucagon Adrenal cortex: aldosterone and cortisol Adrenal Medulla: Adrenaline and Noradrenaline Thyroid Gland: thyroxine and Tri-iodothyronine Testis: testosterone (androgen) Ovary and placenta: oestradiol (oestrogens), progesterone  Chemical Structure of Hormones polypeptide modified amino acid protein sex steroid fatty acid GnRH melatonin LH Estradiol PGF2 TRH FSH Progesterone CRH Prolactin Testosterone GHRH ACTH Somatistatin TSH Oxytocin GH or STH Relaxin Inhibin hypothalamic pineal pituitary, gonad, many gonad adrenal sources Chemical Structure of Hormones Molecular size of hormones that regulate reproduction Hormone Molecular Weight FSH 30,000 to 37,000 LH 26,000 to 32,000 Prolactin 23,000 to 25,000 HCG 37,700 eCG 28,000 Inhibin >10,000 Relaxin 6,500 ACTH 4,500 Oxytocin 1,007 GnRH 1,200 Estradiol 300 Testosterone 300 Progesterone 300 PGF2 300 Synthesis & Storage of Hormones Most endocrine glands produce their hormones continually at levels determined by: a) Body requirements. b) Rate of hormone inactivation. c) Rate of hormone clearance from the body.  Hormone Transport The released hormones enter the blood, where they may circulate in 2 forms:  1. Free (unbound) part: the active part which binds to receptor.  2. Bound part: carried by specific albumins and globulins which are synthesized in the liver. In general, steroid and thyroid hormones are bound to transport proteins, whereas polypeptide and other amine hormones circulate in a free form. http://droualb.faculty.mjc.edu/Course%20Materials/Physiology%20101/Chapter%20Notes/Fall%202007/figure_05_07_labeled.jpg Mechanism of Hormone Action  Hormone Transport The plasma half-life of a hormone is correlated with the % of protein binding. For example, ❑ Thyroxin is 99.98% protein bound and has a plasma half-life of 6 days, ❑ Whereas aldosterone, a steroid hormone, is only 15% bound and its plasma half-life of 25 minutes.  Hormones act on specific target cells in two ways ◼ Surface receptors ◼ Within target cells (internal receptor) Based on their affinity for water and lipids, hormones may be further classified as: * Lipophilic or lipid-soluble with intracellular receptors in the cytoplasm or nucleus: steroid hormones; thyroxine; vitamin D3. Lipophilic hormones mediate allosteric modulation of transcription factors. * Lipophilic, with target cell-surface receptors in the plasma membrane: prostaglandins. * Hydrophilic or water-soluble with target cell-surface receptors in the plasma membrane: peptides; glycoproteins; biogenic amines (catecholamines). These receptors are coupled to second messenger systems to allow mediation of hormone action in the target cell, the hormone in question being the first messenger. Surface receptor – amino acid derived hormone Internal receptor – steroid hormones  Effects of a hormone on a target cell may include: An alteration in the rate of intracellular protein synthesis; An alteration in the rate of enzyme activity; Modification of plasma membrane transport; Induction of secretory activity. ◼ In all cases activation of the receptor can lead to a cascade of related and consequential molecular events inside the cell. ◼ Events including generation of second messengers, changes in ion fluxes, activation or inhibition of protein kinases, activation or inhibition of transcription factors ◼ eventually lead to the regulation of the activity of key metabolic enzymes or other cellular function or changes in the level of transcription of genes coding for key proteins Intracellular Signalling Cascades Signal Transfer Signal Transformed and Relayed Signal Amplified Signal Diverges Modulated Effect Receptor Structure  Protein Hormones (Ca2+ Second Messenger) Ca2+ GnRH Receptor Plasma DAG PIP2 Membrane G-protein PLC IP3 Protein Kinase C R Ca2+ Ca2+ Secretory Granules Endoplasmic Reticulum Fusion Plasma Membrane LH Calcium Second Messenger Hormones ◼ GnRH ❑ triggers release of LH in anterior pituitary ◼ Oxytocin ❑ triggers contractions of smooth muscle ◼ PGF2 ❑ triggers apoptosis of cell ❑ inhibition of progesterone synthesis  Mechanism of Hormone Action Protein Hormones LH (cAMP second messenger) Receptor G Plasma Membrane Adenylate Cyclase cAMP Testosterone ATP R cAMP cAMP R Protein Kinase A S-ER C (PKA) Steroid Synthesis C (+ PO4) Mitochondria Pregnenolone Cholesterol Histones Cholesterol Nucleus DNA Protein R-ER Synthesis mRNA Protein Synthesis (Enzymes) cAMP Second Messenger Hormones ◼ Anterior Pituitary Hormones ❑ LH, FSH, Prolactin ❑ STH, ACTH, TSH ◼ Placental Hormones ❑ eCG Steroid Hormone Action Steroid (estrogen) Cell Membrane Diffusion? Change in Cell Physiology Cytoplasm Nucleus New Receptor Protein DNA R-ER mRNA Protein synthesis Steroid Hormone Mechanism ◼ Estradiol ◼ Testosterone, Dihydrotestosterone ◼ Cortisol Signalling via the insulin receptor Feedback Loops Mechanisms of Hormone Action ◼ Response depends on both hormone and target cell ◼ Lipid-soluble hormones bind to receptors inside target cells ◼ Water-soluble hormones bind to receptors on the plasma membrane ❑ Activates second messenger system ❑ Amplification of original small signal ◼ Responsiveness of target cell depends on ❑ Hormone’s concentration ❑ Abundance of target cell receptors ❑ Influence exerted by other hormones ◼ Permissive, synergistic and antagonistic effects  Free hormone Blood capillary 1 Lipid-soluble Transport hormone protein diffuses into cell 2 Activated Nucleus receptor-hormone Receptor complex alters gene expression DNA Cytosol mRNA 3 Newly formed mRNA directs Ribosome synthesis of specific proteins New on ribosomes protein 4 New proteins alter cell's activity Target cell  Blood capillary 1 Binding of hormone (first messenger) to its receptor activates G protein, Water-soluble which activates adenylate cyclase hormone Receptor Adenylate cyclase Second messenger G protein ATP cAMP 2 Activated adenylate cyclase converts ATP to cAMP Protein kinases 6 Phosphodiesterase inactivates cAMP 3 cAMP serves as a Activated second messenger protein to activate protein kinases kinases 4 Activated protein Protein kinases phosphorylate ATP cellular proteins ADP Protein— P 5 Millions of phosphorylated proteins cause reactions that produce physiological responses Target