PGY 206 Exam 2 Notes
PGY 206 Exam 2 Notes PGY 206
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This 47 page Study Guide was uploaded by Sharon Liang on Tuesday March 1, 2016. The Study Guide belongs to PGY 206 at University of Kentucky taught by Dr. Dexter Speck in Spring 2016. Since its upload, it has received 178 views. For similar materials see Elementary Physiology in Physiology at University of Kentucky.
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Date Created: 03/01/16
PGY 206 Endocrine System Types of Endocrine Communication Autocrine Paracrine: adrenal cortex, pancreatic islets Endocrine Neuroendocrine: hypothalamic hormones that regular the anterior pituitary Endocrine Glands and Hormones Secrete biologically active molecules into blood - Lacks ducts Carry hormones to target cells that contain specific receptor proteins for that hormone Target cells can respond in a specific fashion General Functions of the Endocrine System Maintain homeostasis of internal environment - Plasma (glucose, calcium) Adaptation in changes in external environment - Response to stress (injury, danger, psychological/emotional stress, temperature) in many hormones – plasma (epinephrine) Control of many processes in multiple tissues requiring coordination of complex events at the whole body level - Ion and fluid balance – ADH and aldosterone (renal section) - Energy metabolism – fuel storage and utilization – insulin, glucagon, thyroid hormones, and others - Digestion – (GI section) - Growth and development – GH, TH, etc. - Reproduction – sex hormones Endocrine System – major communicative/integrative system Nervous System Endocrine System Functional unit Neuron Gland cell Chemical messenger Neurotransmitter Hormone Mode of transmission Action potentials Circulation Reaction time Milliseconds - seconds Minutes - days Target cell must have specific receptor proteins Combination of regulatory molecule with its receptor proteins must cause a specific sequence of changes There must be a mechanism to quickly turn off the action of a regulator Hormones Overview “hormone” in Greek means “to excite” and sometimes they inhibit Hormones are chemical messengers which - Are secreted by specific cells - Are released into the bloodstream in very small amounts - Communicate information to their target cells to regulate, not initiate, functions in their target cells. For example, they can either increase or decrease a given function Hormones exert their effects at the cellular level by regulating cell division, differentiation, activation, activation, apoptosis, motility, secretion and nutrition uptake At the molecular level hormones regulate: gene transcription, protein synthesis and degradation, enzyme activity and protein: protein interactions A single gland may secrete multiple hormones such as thyroid, pancreas, anterior pituitary gland A hormone may be secreted by more than one gland such as somatostasin Life Cycle of a Hormone All actions of hormones are mediated by receptors Receptors: have high affinity binding sites for hormones - Confer specificity on the endocrine system because numerous hormones circulate in the bloodstream and each can access all cells Chemical Classifications of Hormones Hormones can be divided into - Polar (hydrophilic, water soluble): glycoproteins can’t be taken orally; for example insulin is a hormone that must be injected - Nonpolar (lipophilic, water insoluble): steroids can be taken orally; examples include steroid hormones and T ; can gai4 entry into target cells Amines (hydrophilic) - Hormones derived from tyrosine and tryptophan. Examples include norepinephrine, epinephrine, and T 4 Polypeptides and proteins (hydrophilic) - Polypeptides: chains of <100 amino acids in length such as ADH - Protein hormones: polypeptide chains of >100 amino acids such as a growth hormone Glycoproteins - Long polypeptides ( (>100) bound to ≥ 1 carbohydrate (CHO)) such as FSH and LH Steroids are lipids derived from cholesterol meaning they’re lipophilic hormones (they can get into target cells) - Corticosteroids secreted in adrenal cortex i. Cortisol ii. Aldosterone - Sex steroids secreted in gonads i. Testosterone ii. Estradiol iii. Progesterone Types of Hormones Based on Structure 1) Amino acid derived or Tyrosine derivatives - Catecholamines produced by the adrenal medulla and CNS i. Dopamine, norepinephrine, epinephrine (Amine hormones: hydrophilic) - Thyroid hormones (hydrophobic): iodothyronines produced by thyroid gland i. Triiodothyronine (T ) 3 ii. Thyroxine (T ) 4 2) Steroid hormones (hydrophobic) - Derivatives of cholesterol - Synthesized by adrenal cortex (aldosterone, cortisol, androstenedione), gonads (testosterone, estradiol), placenta (progesterone, estrogens), and kidney (vitamin D ) 3 - Lipophilic, cross membranes easiliy - Have intracellular receptors - Water insoluble: transported in blood mostly bound to proteins - Glandular storage is minimal because they easily diffuse out of the cell - Can be orally administered 3) Peptide hormones (<20 amino acids) - Subset of protein hormones - Hypothalamic GnRH, TRH, somatostatin, oxtocin, and ADH, and angiotensin 4) Protein hormones (>20 amino acids) - Stored inside cells in membrane bound granules - Most circulate unbound or free (a few circulate bound) - Are relatively polar (hydrophilic), don’t cross membranes easily - Have extracellular receptors - Can’t be orally administered because it can be digested Binding of Water-Soluble Hormones Binding of Lipid-Soluble Hormones Receptor Types 1) Membrane receptors: the hormone binding site is extracellular Transmit their signal inside the cell via a signaling pathway, whereby hormone binding at an extracellular site induces a conformational change (signal) that activates one or more intracellular 2 nd messengers that bind to effector proteins, which in turn result in the hormone’s action Mediate all protein and peptide hormones actions including ion channel or enzyme activity, gene transcription, and protein synthesis 2) Intracellular receptors Steroid receptors are intracellular ligand activating proteins acting as transcription factors Located in cytoplasm or nucleus Slower acting than protein hormones because their action requires genomic transcription and subsequent translational processes Recent evidence exists for plasma membrane steroid receptors that mediate rapid responses to steroid hormones Intracellular 2 ndMessengers Cyclic nucleotides (cyclic AMP, GMP) that bind to effector kinases such as PKA or ion channels - from adenylyl or guanylyl cyclase activation ion-calcium: direct or indirect (via calbindin) regulation of effector proteins lipid messengers: from activation of phospholipase C, which catalyzes formation of: - diacylglycerol (DAG): activates protein kinase C (PKC) - inositol triphosphate (IP )3 which increases intracellular (calcium) Adenylate Cyclase (cAMP) binding of epinephrine to beta-adrenergic receptor protein causes dissociation of a subunit of G-protein G-protein subunit binds to and activates adenylate cyclase ATP cAMP + PP i cAMP attaches to inhibitory subunit of protein kinase Inhibitory subunit dissociates and activates protein kinase Phosphorylates enzymes within the cell to produce hormone’s effects Modulates activity of enzymes present in the cell Alters metabolism of cell cAMP inactivated by phosphodiesterase - hydrolyzes cAMP to inactivate fragments 2+ Phospholipase-C-Ca binding or epinephrine to alpha-adrenergic receptor in plasma membrane activates a G-protein intermediate, phospholipase C - phospholipase C splits phospholipid into IP and 3AG (both derivatives serve as 2 ndmessengers) IP3diffuses through cytoplasm to ER. - Binding of IP 3o receptor protein in ER causes Ca 2+channels to open Ca+ diffuses into cytoplasm 2+ - Ca binds to calmodulin Calmodulin activates specific protein kinase enzymes - Alters metabolism of the cell producing hormone’s effects nd Epinephrine can act through 2 2 messenger systems Tyrosine Kinase (TrK) Insulin receptor consists of 2 units that dimerize when they bind with insulin - Insulin binds to ligand-binding site on plasma membrane, activating enzymatic site in the cytoplasm Autophosphorylation occurs increasing TrK activity Activates signaling molecules - Stimulates glycogen, fat, and protein synthesis - Stimulation insertion of GLUT-4 carrier proteins Hormones that Bind to Nuclear Receptor Proteins Lipophilic steroids and thyroid hormones are attached to plasma carrier proteins - Hormones dissociate from carrier proteins to pass through lipid component of the target plasma membrane Receptors for the lipophilic hormones are known as nuclear hormone receptors Nuclear Hormone Receptors Steroid receptors are located in cytoplasm and nucleus Function within cell to activate genetic transcription - mRNA directs synthesis of specific enzyme proteins that change metabolism Each nuclear hormone receptor has 2 regions: 1) A ligand (hormone) binding domain 2) DNA-binding domain Receptor must be activated by binding to hormone before binding to specific region of DNA called HRE (hormone responsive element) - Located adjacent to gene that’ll be transcribed Mechanisms of Steroid Hormone Action Cytoplasmic receptor binds to steroid hormone Translocates to nucleus DNA-binding domain binds to specific HRE of DNA Dimerization occurs - Process of 2 receptor units coming together at the 2 half-sites Stimulates transcription of particular genes Mechanisms of Thyroid Hormone Action T 4thyroxine) passes into cytoplasm and is converted to T 3 Receptor proteins located in nucleus - T3binds to ligand binding domain - Other half-site is Vitamin A derivative (9-cis-Retinoic acid). This is where DNA binding domain can then bind to the half-site of the HRE - 2 partners can bind to the DNA to activate HRE. This stimulates transcription of genes Hormones Secreted by the Primary Endocrine Glands Hypothalamus (hypophysiotrophic hormones) - GnRH (gonadotrophin releasing hormone) - GHRH (GH releasing hormone) - CRH (corticotrophin releasing hormone) - TRH (TSH releasing hormone) Thyroid - T3(triiodothyroid hormone) - T4(thyroxine) - Calcitonin Adrenals - Aldosterone - Cortisol - Corticosterone - DHEA (dehydroepiandrosterone) - Androstenedione - Epinephrine - Norepinephrine Pituitary - Anterior pituitary: trophic hormones i. FSH (follicle stimulating hormone) ii. LH (luteinizing hormone) iii. ACTH (adrenocorticotrophic hormone): stimulate cortisol and corticosterone iv. TSH (thyroid stimulating hormone): stimulates T and T 3 4 v. Growth hormone (GH) vi. PRL (prolactin) - Posterior pit: neuroendocrine hormones i. ADH (antidiuretic hormone) ii. OXY (oxytocin) Parathyroids - PTH (parathyroid hormone) Pancreas - Insulin - Glucagon - Somatostatin Subdivisions of the Brain Hypothalamus-Pituitary Complex The hypothalamus region lies inferior and anterior to the thalamus. It connects to the pituitary gland by the stalk-line infundibulum. The pituitary gland consists of an anterior and posterior lobe, with each lobe secreting different hormones in response to signals from the hypothalamus Pituitary Gland (Hypophysis) Pituitary gland is located in the diencephalon Structurally