cell Control of Hormone Secretion ◼ Regulated by ❑ Signals from nervous system ❑ Chemical changes in the blood ❑ Other hormones ◼ Most hormonal regulation by negative feedback ❑ Few examples of positive feedback Positive feedback mechanisms Estrogens mediate a positive feedback increase in the pulsatile release of gonadotrophin releasing hormone (GnRH), luteinising hormone (LH) and follicle stimulating hormone (FSH) prior to ovulation. Ovulation terminates the positive feedback loop abruptly. Oxytocin release is increased in a positive feedback loop by myometrial contraction during childbirth, with termination of the loop on delivery. Oxytocin release is also increased via the milk ejection reflex by contraction of mammary duct myo-epithelial cells during suckling at the breast. This loop terminates on removal of the stimulus to the nipples. Mechanisms of endocrine disease ◼ Hormone deficiency, due to destruction of the gland (infarction, infection, neoplasm, auto-immune processes), genetic defects of hormone production, or inactivating mutations of hormone receptors. ◼ Hormone excess, due to exogenous intake, overproduction by either endocrine gland or through ectopic hormone production or activating mutations of cell surface receptors. ◼ Gland enlargement leading to space-occupying lesions producing pressure effects.  Hormone Secreting Tissues ◼ Virtually all organs of the body exhibit endocrine function I-Endocrine glands II- Organs with endocrine functions 1- Hypothalamus 1- Heart 2- Pituitary gland 2- Kidney 3- Thyroid gland. 3- Liver 4- Parathyroid glands 4- Skin 5- Suprarenal glands 5-GIT 6- Endocrine portion of the pancreas 6- Placenta 7- Primary sex organs: testes and ovaries 8- Thymus gland 9- Pineal gland  Target Cell Activation Hormones influence number of their receptors – Up-regulation—target cells form more receptors in response to low hormone levels – Down-regulation—target cells lose receptors in response to high hormone levels © 2013 Pearson Education, Inc.  Figure 16.4a Three types of endocrine gland stimuli. Slide 1 Humoral Stimulus Hormone release caused by altered levels of certain critical ions or nutrients. Capillary (low Ca2+ in blood) Thyroid gland (posterior view) Parathyroid glands Parathyroid glands PTH Stimulus: Low concentration of Ca2+ in capillary blood. Response: Parathyroid glands secrete parathyroid hormone (PTH), which increases blood Ca2+. © 2013 Pearson Education, Inc.  Neural Stimuli Nerve fibers stimulate hormone release – Sympathetic nervous system fibers stimulate adrenal medulla to secrete catecholamines © 2013 Pearson Education, Inc.  Figure 16.4b Three types of endocrine gland stimuli. Slide 1 Neural Stimulus Hormone release caused by neural input. CNS (spinal cord) Preganglionic sympathetic fibers Medulla of adrenal gland Capillary Stimulus: Action potentials in preganglionic sympathetic fibers to adrenal medulla. Response: Adrenal medulla cells secrete epinephrine and norepinephrine. © 2013 Pearson Education, Inc. Hormonal Stimuli Hormones stimulate other endocrine organs to release their hormones – Hypothalamic hormones stimulate release of most anterior pituitary hormones – Anterior pituitary hormones stimulate targets to secrete still more hormones – Hypothalamic-pituitary-target endocrine organ feedback loop: hormones from final target organs inhibit release of anterior pituitary hormones  Figure 16.4c Three types of endocrine gland stimuli. Slide 1 Hormonal Stimulus Hormone release caused by another hormone (a tropic hormone). Hypothalamus Anterior pituitary gland Thyroid Adrenal Gonad gland cortex (Testis) Stimulus: Hormones from hypothalamus. Response: Anterior pituitary gland secretes hormones that stimulate other endocrine glands to secrete hormones. © 2013 Pearson Education, Inc. Interaction of Hormones at Target Cells ◼ Multiple hormones may act on same target at same time ❑ Permissiveness: one hormone cannot exert its effects without another hormone being present ❑ Synergism: more than one hormone produces same effects on target cell → amplification ❑ Antagonism: one or more hormones oppose(s) action of another hormone © 2013 Pearson Education, Inc. Hypothalamus and Pituitary Gland ◼ Hypothalamus is a major link between nervous and endocrine system ◼ Pituitary attached to hypothalamus by infundibulum ❑ Anterior pituitary or adenohypophysis ❑ Posterior pituitary or neurohypophysis  Figure 16.5a The hypothalamus controls release of hormones from the pituitary gland in two different ways (1 of 2). Slide 1 Paraventricular nucleus Hypothalamus 1 Hypothalamic neurons synthesize oxytocin or antidiuretic hormone (ADH). Posterior lobe of pituitary Optic chiasma Supraoptic nucleus Infundibulum 2 Oxytocin and ADH are (connecting stalk) transported down the axons of Inferior the hypothalamic- hypophyseal Hypothalamic- hypophyseal tract to the posterior pituitary. hypophyseal artery tract Axon terminals 3 Oxytocin and ADH are stored in axon terminals in Posterior lobe the posterior pituitary. of pituitary Oxytocin 4 When hypothalamic neurons ADH fire, action potentials arriving at the axon terminals cause oxytocin or ADH to be released into the blood. © 2013 Pearson Education, Inc.  Figure 16.5b The hypothalamus controls release of hormones from the pituitary gland in two different ways (2 of 2). Slide 1 Hypothalamus Hypothalamic neurons synthesize GHRH, GHIH, TRH, Anterior lobe CRH, GnRH, PIH. of pituitary Superior hypophyseal artery 1 When appropriately stimulated, 2 Hypothalamic hormones hypothalamic neurons secrete travel through portal veins to releasing or inhibiting hormones the anterior pituitary where into the primary capillary plexus. they stimulate or inhibit Hypophyseal release of hormones made in the anterior pituitary. portal system Primary capillary 3 In response to releasing plexus A portal hormones, the anterior Hypophyseal system is pituitary secretes hormones two into the secondary capillary portal veins capillary plexus. This in turn empties Secondary plexuses into the general circulation. capillary plexus (beds) connected GH, TSH, ACTH, by veins. FSH, LH, PRL Anterior lobe of pituitary © 2013 Pearson Education, Inc. Role of the Pituitary  The pituitary is the “master gland” that signals other glands to produce their hormones when needed.  