and functionally divided into anterior and posterior lobes Anterior pituitary - Master gland (adenohypophysis) - Derived from a pouch of epithelial tissue that migrates upward from the mouth i. Consists of 2 parts 1) Pars distalis: anterior pituitary 2) Pars tuberalis: thin extension in contact with the infundibulum - Manufactures seven hormones. The hypothalamus produces separate hormones that stimulate or inhibit hormone production in the anterior pituitary. Hormones from the hypothalamus reach the anterior pituitary via hypophyseal portal system Posterior pituitary (neurohypophysis) - Formed by downgrowth of the brain during fetal development - Contact with infundibulum i. Nerve fibers extend through infundibulum - Neurosecretory cells in the hypothalamus release oxytocin or ADH into the posterior lobe of the pituitary gland. These hormones are stored or released into the blood via capillary plexus Pituitary Hormones 1) Anterior Pituitary Trophic effects - High blood (hormone) causes target organ to hypertrophy - Low blood (hormone) causes target organ to atrophy Hormonal control rather than neural Hypothalamus neurons synthesize “releasing” and “inhibiting” hormones Hormones are transported to axon endings of median eminence Hormones secreted into hypothalamo-hypophyseal portal system regulate the secretions of the anterior pituitary 2) Posterior Pituitary Stores and releases 2 hormones produced in the hypothalamus i. ADH/vasopressin: promotes the retention of water by kidneys meaning less water excreted in the urine ii. Oxytocin: stimulates contraction of the uterus during parturition also stimulates contractions of the mammary gland alveoli during milk-ejection reflex. Hypothalamus neuron cell bodies produce: - ADH: supraoptic nuclei - Oxytocin: paraventricular nuclei Transported along the hypothalamo-hypophyseal tract Release controlled by neuroendocrine reflexes - “sucking reflex (let down)” is oxytocin-mediated, elicited by sensory input to hypothalamus leading to ADH secretion Regulation of Hormone Actions Feedback systems or loops alter amount of hormone synthesized and secreted - Negative: maintains homeostasis of target organ hormone level via set point i. Hypothalamic pituitary target gland axis: 3 hormones are involved at 3 sites - Positive: less common; explosive; no homeostasis i. Oxytocin parturition (birth) ii. Estradiol induction of pre-ovulatory gonadotrophin surges (ovulation) Feedback Control of the Anterior Pituitary Anterior pituitary and hypothalamic secretions are controlled by the target organs they regulate - Secretions are controlled by negative feedback inhibition by target gland hormones Negative feedback at 2 levels 1) The target gland hormone can act on hypothalamus and inhibit secretion of releasing hormones 2) The target gland hormone can act on anterior pituitary and inhibit response to the releasing hormone Hypothalamus pituitary axis thyroid axis - Secretion of thyroxine from thyroid is stimulated by TSH and the secretion of TSH is stimulated by TRH Negative feedback effect - Stimulation balanced by thyroxine-induced reduced responsiveness to TRH Negative feedback loop: retrograde transport of blood from anterior pituitary to hypothalamus - Hormone released by anterior pituitary inhibits secretion of releasing hormone Positive feedback effect: during the menstrual cycle, estrogen stimulates “LH surge” Higher Brain Function and Pituitary Secretion Axis refers to a: relationship between brain, anterior pituitary and a particular target gland - Hypothalamus pituitary adrenal axis Hypothalamus receives input from higher brain centers. Therefore, psychological stress affects circadian rhythm (day/night cycles) and menstrual cycle Adrenal Glands Both adrenal glands sit atop the kidneys and are composed of an outer cortex and inner medulla, all surrounded by a connective tissue capsule. The cortex can be subdivided into additional zones, all of which produce different types of hormones. Adrenal cortex - Doesn’t receive neural innervation - Must be stimulated hormonally (ACTH) Consists of 3 zones 1) Zona glumerulosa 2) Zona fasciculate 3) Zona reticularis Secretes “corticosteroids” Functions of Adrenal Medulla Cells secrete epinephrine and norepinephrine (catecholamines) Innervated by preganglionic sympathetic axons. “Fight or Flight” - Increase HR and cardiac output - Increase respiratory rate - Vasoconstrict blood vessels, thus increasing venous return - Stimulate glycogenolysis (breakdown of glycogen and glucose e.g. liver) - Stimulate lipolysis (hydrolysis of fats into fatty acids and glycerol) Functions of the Adrenal Cortex Zona glumerulosa - Produces mineralocorticoids (aldosterone): stimulate kidneys to reabsorb + + Na and secrete K Zona fasciclulata - Secretes glucocorticoids (cortisol, hydrocortisone): inhibit glucose utilization and stimulate gluconeogenesis (raises blood [glucose]) Zona reticularis - Sex steroids (DHEA): supplement sex steroids Cortisol is released in response to stress and low [glucocorticoids] in blood Primary functions: - Increase blood sugar (homeostasis) - Suppress immune system - Aid in fat, protein, and carbohydrate metabolism Dysfunctions of the Adrenal Cortex Hyposecretion of corticosteroids (glucocorticoids and mineralcorticoids) - Results in Addison’s disease (hypoglycemia, dehydration, weight loss, hypotension) Hypersecretion of corticosteroids (ACTH) results in Cushing’s syndrome - “puffy,” “buffalo hump,” “moon face” - Hyperglycemia, muscle weakness, hypertension - Due to anterior pituitary oversecretion or tumor of adrenal cortex Negative Feedback Loop - Release of adrenal glucocorticoids is stimulated by the release of hormones from the hypothalamus and pituitary gland. This signaling is inhibited when glucocorticoid levels become elevated by causing negative signals to the pituitary gland and hypothalamus. Stress and the Adrenal Gland Thyroid Hormones Thyroid gland is located just below the larynx Thyroid is the largest of the pure endocrine glands Thyroid secretes T an3 T 4 Needed for proper growth and basal metabolic rate The thyroid gland is located in the neck where it wraps around the trachea. The glandular tissue is composed primarily of thyroid follicles. The larger parafollicular cells often appear in the matrix of follicle cells. Thyroid Hormones Follicular cells secrete T 4 Parafollicular cells secrete calcitonin Scan of the thyroid gland 24 hours after the intake of radioactive iodine Iodide (I ) actively transported into the follicle and secreted into the colloid o Oxidized to iodine (I ) Iodine attached to tyrosine within thyroglobulin chain - Attachment of 1 iodine produces monoiodothyrosine (MIT). - Attachment of 2 iodines produces diiodothyrosine (DIT). (MIT and DIT) or (2 DIT) molecules couple together T and T produced 3 4 TSH stimulates endocytosis out of follicular cell - Enzymes hydrolyze T and T3from th4roglobulin Attached to TBG (thyroxine binding globulin; carrier protein) and released into blood Actions of T 4 4 is transported in blood, with 99.5% of the secreted T being p4otein-bound, principally to TBG 4 is involved in controlling the rate of metabolic processes in the body and influencing the physical development 4 is a prohormone and a reservoir for the active thyroid hormone T which is 3 about 4x more potent. T is converted in the tissues of deiodinases to T . 4 3 Actions of T 3 Stimulates protein synthesis Promotes maturation of nervous system. Stimulates rate of cellular respiration (mitochondria) by: - Production of uncoupling proteins + + - Increase active transport by Na /K pumps - Lower cellular [ATP] Increases metabolic heat Increases metabolic rate - Stimulates increased consumption of glucose, fatty acids, and other molecules Mechanism of Thyroid Hormone Action T4passes into cytoplasm and is converted to T 3 Receptor proteins located in nucleus - T 3inds to ligand-binding domain - Other half-site is vitamin A derivative (9-cis-Retinoic acid) i. DNA binding domain can then bind to the half-site of HRE - 2 partners can bind to the DNA to activate HRE i. Stimulate transcription of genes Diseases of Thyroid Iodine-deficiency (endemic) goiter: - Abnormal growth of the thyroid gland i. In the absence of sufficient iodine, can’t produce adequate amounts of T 3nd T 4 a. Lack of negative feedback inhibition 1. Stimulates TSH, which causes abnormal growth Adult myxedema (due to severe hypothyroidism): dry, thick skin - Accumulation of mucoproteins and fluid in subcutaneous tissue (swell) - Symptoms: i. Decreased BMR ii. Weight gain iii. Decreased ability to adapt to cold iv. Lethargy Graves’ disease: goiter - Autoimmune disorder: i. Auto-abs exert TSH-like effects on thyroid a. Not affected by negative feedback Cretinism-hypothyroidism: - Hypothyroid from end of 1 trimester to 6 months postnatally i. Severe mental retardation… may be rescued with thyroxine treatment Classic negative feedback loop controls the regulation of thyroid hormone levels Feedback Control of the Anterior Pituitary Hypothalamus-pituitary-thyroid axis - Secretion of thyroxine from thyroid is stimulated by TSH and secretion of TSH is stimulated by TRH Negative feedback effect - Stimulation balanced by thyroxine-induced reduced responsiveness to TRH Parathyroid glands The small parathyroid glands are embedded in the posterior surface of the thyroid gland Embedded in the lateral lobes of the thyroid gland Parathyroid hormone (PTH): only hormone secreted by parathyroid glands Single most important hormone in the control of blood [Ca ] 2+ 2+ Stimulated by decreased blood [Ca ] Promotes rise in blood [Ca ] by acting on bones, kidney, and intestines PTH increases blood calcium levels when they drop too low. Conversely, calcitonin, which is released from the thyroid gland, decreases blood calcium levels when they go up too high. Basically, these 2 mechanisms maintain blood calcium at homeostasis. Pancreas The pancreatic exocrine function involves the acinar cells secreting digestive enzymes that are transported into the small intestine by the pancreatic duct. Its endocrine function involves the secretion of insulin (produced by beta cells) and glucagon (produced by alpha cells) within the pancreatic islets. These 2 hormones regulate the rate of glucose metabolism in the body. Alpha cells secrete glucagon - Stimulus is decreased in blood [glucose] - Stimulates glycogenolysis and lipolysis - Stimulates conversion of fatty acids to ketones (energy stores) Beta cells secrete insulin - Stimulus is increased in blood [glucose] - Promotes entry of glucose into cells - Converts glucose to glycogen and fat - Aids entry of amino acids into cells GLUT4 carrier proteins permit the facilitated diffusion of glucose from the extracellular fluid into the cell Glucose is used for ATP production following its oxidative phosphorylation Diabetes mellitus: fasting hyperglycemia with glucose present in urine Type 1 diabetes (insulin dependent): destruction of beta cells (no insulin) Type 2 diabetes (non-insulin dependent): decreased tissue sensitivity to the effects of insulin (need more insulin) Oral Glucose Tolerance Test Measure of the ability of beta cells to secrete