The anterior lobe of the pituitary receives signals from the hypothalamus, and responds by sending out the appropriate hormone to other endocrine glands.  The posterior pituitary receives oxytocin or antidiuretic hormone (ADH) from the hypothalamus, relays them to the body as necessary.  Pituitary Hormones Pituitary Hormone Functions Follicle-stimulating Stimulates egg maturation in the ovary and release of sex hormone (FSH) hormones. Lutenizing hormone Stimulates maturation of egg and of the corpus luteum surrounding the egg, which affects female sex hormones and the menstrual cycle. Thyroid-stimulating Stimulates the thyroid to release thyroxine. hormone Adrenocorticotropic Causes the adrenal gland to release cortisol. hormone Melanocyte- Stimulates synthesis of skin pigments. stimulating hormone Growth hormone Stiimulates growth during infancy and puberty. Antidiuretic hormone Signals the kidney to conserve more water. Oxytocin Affects childbirth, lactation, and some behaviors. Anterior pituitary ❑ Release of hormones stimulated by releasing and inhibiting hormones from the hypothalamus ❑ Also regulated by negative feedback ❑ Hypothalamic hormones made by neurosecretory cells transported by hypophyseal portal system ❑ Anterior pituitary hormones that act on other endocrine systems called tropic hormones Hormones of the Anterior Pituitary ◼ Growth hormone (GH) ❑ Growth hormone is a single chain polypeptide comprising 191 amino acids ❑ Growth hormone is secreted in an irregular and intermittent pulsatile fashion by somatotrophs. ❑ Secretion shows diurnal variation, peak secretion occurring during sleep. ❑ Secretion is stimulated by GHRH and inhibited by somatostatin. Growth Hormone (GH, or Somatotropin) ◼ Produced by somatotropic cells ◼ Direct actions on metabolism ❑ Increases blood levels of fatty acids; encourages use of fatty acids for fuel; protein synthesis ❑ Decreases rate of glucose uptake and metabolism – conserving glucose ❑ → Glycogen breakdown and glucose release to blood (anti-insulin effect) © 2013 Pearson Education, Inc. Growth hormone actions ◼ Promotes linear growth: ❑ Induces precursor cells to differentiate and secrete IGF-1, which stimulates cell division. ❑ Stimulates protein synthesis: increases amino acid transport into muscle, liver and adipose cells and accelerates transcription and translation of mRNA. ◼ Anti-insulin effects: ❑ Adipocytes more responsive to lipolytic stimuli; ❑ Stimulation of gluconeogenesis; ❑ Reduced ability of insulin to stimulate glucose uptake. ◼ Muscle: ❑ Reduced glucose uptake; ❑ Increased amino acid uptake; ❑ Increased protein synthesis; ❑ Increased lean body mass. ◼ Metabolism: ❑ Increased plasma glucose; ❑ Increased plasma free fatty acids; ❑ Reduced plasma amino acids; ❑ Reduced plasma urea. ◼ Adipose tissue: ❑ Reduced glucose uptake; ❑ Increased lipolysis; ❑ Reduced adiposity. Figure 16.6 Growth-promoting and metabolic actions of growth hormone (GH). Hypothalamus secretes growth Feedback Inhibits GHRH release hormone–releasing Stimulates GHIH release hormone (GHRH), and Anterior pituitary GHIH (somatostatin) Inhibits GH synthesis and release Growth hormone (GH) Indirect actions Direct actions (growth- (metabolic, promoting) anti-insulin) Liver and other tissues Produce Insulin-like growth factors (IGFs) Effects Effects Fat Carbohydrate Skeletal Extraskeletal metabolism metabolism Increases, stimulates Reduces, inhibits Increased protein Initial stimulus Increased cartilage Increased Increased blood synthesis, and formation and fat breakdown glucose and other Physiological response cell growth and skeletal growth and release anti-insulin effects proliferation Result © 2013 Pearson Education, Inc.  Thyroid-stimulating Hormone (Thyrotropin) ◼ Produced by thyrotropic cells of anterior pituitary ◼ Stimulates normal development and secretory activity of thyroid ◼ Stimulates synthesis and secretion of thyroid hormones by thyroid ◼ Release triggered by thyrotropin-releasing hormone from hypothalamus ◼ Inhibited by rising blood levels of thyroid hormones that act on pituitary and hypothalamus © 2013 Pearson Education, Inc. Figure 16.8 Regulation of thyroid hormone secretion. Hypothalamus TRH Anterior pituitary TSH Thyroid gland Thyroid hormones Stimulates Target cells Inhibits © 2013 Pearson Education, Inc. Adrenocorticotropic Hormone (Corticotropin) ◼ Regulation of ACTH release ❑ Triggered by hypothalamic corticotropin-releasing hormone (CRH) in daily rhythm ❑ Internal and external factors such as fever, hypoglycemia, and stressors can alter release of CRH © 2013 Pearson Education, Inc. Gonadotropins ◼ Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) ◼ Secreted by gonadotropic cells of anterior pituitary ◼ FSH stimulates gamete (egg or sperm) production ◼ LH promotes production of gonadal hormones ◼ Absent from the blood in prepubertal boys and girls © 2013 Pearson Education, Inc.  Hormones of the Anterior Pituitary ◼ Prolactin ❑ This is a 198 amino acid single chain polypeptide ❑ Secretion occurs in a sleep-related circadian rhythm in both males and females. ❑ Hypothalamic control of secretion is primarily inhibitory, mediated by PRL-release-inhibiting factor (dopamine). ◼ Actions ❑ Increased sensitivity of the testis to LH stimulation, sustaining testosterone levels. ❑ Normal corpus luteum function. ❑ Initiation and maintenance of lactation in the post-partum period: it induces lobulo-alveolar growth of the breasts and stimulates lactogenesis after parturition. ❑ Osmoregulation. ❑ Immune regulation. Posterior pituitary ❑ Does not synthesize hormones ❑ Stores and releases hormones made by the hypothalamus ◼ Transported along hypothalamohypophyseal tract ◼ Oxytocin and ADH ❑ Each composed of nine amino acids ❑ Almost identical – differ in two amino acids  Hormones Stored at posterior Pituitary: Oxytocin ◼ Oxytocin is released from the supraoptic and paraventricular nuclei of the hypothalamus. ◼ Propagation of action potentials along the hypothalamiconeural–hypophyseal tract to posterior pituitary gland nerve terminals leads to calcium influx, which stimulates release of