insulin Ability of insulin to lower blood glucose Normal person’s rise in blood [glucose] after drinking solution becomes normal in 2 hours Gastrointestinal or Digestive System Digestive tract: mouth to anus Alimentary canal Accessory organs - Teeth, tongue, salivary glands, liver, gallbladder, pancreas Functions to digest and absorb Important Structures for Absorption How do molecules move? - Diffusion: J = ( gradient) x surface area/thickness What aids diffusion? - Increased surface area - Increased gradient - Thin membrane for diffusion Functions of the GI Tract Motility: movement of food through the GI tract - Ingestion: taking food into mouth - Mastication: chewing food and mixing it with saliva - Deglutition: swallowing food - Peristalsis: rhythmic wave-like contractions that move food through the GI tract Secretion (endocrine and exocrine) - - Exocrine: HCl, H O2 HCO , b3le, lipase, pepsin, amylase, trypsin, elastase, and histamine are secreted in the lumen of the GI tract - Endocrine: stomach and small intestine secrete hormones to help regulate the GI system i. Gastrin, secretion, CCK (cholecystokinin), GIP ii. GLP-1, guanylin, VIP, and somatostatin Digestion: breakdown of food particles into subunits (chemical structure change) Absorption: process of the passage of digestion (chemical subunits) into blood or lymph Storage elimination: temporary storage and elimination of indigestible food Functions of the GI Tract (Specific Motilities) Antral-pyloric pumping: stomach - Retropulsion Segmentation: mixing movements - Peristalsis: Starling’s law of intestine Haustrations: mixing of movements Mass movement: periodic propulsion GI Tract Structures Muscles through most of the GI tract are smooth Skeletal muscle is found only at both ends: controlled mainly by somatic nervous system-limited ANS Tongue, upper esophageal sphincter Upper esophagus External and sphincter Digestive System (GI) GI tract divided into - Alimentary canal - Accessory digestive organs GI tract is 30 feet long extending from mouth to anus Layers of GI tract Composed of 4 layers 1) Mucosa - Lines lumen of the GI tract Consists of simple columnar epithelium - Lamina propria Thin layer of connective tissue containing lymph nodules - Muscularis mucosae Thin layer of smooth muscle responsible for folds o Folds increase surface area for absorption - Goblet cells Secrete mucus 2) Submucosa - Thick, highly vascular, CT - Absorbed molecules enter blood and lymphatic vessels - Submucosal glands - Submucosal plexus (Meissner’s plexus) Provide autonomic nerve supply to the muscularis mucosae 3) Muscularis externa - Responsible for segmental contractions and peristaltic movement through GI tract Inner circular layer of smooth muscle Outer longitudinal layer of smooth muscle - Contractions of these layers move food through the tract; pulverize and mix the food - Mixing vs propulsion - Myenteric plexus located between the 2 muscle layers Major nerve supply to the GI tract o Fibers and ganglia from both sympathetic and parasympathetic nervous systems 4) Serosa - Binding and protective outer layer - Consists of connective tissue covered with simple squamous epithelium Features of Smooth Muscle Small cells interconnected by gap junctions or “nexus” – connexin proteins Autorhythmic: they generate their own cyclic depolarization – “slow wave” Contractions of Intestinal Smooth Muscles Occur automatically in response to endogenous pacemaker activity Rhythm of contractions is paced by graded depolarizations called slow waves. - Slow waves produced by interstitial cells of Cajal - Slow waves spread from 1 smooth muscle cell to another through nexuses Visceral smooth muscle vs striated muscle 1) Visceral smooth Neural Autonomics Both excitatory and inhibitory neurotransmitters EC coupling dependent on extracellular calcium Syncytium Plexuses SNS decreases BER, PNS increases 2) Striated Somatic Only excitatory neurotransmitters Acetylcholine Intracellular calcium Motor units Smooth Muscle 1) Localization Muscularis mucosa Muscularis externa - Circular and longitudinal 2) Syncytium: “unitary muscle” Electrical-gap junction-nexus Mechanical-intermediate junction Longitudinal layer-interstitial cells of Cajal Circular layer-most tightly coupled 3) Structure of smooth muscle cell Dense bodies-intracellular skeleton - Cytoskeleton Intermediate filaments - Desmin and vimentin Regulation of GI Tract Extrinsic innervation - PNS Vagus and sacral spinal nerves o Stimulate motility and GI secretions - SNS Postganglionic sympathetic fibers that pass through submucosal and myenteric plexuses and innervate GI tract o Reduce peristalsis and secretory activity Enteric nervous system - Sites where parasympathetic fibers synapse with postganglionic neurons that innervate smooth muscle Submucosal and myenteric plexuses - Local regulation of GI tract Paracrine secretion - Molecules acting locally Hormonal secretion - Secreted by mucosa Enteric Nervous System Submucosal and myenteric plexuses contain 100 million neurons Include preganglionic parasympathetic axons, ganglion cell bodies, postganglionic sympathetic axons; and afferent intrinsic and extrinsic sensory neurons Peristalsis - Acetylcholine and substance P stimulate smooth muscle contraction above the bolus - NO, VIP, and ATP stimulate smooth muscle relaxation below the bolus Intestinal Reflexes Intrinsic and extrinsic regulation controlled by intrinsic and paracrine regulators Gastroileal reflex: increased gastric activity causes increased motility of ileum and movement of chime through ileocecal sphincter Ileogastric reflex: distension of ileum, decreases gastric motility Intestino-intestinal reflex: overdistension in 1 segment causes relaxation throughout the rest of the intestine Endocrine and Paracrine Regulators of the Gut Gastrin CCK (cholecystokinin) Secretin Serotonin (5-HT): stimulates intrinsic afferents which send impulses into intrinsic nervous system and activates motor neurons Motilin: stimulates contraction of the duodenum and stomach antrum From Mouth to Stomach Mastication (chewing) - Teeth are accessory organs. Chewing reflex. Increases surface area and speeds digestion - Mixes food with saliva which contain amylase (enzyme that can catalyze partial digestion of starch) Salivary glands - Parotid, submandibular, sublingual, oral - Saliva contains enzymes, fluoride, water, mucus - Salivary alpha-amylase begins starch digestion Deglutition (swallowing) - Begins as a voluntary activity - Requires about 25 muscles, 5 cranial nerves, brainstem control - Involves 3 phases Oral phase is voluntary Pharyngeal and esophageal phases are involuntary and can’t be stopped - Larynx is raised - Epiglottis covers entrance to respiratory tract Involuntary muscular contractions and relaxations in the mouth, pharynx, larynx, and esophagus are coordinated by swallowing center in the medulla. Esophagus - Connects pharynx to stomach Upper third contains skeletal muscle Middle third contains a mix of skeletal and smooth muscle Terminal portion only contains smooth muscle - Peristalsis Produced by a series of localized reflexes in response to distension of wall by bolus - Wave-like muscular contractions Circular smooth muscle contract behind relaxes in front of the bolus Followed by longitudinal contraction (shortening) of smooth muscle at a rate of 2-4 cm/sec After food passes through the stomach, LES constricts Primary and Secondary Peristalsis Primary peristalsis – controlled by brainstem; requires vagal efferent activity; takes about 5 seconds from pharynx to LES If food doesn’t move through esophagus – it initiates a local reflex called secondary peristalsis Secondary peristalsis is slower, weaker, and not as well-coordinated Heartburn (Gastroesophageal Reflux Disease [GRD, GERD], esophagitis) Burning sensation caused by reflux of acid from the stomach into esophagus Symptoms similar to those of heart attack Occurs with large meals, pregnancy, obesity, alcohol consumption Can result in esophageal ulcers Factors that Decrease LES Pressure Fat Ethanol Chocolate Peppermint Caffeine and theophylline Smoking Barbiturates Progesterone (pregnancy) Stomach Most distensible part of GI tract - Empties into duodenum Functions - Stores food - Initiates digestion of proteins - Kills bacteria - Moves food into intestine Contractions of the stomach churn chime - Mix chime with gastric secretions - Push food into intestine Gastric mucosa has gastric pits in the folds Columnar epithelial cells secrete mucus and alkaline fluid Cells that line the folds deeper in the mucosa are gastric glands Gastric Glands Secrete gastric juice - Goblet cells: mucus - Parietal cells: HCl and intrinsic factor - Chief cells: pepsinogen - Enterochromaffin-like cells (ECL): histamine, serotonin, and ghrelin - G cells: gastrin - D cells: somatostatin HCl Production + Parietal cells secrete H into gastric lumen by primary active transport through H /K ATPase pump Parietal cell’s basolateral membrane takes in Cl against its electrochemical - gradient by coupling its transport with HCO 3 HCl production is stimulated by changing conformation of parietal cells This change is stimulated by: - Gastrin: from G cells - Ach: from PNS activation - Histamine: H2 receptors Potentiation: because histamine potentiates Ach and gastrin effects blocking it has great effect HCl Functions Makes gastric juice very acidic - Denatures ingested proteins (alter tertiary structure) so they become more digestible Activates pepsinogen to pepsin - Pepsin is more active at a pH of 2.0 Digestion and Absorption in the Stomach Proteins partially digested by pepsin (about 15-25% normally) Carbohydrate digestion by salivary amylase is soon inactivated by acidity Alcohol and aspirin are the only commonly ingested substances absorbed – but important for “rapidly absorbed drug formulations.” Peptic Ulcers – gastric or duodenal Peptic ulcers: - Erosions of the mucosa of the stomach or duodenum extending into the muscularis externa, produced by action of HCl, refluxed bile salts, or ingested substances - Erosions are normal, you have them, but ulcers aren’t normal Gastric mucosal barrier - A natural protective mechanism for lining of stomach – aided by rapid turnover of cells, tight junction between cells, secretion of alkaline mucus, prostaglandins, high blood flow (to dilute and “wash out”). - Attack factors – acid, pepsin, bacteria, bile salts, aspirin, alcohol, etc. Zollinger-Ellison syndrome: - Ulcers of the duodenum are produced by excessive gastric acid secretions Helicobacter pylori: - Bacterium that resides in GI tract that may produce ulcers Acute gastritis: - Histamine released by tissue damage and inflammation stimulate further acid secretion Defense vs attack mechanisms Protective Mechanisms of the Stomach Parietal and chief cells are impermeable to HCl Alkaline mucus contains HCO 3- Tight junctions between adjacent epithelial cells Rapid rate of cell divisions (entire epithelium replaced in 3 days) Prostaglandins inhibit gastric secretions Emesis Protective mechanism for vomiting Peripheral receptors: - Intestinal receptors; visual and vestibular Central receptors: - Psychogenic; area postrema; pregnancy Efferents: - Smooth muscle relaxes in sphincters - Skeletal muscle for respiration generates force Chronic vomiting causes loss in H and K + - Metabolic alkalosis - Dehydration and hypokalemia Small Intestine Each villus is a fold in the mucosa Covered with columnar epithelial cells interspersed with goblet cells Epithelial cells at the tips of villi are exfoliated and replaced by mitosis in crypt of Lieberkuhn Lamina propria contain lymphocytes, capillaries, and central lacteal Intestinal Contractions and Motility 2 major types of contraction occur in the small intestine 1) Peristalsis - Slow movement - Pressure at the pyloric end of small intestine is greater at distal end 2) Segmentation - Major contractile activity of small intestine - Contraction of circular smooth muscle (mix chime) Intestinal Enzymes Microvilli contain brush border enzymes that aren’t secreted into the lumen - Brush border enzymes remain attached to the cell membrane with their active sites exposed to the chime Absorption requires both brush border enzymes and pancreatic enzymes Most common defect is loss of lactase leading to lactose intolerance Absorption in Small Intestine Duodenum and jejunum: 2+ - Carbohydrates, amino acids, lipids, iron, water, and Ca Ileum: - Bile salts, vitamin B 12electrolytes, and water Large Intestine Outer surface bulges outward to form haustra Little absorptive function - Max water transport is about 4 L daily but does work against large gradient - Absorbs water, electrolytes, several vitamin B complexes, vitamin K, and folic acid Intestinal microbiota produce significant amounts of folic acid and vitamin K Bacteria ferment indigestible molecules to produce short-chain fatty acids Secretes water via active transport of NaCl into intestinal lumen - Membrane contains Na /K pumps+ Fluid and Electrolyte Absorption in the Intestine Small intestine: - Most of the fluid and electrolytes are absorbed by the small intestine Absorbs about 90% of the remaining volume - Absorption of water occurs passively as a result of the osmotic gradient created by active transport Aldosterone stimulates salt and water absorption in ileum Large intestine: - Absorbs about 90% of remaining volume Absorption of water occurs passively as a result of the osmotic gradient created by active transport of Na and Cl - Defecation Waste material passes to the rectum Occurs when rectal pressure rises and external and sphincter relaxes Defecation reflex: - Longitudinal rectal muscles contract to increase rectal pressure Relaxation of internal anal sphincter - Excretion is aided by contractions of abdominal and pelvic skeletal muscles Pushes feces from rectum Constipation: too much water reabsorbed leading to very hard feces and difficulty in defecation aka “fecoliths” Diarrhea: too little water absorbed leading to fluid loss along with feces - Secretory - Osmotic - Motile: hypermotile or hypomotile Liver Structure Liver largest internal organ - Hepatocytes (major functional cell in liver) form hepatic plates 1-2 cells thick - Arranged into functional units called lobules Plates separated by sinusoids - More permeable than other capillaries Also contains phagocytic Kupffer cells Secretes bile into bile canaliculi which are drained by bile ducts Hepatic Portal System 2 capillary beds in a series Products of digestion that are absorbed are delivered to the liver Intestinal capillaries (plus those from most of gut) drain into the hepatic portal vein, which carries blood to the liver - ¾ blood is deoxygenated from intestine - ¼ blood is oxygenated (hepatic artery) - Hepatic veins drains liver Enterohepatic Circulation Compounds that recirculate between liver and intestine - Many compounds can be absorbed through small intestine and enter hepatic portal blood - Variety of exogenous compounds are secreted by the liver into the bile ducts Can excrete these compounds into the intestine with bile Bile Production and Secretion The liver produces and secretes 250-1500 mL of bile daily. Bile contains water, HCO , 3ile salts and bile pigments Bile pigment (bilirubin) is produced in spleen, bone marrow, and liver - Derivative of the heme groups (without iron) to hemoglobin Free bilirubin combines with glucuronic acid and forms conjugated bilirubin - Secreted into bile Converted by bacteria in intestine and urobilinogen - Urobilinogen is absorbed by intestine and enters the hepatic vein Recycled or filtered by kidneys and excreted in urine Bile acids are derivatives of cholesterol - Major pathway of cholesterol breakdown in the body Principal bile acids are: - Cholic acid - Chenodeoxycholic acid Combine with glycine or taurine to form bile salts o Bile salts aggregate as micelles 95% of bile acids are absorbed by ileum Detoxification of Blood Liver can remove hormones, drugs, and other biologically active molecules from the blood (alcohol, valium, etc.) Inactivation of steroid hormones and drugs - Excretion into bile - Phagocytosis by Kupffer cells - Chemical alteration of molecules Ammonia is produced by deamination of amino acids in liver Liver converts it to urea o Excreted in urine Production of Plasma Proteins Albumin and most of the plasma globulins (except immunoglobulins) are produced by the liver Albumin - Constitutes 70% of total plasma protein Contributes most to the colloid osmotic pressure in the blood. EDEMA Globulins - Transports cholesterol and hormones - Produce blood clotting factors I, II, III, V, VII, IX, XI Gallbladder Sac-like organ attached to the inferior surface of liver Stores and concentrates bile As the gallbladder fills with