oxytocin by exocytosis. ◼ Release is stimulated by suckling at the breast leading to nipple stimulation, activation of stretch receptors in the walls of the uterus and vagina, pregnancy and at parturition. ◼ Actions ❑ Causes the release of milk by contraction of myo- epithelial cells of the breasts (milk let-down); ❑ Responsible for the contraction of uterine smooth muscle at parturition. Antidiuretic Hormone (ADH) ❑ Decreases urine production by causing the kindeys to return more water to the blood ❑ Also decreases water lost through sweating and constriction of arterioles which increases blood pressure (vasopressin)  1 High blood osmotic 5 Low blood osmotic pressure stimulates pressure inhibits hypothalamic hypothalamic osmoreceptors osmoreceptors Osmoreceptors 2 Osmoreceptors activate the 6 Inhibition of osmo- neurosecretory cells receptors reduces or that synthesize and stops ADH secretion release ADH Hypothalamus 3 Nerve impulses liberate ADH from axon terminals in the posterior pituitary into the bloodstream ADH Target tissues 4 Kidneys retain Sudoriferous Arterioles constrict, more water, (sweat) glands which increases which decreases decrease water blood pressure urine output loss by perspiration from the skin Homeostasis and Hormones  Thyroid and temperature control  Thyroid, Parathyroid, and calcium  Pancreas and glucose control  Controlling sleep cycles (melatonin)  Controlling reproductive cycles (melatonin, sex hormones)  Growth (growth hormone)  Responding to stress or emergencies (epinephrine and other hormones)  Endocrine Hormones Gland Hormones Functions Thyroid Thyroxine Regulates metabolism Calcitonin Inhibits release of calcium from the bones Parathyroids Parathyroid hormone Stimulates the release of calcium from the bones. Islet cells (in Insulin Decreases blood sugar by promoting uptake of glucose by cells. the pancreas) Glucagon Increases blood sugar by stimulating breakdown of glycogen in the liver. Testes Testosterone Regulates sperm cell production and secondary sex characteristics. Ovaries Estrogen Stimulates egg maturation, controls secondary sex characteristics. Progesterone Prepares the uterus to receive a fertilized egg. Adrenal Epinephrine Stimulates “fight or flight” response. medulla Adrenal Glucocorticoids Part of stress response, increase blood glucose levels and decrease cortex immune response. Aldosterone Regulates sodium content in the blood. Testosterone Adult body form (greater muscle mass), libido. Pineal gland Melatonin Sleep cycles, reproductive cycles in many mammals. Thyroid Gland ◼ Located inferior to larynx ◼ 2 lobes connected by isthmus ◼ Thyroid follicles produce thyroid hormones ❑ Thyroxine or tetraiodothyronine (T4) ❑ Triiodothyronine (T3) ◼ Both increase BMR, stimulate protein synthesis, increase use of glucose and fatty acids for ATP production ◼ Parafollicular cells or C cells produce calcitonin ❑ Lowers blood Ca2+ by inhibiting bone resorption Thyroid Gland ◼ Two lateral lobes connected by median mass called isthmus ◼ Composed of follicles that produce glycoprotein thyroglobulin ◼ Colloid (fluid with thyroglobulin + iodine) fills lumen of follicles and is precursor of thyroid hormone ◼ Parafollicular cells produce the hormone calcitonin © 2013 Pearson Education, Inc. Thyroid Hormone (TH) ◼ Actually two related compounds ❑ T4 (thyroxine); has 2 tyrosine molecules + 4 bound iodine atoms ❑ T3 (triiodothyronine); has 2 tyrosines + 3 bound iodine atoms ◼ Affects virtually every cell in body © 2013 Pearson Education, Inc. Thyroid Hormone ◼ Major metabolic hormone ◼ Increases metabolic rate and heat production (calorigenic effect) ◼ Regulation of tissue growth and development ❑ Development of skeletal and nervous systems ❑ Reproductive capabilities ◼ Maintenance of blood pressure © 2013 Pearson Education, Inc. Figure 16.10 Synthesis of thyroid hormone. Slide 1 Thyroid follicular cells Colloid 1 Thyroglobulin is synthesized and discharged into the follicle lumen. Tyrosines (part of thyroglobulin molecule) Capillary 4 Iodine is attached to tyrosine in colloid, forming DIT and MIT. Golgi apparatus Rough Thyro- ER Iodine globulin 3 Iodide DIT MIT colloid is oxidized to iodine. Iodide (I−) 2 Iodide (I–) is trapped (actively transported in). T4 5 Iodinated tyrosines are T3 linked together to form T3 Lysosome and T4. T4 6 Thyroglobulin colloid is endocytosed and combined T3 7 Lysosomal enzymes with a lysosome. T4 Colloid in cleave T4 and T3 from thyroglobulin and hormones lumen of T3 follicle diffuse into bloodstream. To peripheral tissues © 2013 Pearson Education, Inc. Transport and Regulation of TH ◼ T4 and T3 transported by thyroxine-binding globulins (TBGs) ◼ Both bind to target receptors, but T3 is ten times more active than T4 ◼ Peripheral tissues convert T4 to T3 © 2013 Pearson Education, Inc. Figure 16.8 Regulation of thyroid hormone secretion. Hypothalamus TRH Anterior pituitary TSH Thyroid gland Thyroid hormones Stimulates Target cells Inhibits © 2013 Pearson Education, Inc. Control of thyroid hormone secretion ❑ Thyrotropin-releasing hormone (TRH) from hypothalamus ❑ Thyroid-stimulating hormone (TSH) from anterior pituitary ❑ Situations that increase ATP demand also increase secretion of thyroid hormones  1 Low blood levels of T3 and T3 or low metabolic rate stimulate release of Hypothalamus TRH 2 TRH, carried by hypophyseal portal veins to anterior pituitary, 5 Elevated stimulates T3inhibits release of TSH release of by thyrotrophs TRH and TSH TSH (negative feedback) Anterior 3 TSH released into blood stimulates pituitary thyroid follicular cells 4 T3 and T4 released into Thyroid blood by follicle follicular cells Actions of Thyroid Hormones: Increase basal metabolic rate Stimulate synthesis of Na+/K+ ATPase Increase body temperature (calorigenic effect) Stimulate protein synthesis Increase the use of glucose and fatty acids for ATP production Stimulate lipolysis Enhance some actions of catecholamines Regulate development and growth of nervous tissue and bones Calcitonin ◼ Produced by parafollicular (C) cells ◼ Antagonist to parathyroid hormone (PTH) ◼ At higher than normal doses ❑ Inhibits osteoclast activity and release of Ca2+ from bone matrix ❑ Stimulates Ca2+ uptake and incorporation into bone matrix © 2013 Pearson Education, Inc. Parathyroid Glands ◼ Embedded in lobes of thyroid gland ◼ Usually 4 ◼ Parathyroid hormone (PTH) or parathormone ❑ Major regulator of calcium, magnesium, and phosphate ions in the blood ❑ Increases number and activity of osteoclasts ❑ Elevates bone resorption ◼ Blood calcium level directly controls secretion of both calcitonin and PTH via negative feedback Parathyroid Glands ◼ Four to eight tiny glands embedded in posterior aspect of thyroid ◼ Contain oxyphil cells (function unknown) and parathyroid cells that secrete parathyroid hormone (PTH) or parathormone ◼ PTH—most important hormone in Ca2+ homeostasis © 2013 Pearson Education, Inc. Figure 16.12 The parathyroid glands. Pharynx (posterior aspect) Capillary Thyroid Parathyroid gland cells Parathyroid glands (secrete parathyroid Esophagus hormone) Trachea Oxyphil cells © 2013 Pearson Education, Inc. Figure 16.13 Effects of parathyroid hormone on bone, the kidneys, and the intestine. Hypocalcemia (low blood Ca2+) PTH release from parathyroid gland Osteoclast activity Ca2+ reabsorption Activation of in bone causes Ca2+ in kidney tubule vitamin D by kidney and PO43- release into blood Ca2+ absorption from food in small intestine Ca2+ in blood Initial stimulus Physiological response © 2013 Pearson Education, Inc. Result Roles of Calcitonin, Parathyroid hormone, Calcitrol in Calcium Homeostasis 1 High level of Ca2+ in blood 3 Low level of Ca2+ in blood stimulates thyroid gland stimulates parathyroid parafollicular cells to gland chief cells to release release more CT. more PTH. 6 CALCITRIOL stimulates increased absorption of Ca2+ from foods, which increases blood Ca2+ level. 5 PTH also stimulates the kidneys to release 4 PARATHYROID HORMONE (PTH) 2 CALCITONIN inhibits CALCITRIOL. promotes release of Ca2+ from osteoclasts, thus decreasing bone extracellular matrix into blood Ca2+ level. blood and slows loss of Ca2+ in urine, thus increasing blood Ca2+ level. Adrenal (Suprarenal) Glands ◼ Paired, pyramid-shaped organs atop kidneys ◼ Structurally and functionally are two glands in one ❑ Adrenal medulla—nervous tissue; part of sympathetic nervous system ❑ Adrenal cortex—three layers of glandular tissue that synthesize and secrete corticosteroids © 2013 Pearson Education, Inc. Adrenal Glands ◼ 2 structurally and functionally distinct regions ❑ Adrenal cortex ◼ Mineralocorticoids affect mineral homeostasis ◼ Glucocorticoids affect glucose homeostasis ❑ cortisol ◼ Androgens have masculinzing effects ❑ Dehydroepiandrosterone (DHEA) only important in females ❑ Adrenal medulla ◼ Modified sympathetic ganglion of autonomic nervous system ◼ Intensifies sympathetic responses ◼ Epinephrine and norepinephrine  Figure 16.14 Microscopic structure of the adrenal gland. Hormones Capsule secreted Zona glomerulosa Aldosterone Zona fasciculata Adrenal gland Cortex Medulla Cortex Cortisol and androgens Kidney Zona reticularis Medulla Adrenal medulla Epinephrine and norepinephrine Drawing of the histology of the Photomicrograph (115x) adrenal cortex and a portion of the adrenal medulla © 2013 Pearson Education, Inc. Adrenal (Suprarenal) Glands ◼ Adrenal glands – paired, pyramid-shaped organs atop the kidneys ◼ Weigh 6-10 g. ◼ Structurally and functionally, they are two glands in one ❑ Adrenal cortex (80-90%)– glandular tissue derived from embryonic mesoderm ❑ Adrenal medulla (10-20%)– formed from neural ectoderm, can be considered a modified sympathetic ganglion Adrenal Cortex ◼ Synthesizes and releases steroid hormones (corticosteroids) ◼ Different corticosteroids are produced in each of the three layers: ❑ Zona glomerulosa – mineralocorticoids (mainly aldosterone) ❑ Zona fasciculata – glucocorticoids +Androgens (mainly cortisol and corticosterone) ❑ Zona reticularis – gonadocorticoids + glucocorticoids (mainly dehydroepiandrosterone DHEA) HPA Axis Steroid Hormones: Structure Steroid Hormones Synthesis ◼ Steroids are derivatives of cholesterol ◼ Cholesterol is from the lipid droplets in cortical cells (cholesterol esters in LDL) ◼ Removed cholesterol is replenished by cholesterol in LDL in blood or synthesized from acetate Steroid Hormones Synthesis ◼ Steroid hormones are synthesized and secreted on demand (not stored) ◼ The first and rate-limiting step in the synthesis of all steroid hormones is conversion of cholesterol to pregnenolone by the enzyme cholesterol dismolase (aka cholesterol side chain cleavage (SCC) enzyme ◼ Newly synthesized steroid hormones are rapidly secreted from the cell ◼ Following secretion, all steroids bind to some extent to plasma proteins: CBG and albumin The Essential Steroids ◼ Primary glucocorticoid: ❑ Cortisol (a.k.a. hydrocortisone) ◼ Primary mineralocorticoid: ❑ Aldosterone Glucocorticoids ◼ Keep blood glucose levels relatively constant ◼ Maintain blood pressure by increasing action of vasoconstrictors ◼ Cortisol (hydrocortisone) ❑ Only one in significant amounts in humans ◼ Cortisone ◼ Corticosterone © 2013 Pearson Education, Inc. Cortisol ◼ A glucocorticoid ◼ Frequently referred to as the ‘stress hormone’ ❑ Released in response to physiological or psychological stress ◼ Examples: exercise, illness, injury, starvation, extreme dehydration, electrolyte imbalance, emotional stress, surgery, etc. Cortisol ◼ Critical actions on many physiologic systems, including: ❑ Maintains cardiovascular function ❑ Provides blood pressure regulation ❑ Enables carbohydrate metabolism ◼ acts on the liver to maintain normal glucose levels ❑ Immune function actions ◼ Reduces inflammation ◼ Suppresses immune system Cortisol ◼ When cortisol is not produced or released by the adrenal glands, humans are unable to respond appropriately to physiologic stressors ◼ Rapid deterioration resulting in organ damage and shock/coma/death can occur, especially in children Why we need cortisol ◼ Cortisol has a necessary effect on the vascular system (blood vessels, heart) and liver during episodes of physiologic stress Why? ◼ Adrenal glands tend to get ‘lazy’ when steroids are regularly administered by mouth, I.M. injection or I.V. infusion ◼ To illustrate how quickly…Just 2-4 weeks of daily oral cortisone administration is