bile, it expands. - Contraction of the muscularis layer of the gallbladder ejects bile into the common bile duct into duodenum When small intestine is empty, sphincter of Oddi closes - Bile is forced up to the cystic duct to gallbladder Gallstones Cholesterol stones: too much cholesterol in bile Calcium stones Other types of crystals forming – “magic crystals” – supersaturated solution Effects of obstructing ducts… Pancreas Exocrine - Acini Secrete pancreatic juice Endocrine - Islets of Langerhans Secrete insulin and glucagon Pancreatic Juice - Contains water, HCO , a3d digestive enzymes Complete digestion of food requires action of both pancreatic and brush border enzymes - Most pancreatic enzymes are produced as zymogens - Trypsin (when activated by enteropeptidase) triggers the activation of other pancreatic enzymes Pancreatic trypsin inhibitor attaches to trypsin - Inhibits its activity in pancreas Neural and Endocrine Regulation Neural and endocrine mechanisms modify activity of the GI system GI tract is both an endocrine gland and a target action for hormones Regulation of Gastric Function Gastric motility and secretion are automatic Waves of concentration are initiated spontaneously by pacesetter cells Extrinsic control of gastric function (and all GI function) can be divided into 3 phases 1) Cephalic 2) Gastric 3) Intestinal Cephalic Phase Stimulated by sight, smell, and taste of food Activation of vagus: - Stimulates chief cells to secrete pepsinogen - Directly stimulates G cells to secrete gastrin - Directly stimulates ECL cells to secrete histamine - Indirectly stimulates parietal cells to secrete HCl Continues to the 1 30 minutes of a meal Gastric Phase Arrival of food in stomach stimulates the gastric phase Gastric secretion stimulated by: - Distension - Chemical nature of chime (amino acids and short polypeptides) Stimulates G cells to secrete gastrin Stimulates chief cells to secrete pepsinogen Stimulates ECL cells to secrete histamine o Histamine stimulates secretion of HCl - Positive feedback effect As more HCl and pepsinogen are secreted, more polypeptides and amino acids are released - Negative feedback effect As pH decreases, inhibits G cell release of gastrin Secretion of HCl is also regulated by a negative feedback effect: - HCl secretion decreases if pH < 2.5 - At pH of 1.0, gastrin secretion ceases D cells stimulate secretion of somatostatin o Paracrine regulator to inhibit secretion of gastrin Intestinal Phase Inhibits gastric activity when chime enters small intestine Arrival of chime increases osmolality and distension - Activates sensory neurons of vagus and produces an inhibitory neural reflex Inhibits gastric motility and secretion In the presence of fat, enterogasterone inhibits gastric motility and secretion Hormone secretion - Inhibit gastric activity Somatostatin, CCK, secretion, enterogasterone, and GLP-1 Secretion of Pancreatic Juice and Bile Stimulated By Secretin - Occurs in response to duodenal pH < 4.5 - Stimulates production of HCO by pancreas 3 - - Stimulates the liver to secrete HCO into3the bile CCK - Occurs in response to fat and protein content of chime in duodenum - Stimulates production of pancreatic enzymes - Enhances secretin - Stimulates contraction and emptying of gallbladder Digestion and Absorption of Carbohydrates Salivary amylase - Begins starch digestion Pancreatic amylase - Digests starch to oligosaccharides - Oligosaccharides hydrolyzed by brush border enzymes + Glucose is transported by secondary active transport with Na into capillaries Digestion and Absorption of Proteins Digestion begins in the stomach when pepsin digests proteins to form polypeptides In the duodenum jejunum - Endopeptidases cleave peptide bonds in the interior of the polypeptide Trypsin (trypsinogen activated by enteropeptidase/enterokinase) Chymotrypsin Elastase - Exopeptidases cleave peptide bonds from ends of the polypeptide Carboxypeptidase Aminopeptidase Free amino acids absorbed by cotransport with Na + Dipeptides and tripeptides transported by secondary active transport using a Na gradient to transport them into a cytoplasm Hydrolyzed into free amino acids and then secreted into blood Digestion and Absorption of Lipids Arrival of lipids in the duodenum serves as a stimulus for secretion of CCK which releases bile Emulsification - Bile salts are secreted into duodenum to break up fat droplets Pancreatic lipase and colipase hydrolyze triglycerides to free fatty acids and monoglycerides - Colipase coats the emulsification droplets and anchors the lipase enzyme to them - Form micelles and move to brush border Free fatty acids, monoglycerides, and lysolecithin leave micelles and enter into epithelial cells - Inside the enterocyte, resynthesize triglycerides and phospholipids within cell Combine with a protein to form chylomicrons Secreted into central lacteals Transport of Lipids In blood, lipoprotein lipase hydrolyzes triglycerides to free fatty acids and glycerol for use in cells Remnants containing cholesterol are taken into the liver - Form VLDLs which take triglycerides into cells - Once triglycerides are removed, VLDLs are converted to LDLs LDLs transport cholesterol to organs and blood vessels - HDLs are transport excess cholesterol back to liver Absorption of Fat Absorption of Vitamins Fat soluble: require same mechanisms as fat absorption (A, D, E, K) Water soluble - Mostly diffusion - Some use active transport mechanisms - Vitamin B : 12trinsic factor from parietal cells; complex of IF-B 12 is absorbed in terminal ileum
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