sufficient to cause the adrenals to be slightly less responsive to stressors Aldosterone ◼ A mineralocorticoid ◼ Regulates body fluid by influencing sodium balance ◼ The human body requires certain amounts of sodium and water in order to maintain normal metabolism of fats, carbohydrates and proteins ◼ Water/sodium balance is maintained by aldosterone ◼ Without aldosterone, significant water and sodium imbalances can result in organ failure/death  Mineralocorticoids ◼ Synthesized in zona glomerulosa ◼ Regulate the electrolyte concentrations of extracellular fluids ◼ Aldosterone – most important mineralocorticoid ❑ Maintains Na+ balance by reducing excretion of sodium from the body ❑ Stimulates reabsorption of Na+ by the kidneys and K+ excretion Mineralocorticoids ◼ Aldosterone secretion is stimulated by: ❑ Decreasing blood volume or pressure (renin- angeotensin system) is the major stimulant ❑ Low blood Na+ ❑ Rising blood levels of K+ ❑ ACTH The Four Mechanisms of Aldosterone Secretion ◼ Renin-angiotensin mechanism – kidneys release renin, which is converted into angiotensin II that in turn stimulates aldosterone release ◼ Plasma concentration of sodium and potassium – directly influences the zona glomerulosa cells ◼ ACTH – causes small increases of aldosterone during stress ◼ Atrial natriuretic peptide (ANP) – inhibits activity of the zona glomerulosa The Four Mechanisms of Aldosterone Secretion Actions of Aldosterone Stimulates sodium reabsorption by distal tubule and collecting duct of the nephron and promotes potassium and hydrogen ion excretion ❑ Increases transcription of Na/K pump ❑ Increases the expression of apical Na channels and an Na/K/Cl cotransporter ◼ Expands ECF volume Gonadocorticoids ◼ Hypersecretion ❑ Adrenogenital syndrome (masculinization) ❑ Not noticeable in adult males ❑ Females and prepubertal males ◼ Boys – reproductive organs mature; secondary sex characteristics emerge early ◼ Females – beard, masculine pattern of body hair; clitoris resembles small penis © 2013 Pearson Education, Inc. Adrenal Medulla ◼ Medullary chromaffin cells synthesize epinephrine (80%) and norepinephrine (20%) ◼ Effects ❑ Vasoconstriction ❑ Increased heart rate ❑ Increased blood glucose levels ❑ Blood diverted to brain, heart, and skeletal muscle © 2013 Pearson Education, Inc. The Stress Response ◼ Eustress in helpful stress / Distress is harmful ◼ Body’s homeostatic mechanisms attempt to counteract stress ◼ Stressful conditions can result in stress response or general adaptation syndrome (GAS) ❑ 3 stages – initial flight-or-fight, slower resistance reaction, eventually exhaustion ❑ Prolonged exposure to cortisol can result in wasting of muscles, suppression of immune system, ulceration of GI tract, and failure of pancreatic beta cells Figure 16.17 Stress and the adrenal gland. Short-term stress Prolonged stress Stress Nerve impulses Hypothalamus CRH (corticotropin- releasing hormone) Spinal cord Corticotropic cells of anterior pituitary Preganglionic To target in blood sympathetic fibers Adrenal cortex Adrenal medulla (secretes steroid (secretes amino acid– hormones) based hormones) ACTH Catecholamines Mineralocorticoids Glucocorticoids (epinephrine and norepinephrine) Short-term stress response Long-term stress response Heart rate increases Kidneys retain Proteins and fats converted Blood pressure increases sodium and water to glucose or broken down Bronchioles dilate Blood volume and for energy Liver converts glycogen to glucose and releases blood pressure Blood glucose increases glucose to blood rise Immune system Blood flow changes, reducing digestive system activity supressed and urine output Metabolic rate increases © 2013 Pearson Education, Inc. Stress Response Pancreas (Pancreatic Islets) ◼ Triangular gland partially behind stomach ◼ Has both exocrine and endocrine cells ❑ Acinar cells (exocrine) produce enzyme-rich juice for digestion ❑ Pancreatic islets (islets of Langerhans) contain endocrine cells ◼ Alpha () cells produce glucagon (hyperglycemic hormone) ◼ Beta () cells produce insulin (hypoglycemic hormone) ❑ Delta or D cells secrete somatostatin – inhibits both insulin and glucagon ❑ F cells secrete pancreatic polypeptide – inhibits somatostatin, gallbladder contraction, and secretion of pancreatic © 2013 Pearson Education, Inc. digestive enzymes Figure 16.18 Photomicrograph of differentially stained pancreatic tissue. Pancreatic islet  (Glucagon- producing) cells  (Insulin- producing) cells Pancreatic acinar cells (exocrine) © 2013 Pearson Education, Inc. Glucagon ◼ Major target—liver ◼ Causes increased blood glucose levels ◼ Effects ❑ Glycogenolysis—breakdown of glycogen to glucose ❑ Gluconeogenesis—synthesis of glucose from lactic acid and noncarbohydrates ❑ Release of glucose to blood © 2013 Pearson Education, Inc. Insulin ◼ Effects of insulin ❑ Lowers blood glucose levels ❑ Enhances membrane transport of glucose into fat and muscle cells ❑ Inhibits glycogenolysis and gluconeogenesis ❑ Participates in neuronal development and learning and memory ◼ Not needed for glucose uptake in liver, kidney or brain © 2013 Pearson Education, Inc. Figure 16.19 Insulin and glucagon from the pancreas regulate blood glucose levels. Stimulates glucose uptake by cells Insulin Tissue cells Stimulates glycogen formationw Pancreas Glucose Glycogen Blood Liver glucose falls to normal range. Stimulus Blood glucose level Stimulus Blood glucose level Blood glucose rises to normal range. Pancreas Glucose Glycogen Liver Stimulates glycogen Glucagon © 2013 Pearson Education, Inc. breakdown Factors That Influence Insulin Release ◼ Elevated blood glucose levels – primary stimulus ◼ Rising blood levels of amino acids and fatty acids ◼ Release of acetylcholine by parasympathetic nerve fibers ◼ Hormones glucagon, epinephrine, growth hormone, thyroxine, glucocorticoids ◼ Somatostatin; sympathetic nervous system © 2013 Pearson Education, Inc. Negative Feedback Regulation of Glucagon and Insulin 1 Low blood glucose (hypoglycemia) stimulates alpha 5 High blood glucose (hyperglycemia) stimulates beta cells cells to secrete to secrete GLUCAGON INSULIN 2 Glucagon acts on 6 Insulin acts on various hepatocytes body cells to: (liver cells) to: accelerate facilitated convert glycogen diffusion of glucose into glucose into cells (glycogenolysis) speed conversion of form glucose from glucose into glycogen lactic acid and (glycogenesis) certain amino acids increase uptake of (gluconeogenesis) amino acids and increase protein synthesis 3 Glucose released speed synthesis of fatty by hepatocytes acids (lipogenesis) raises blood glucose slow glycogenolysis level to normal slow gluconeogenesis 7 Blood glucose level falls 4 If blood glucose 8 If blood glucose continues continues to rise, to fall, hypoglycemia hyperglycemia inhibits inhibits release of release of glucagon insulin Gonads ◼ Gonads – produce gametes and hormones ◼ Ovaries produce 2 estrogens (estradiol and estrone) and progesterone ❑ With FSH and LH regulate menstrual cycle, maintain pregnancy, prepare mammary glands for lactation, maintain female secondary sex characteristics ❑ Inhibin inhibits FSH ❑ Relaxin produced during pregnancy ◼ Testes produce testosterone – regulates sperm production and maintains male secondary sex characteristics ❑ Inhibin inhibits FSH Testes ◼ Testes produce testosterone ❑ Initiates maturation of male reproductive organs ❑ Causes appearance of male secondary sexual characteristics and sex drive ❑ Necessary for normal sperm production ❑ Maintains reproductive organs in functional state © 2013 Pearson Education, Inc. Other Hormone-producing Structures ◼ Heart ❑ Atrial natriuretic peptide (ANP) decreases blood Na+ concentration, therefore blood pressure and blood volume ◼ Kidneys ❑ Erythropoietin signals production of red blood cells ❑ Renin initiates the renin-angiotensin-aldosterone mechanism © 2013 Pearson Education, Inc. Thymus ❑ Located behind sternum between the lungs ❑ Produces thymosin, thymic humoral factor (THF), thymic factor (TF), and thymopoietin ❑ All involved in T cell maturation Pineal Gland ◼ Small gland hanging from roof of third ventricle ◼ Pinealocytes secrete melatonin, derived from serotonin ◼ Melatonin may affect ❑ Timing of sexual maturation and puberty ❑ Day/night cycles ❑ Physiological processes that show rhythmic variations (body temperature, sleep, appetite) ❑ Production of antioxidant and detoxification molecules in cells © 2013 Pearson Education, Inc. PINEAL GLAND (EPIPHYSIS) Synthesizes and secretes melatonin hormone, that communicates information about environmental photoperiod "third eye". Light ------ retina -------- suprachiasmatic nucleus (SCN) of the hypothalamus--------- spinal cord ---------- superior cervical ganglia---------the pineal gland. MELATONIN: Synthesis: tryptophan---- serotonin -- --- melatonin Secretion: peak during the dark------ serotonin N-acetyltransferase (NAT) peaks during the dark phase. Receptors:Two melatonin receptors (MtR) (Mel1A and Mel1B) -------- G protein-coupled cell surface receptors---- regulates expression of Clock genes ----- ---maintain circadian rhythm. MELATONIN: FUNCTION: Integrating photoperiod Circadian rhythms. Reproduction Sleep-wake cycles LOCAL HORMONES ( AUTOCOIDS ) Synthesized by all body cells, except RBCs when stimulated by physical or chemical stimuli. Function: transmit information between neighboring cells (paracrine effect) They are short-lived. CLASSIFICATION OF LOCAL AUTACOIDS 1. Biologically active amines, such as histamine and Serotonin 2. Lipid-derived autacoids, such as eicosanoids 3. Vasoactive polypeptides, such as Kinin and Endothelin 4. Endothelium- derived autacoids, such as nitric oxide 1. HISTAMINE Synthesis: – by basophils and mast cells – histidine-------- Histamine but destroyed by the histiminase enzyme. FUNCTIONS – Local immune responses to cause inflammation or allergy – Regulating physiological function in the gut – Bronchiolar and intestinal smooth muscle contraction – Neurotransmitter. 1. HISTAMINE 1. Allergic and Inflammatory Reactions Histamine leads to increased blood flow, vasodilation and increased vascular permeability Acute and delayed hypersensitivity reactions. Clinical manifestations of histamine release vary from life-threatening anaphylactic reactions, to uticaria (hives),to local wheal and flare reactions. 1. HISTAMINE 2.Secretion of Gastric Acid A principle stimuli for secretion of gastric HCl. H2 blockers suppresses gastric acid secretion. 3.Bronchiolar and intestinal smooth muscle contraction 4.Effects in the Nervous System Histamine acts as a neurotransmitter within the CNS where it is involved in the regulation of wakefulness, cognitive ability and food consumption. 2. SEROTONIN: Function: The enterochromaffin cells of the digestive tract------ regulate gut movement. The serotonergic neurons in the CNS ----- regulate sleep,mood and appetite Stored in blood platelets ------ blood clot-------- release serotonin, to act as a vasoconstrictor and helps to regulate hemostasis and blood clotting. 3. EICOSANOIDS 20-carbon essential fatty acids: 1.Eicosapentaenoic acid (EPA), an ω-3 fatty acid with 5 double bonds 2.Arachidonic acid (AA), an ω-6 fatty acid,with 4 double bonds 3.γ-linolenic acid (GLA) ,an ω-6,with 3 double bonds. The eicosanoids include: Prostanoids – prostaglandins (PGs) – prostacyclins (PGIs), – thromboxanes (TXs) leukotrienes (LTs) lipoxins (LXs). 3. EICOSANOIDS SYNTHESIS: Several stimuli activate phospholipase A2 (PLA2) in the cell membrane and arachidonic acid is released from membrane phospholipids Arachidonic acid is then metabolized enzymes. – The most two important enzymes are: Lipoxygenase (LOX), which results in production of leukotrienes Cyclooxygenase (COX), which results in to prostacyclin (PGI),prostaglandins (PGE and PGF), or thromboxane (TXA) Venom from both snakes and insects contain melittin (PLA2)---- release arachidonic acid ------------ severe inflammation and pain occur at the site of bite 3. EICOSANOIDS C O X exists in at least 2 forms. – 1.COX -1 is found in many tissues:the prostaglandins produced by COX-1 participate in normal physiologic processes – 2.COX -2 is found primarily in inflammatory cells;inflammatory functions PROSTACYCLINS VS THROMBOXANS PROSTAGLANDINS Prostaglandins act as local hormones in their function. Properties: (Vs true hormones) –PGs are produced in almost all the tissues –PGs are not stored but degraded at the site of their production. –PGs are produced in very small amounts and have very short half lives. PROSTAGLANDINS 1.Regulation of blood pressure: PG E is vasodilator------decreased peripheral resistance ------ -- lower the blood pressure-------treatment of hypertension. 2.Inflammation: The prostaglandins PGE1 and PGE2 induce the symptoms of inflammation like redness, swelling, oedema etc ???????? due to arteriolar vasodilation. 3.Reproduction: PGE and PGF PROSTAGLANDINS 4.Pain and Fever: pyrogens (fever inducing agents)----- the formation of PGE2 in the hypothalamus PGE2 along with histamine and bradykinin cause pain. Migraine is also due to PGE2. 5.Action in GI tract: PGE1, PGE2, and PGA1 inhibit gastric secretion (volume, acid and pepsin content) and increase mucus secretion------- PGs have been used for preventing gastric ulcers. PROSTAGLANDINS 6.Immunological Response: PGs secreted by macrophages may modulate or decrease the functions of B andT lymphocytes. 7.Action in Respiration: In general PGFs contract and PGEs relax bronchial and tracheal Thus PGE1 and PGE2 has been used for treatment of asthma. 8. Renal function: Intravenous infusion of PGE andA produces substantial increase in renal plasma flow,glomerular filtration rate and urinary flow--- ---- diuresis. They stimulate renin secretion from JG cells. PROSTAGLANDINS 9.Effects on Metabolism: Prostaglandins influence certain metabolic reactions, probably through the mediation of cyclicAMP. PGEs decreases lipolysis because it binds Gi protein-linked receptors. PGEs have also some insulin like effects on carbohydrate metabolism (Gs protein). They exert PTH like effects on bone, resulting to mobilization of calcium from bone producing hypercalcemia (Gq). They also exertsTSH like effects on thyroid gland. Copyright 2009, John Wiley & Sons, Inc. NSAIDS VERSUS CORTICOSTEROIDS: 1. Non-steroidal anti-inflammatory drugs (NSAIDs) are group of drugs that reduce pain, decrease fever and decrease inflammation – They include aspirin and ibuprofen – Most NSAIDs inhibit the activity of C O X - 1 and C O X - 2,and thereby inhibiting the synthesis of PGs andTXs. – NSAIDs inhibiting C O X - 2 leads to the antiinflammatory,analgesic and antipyretic effects – NSAIDs that inhibiting C O X - 1, particularly aspirin, may cause gastrointestinal bleeding and ulcers 2.Corticosteroids: They have anti-inflammatory action by the inhibition of PLA2 that releases arachidonic acid from phospholipids. Copyright 2009, John Wiley & Sons, Inc. LEUKOTRIENE: in leucocytes, mast cells,and macrophages by the lipo-oxygenase pathway,in response to both immunologic and noninflammatory stimuli. Function of Leukotrienes: In anaphylactic and allergic reactions. –Intense vasoconstriction of bronchial muscles –Vasodilation and increased vascular permeability LIPOXINS: They are formed by the combined action of more than one lipo-oxygenase. Function –They dilates the microvasculature –Inhibit the cytotoxic effects of natural killer cells –Reduce eosinophil infiltration to sites of inflammation.  4. ENDOTHELIN a 21 amino acid peptide that is produced by the vascular endothelium  ET-1 formation and release are stimulated by angiotensin II,ADH, and shearing forces acting on the vascular endothelium.  ET-1 release is inhibited by PGI and A N P as well as by nitric oxide. 4. ENDOTHELIN ET-1 has two receptor types, ETA and ETB. 1. ETA receptors are found in the smooth muscle tissue of blood vessels binding of ET-1 to ETA receptors increases vasoconstriction and the retention of sodium, leading to increased blood pressure. 2.ETB is primarily located on the endothelial cells that line the interior of the blood vessels. binding of ET-1 to ETB receptors, leads to the release of nitric oxide, which causes vasodilatation leading to lowering of blood pressure. Systemic administration of ET-1 causes transient vasodilatation and hypotension (initial endothelial ETB activation), followed by prolong vasoconstriction and hypertension (smooth muscle ETA activation) ADIPOSE TISSUE HORMONES (ADIPOKINES) Adipose tissue secretes a adipokines including:leptin, adiponectin, visfatin, resistin, omentin Adipokines act at both autocrine/paracrine and endocrine level. Adipokines participate in the regulation of glucose and lipid metabolism,energy homeostasis, feeding behavior,insulin sensitivity, inflammation, adipogenesis, immunity,vascular function,coagulation The adipose tissue influences hormones secreted by other endocrine organs. – For example,an excessive amount of adipose tissue can significantly contribute to the formation of insulin resistance, type 2 diabetes or atherosclerosis. LEPTIN Leptin is a 167 amino acid hormone, synthesized mainly by adipocytes of the white adipose tissue and the synthesized amount correlates with the quantity of the adipose tissue in the body. Functions Leptin regulates the energy intake and expenditure by its influence on feeding behavior,appetite, hunger and energy metabolism. Because its amount in bloodstream corresponds to the amount of adipose tissue, it provides the brain with feedback information about the status of energy reserves (HOW?). – Leptin passes through the BB barrier and has an anorexigenic effect on hypothalamus, suppressing appetite and increasing the energy expenditure. – It thus acts against the orexigenic effect of neuropeptideY (NPY), which, on the contrary, increases appetite and stimulates the secretion of insulin. ADIPONECTIN Adiponectin is a protein hormone produced mainly by adipocytes Its concentration in blood is quite high compared to leptin. adiponectin is negatively correlated with the amount of body fat. That is why obese patients have lower plasma concentrations of adiponectin than patients with normal body weight. ADIPONECTIN Function Adiponectin is a hormone mainly influencing the metabolism of saccharides and lipids, increasing the sensitivity of tissues to insulin. Its effect leads to an increased transport and utilization of glucose and free fatty acids in muscles, liver and adipose cells and inhibits gluconeogenesis in liver. Adiponectin, at the same time prevents the development of atherosclerosis, especially at early stages of its formation.