Antidiuretic Hormone (ADH) By Jill Ruiz Carreon

Also known as… Arginine vasopressin (AVP) Argipressin “Pressor” effect is secondary significance “Pressor” = rise in BP due to vasoconstriction

Antidiuretic Hormone 9 amino acids Produced in hypothalamus Released from posterior pituitary (pars nervosa) to the blood Stimulates water retention in the kidneys Less water excreted in urine Regulates and balances water in blood  [H2O]   blood V and P

ADH & the CNS Released into the brain by neurons of the hypothalamo-hypophyseal tract Suprachaismatic nuclei (SCN) Regulation of circadian rhythms Circadian clock genes – transcribed into mRNA  proteins Role in species-typical patterns of social behavior

ADH & the Cardiovascular System Hypotension Increases vasoconstriction  Arterial BP Compensatory / Regulatory However, also seen in patients with heart failure Too many AVP receptors / AVP secretion Sympathetic and renin-angiotensin system activation in heart failure override hypothalamic control of AVP release May contribute to the increase in systemic vascular resistance as well as in renal retention of fluid Minimal pressor effects in humans

ADH & the Kidneys Regulation of extracellular fluid Conserve body water by reducing urine output ADH binds to aquaporins in the plasma membranes of the collecting duct epithelial cells Transports solute-free water through tubular cells Back into blood Decreases plasma osmolarity and increases urine osmolarity

ADH can be categorized as having these two primary action sites: -the blood vessels -the kidneys Left side: Hypothalamus detects hyperosmolarity and decrease in atrial receptor firing This leads to the posterior pituitary gland to secrete ADH, or vasopressin, to bind to the V1 receptors Causing blood vessels to constrict Causing increased systemic vascular resistance Ultimately increasing arterial pressure Right side: Angiotensin II and sympathetic stimulation sends message to hypothalamus for ADH to be released by posterior pituitary ADH then will bind to V2 Receptors Causing fluid reabsorption in the kidneys Increasing blood volume and increasing arterial pressure

Osmotic Sensors & Baroreceptors Work with ADH to maintain water metabolism By sensors in the hypothalamus reacting to the ccn of particles in your blood Na+, K+, Cl-, CO2, etc Unbalanced /   sensors tell kidneys to store or release water to maintain a healthy range Regulate body’s sense of thirst When the particle ccn is unbalanced or when the BP is low, these osmotic sensors and baroreceptors tell the kidneys to store or release water to maintain a healthy balance

Aquaporins Specialized membrane channel proteins Made up of single peptide chain consisting of about 270 aa Facilitate water transport across cell membranes At least 7 expressed in kidneys AQP 1, 2, 3, 4, 6, 7, 11 Role in short- & long-term regulation of water balance and pathophysiology of water balance disorders

Aquaporin Distribution in the Kidneys Aquaporin Group Localization in Kidney AQP 1 APM/BLM of proximal tubules and descending thin limbs AQP 2 APM/VES of principal cells of collecting ducts AQP 3 BLM of collecting ducts AQP 4 BLM of medullary collecting ducts AQP 6 Cortex, Medulla AQP 11 Proximal tubule (Intracellular) AQP: Aquaporin, APM: Apical membrane, BLM: Basolateral membrane, VES: Vesicles

AQP2 Cloned as an ADH-regulated water channel of CD Basal state: AQP2 stored in intracellular vesicular compartment With ADH stimulation, it moves quickly to apical membrane where it acts as water channel for the ccn of urine ADH acts at V2 receptors in BLM of CD principal cells Vasopressin acts at V2 receptors in basolateral membrane of the collecting ducts’ principal cells.  Next slide is the mechanism how it works

Aquaporin 2 (AQP2) At the basolateral membrane, activation of adenyl cyclase with the help of the enzyme, adenylate cyclase,  production of cyclic Adenosine Monophosphate from ATP  cAMP then will bind to protein kinase A (PKA)  which activates the catalytic subunit of PKA  PKA phosphorylates transcription factors like cAMP responsive element-binding protein (CREB-P) and c-jun / c-fos for synthesis of AQP2 in the intracellular vesicle and possibly other membrane prots  Binding of CREB-P and c-jun / c-fos proteins  increases gene transcription of AQP2  synthesis of AQP2 protein  which then enters the regulated trafficking sys NOT SHOWN in diagram – there are microtubular motor prots and vesicle targeting receptors (VAMP-2, Syntaxin-4, and NSF) that possibly add specificity of AQP2 targeting apical membrane to increase water permeability

ADH works on medulla collecting ducts -AQP3 -AQP4  Rapid reabsorption of water

AVPR1A Receptor Protein-coding gene Subfamily of G-protein coupled receptors AVPR1B, V2R and OXT receptors Mediates: Vasoconstriction Antidiuresis ACTH release Cell contraction and proliferation Platelet aggregation Release of coagulation factor Glycogenolysis By G proteins that stimulate a phosphatidylinositol-calcium second messenger system OXT receptors => ADH works similar to oxytocin

Vasopressin V2 Receptor AVPR2 gene provides for production of this protein Located on Chromosome Xq28 ADH + V2 Receptor = trigger chemical reactions for body’s water balance control Xq28 = located on long arm of X chrom, at position 28

When body’s fluid intake is low or when sweating, the body produces more ADH. As ADH reaches and binds to V2 receptor, it directs the kidneys to concentrate urine by reabsorbing some of the water back into the bloodstream via the AQP2 protein & lowering the serum sodium

Excess Production of ADH SIADH Symptoms: Headache, Nausea, Vomiting Associated with: Leukemia, lymphoma, lung / pancreatic / bladder / brain cancers, systemic cancers that produce ADH, MS, Epilepsy, Acute intermittent porphyria, TB, dehydration, brain trauma, and surgery Nephrogenic diabetes insipidus  very dilute urine Symptoms: excessive urination (polyuria), extreme thirst (polydipsia) Syndrome of Inappropriate ADH Porphyria – genetic disorder that affects heme production Nephrogenic diabetes insipidus -norm OR high ADH content in blood -BUT kidney can’t respond to it  dilute urine -UNLIKE diabetes mellitus – since that affects the level of insulin hormone in blood

Deficiency of ADH May be due to compulsive water drinking or low blood serum osmolality Central diabetes insipidus  in production of ADH by hypothalamus or realease of ADH from pituitary gland Symptoms: excessive urination (polyuria), extreme thirst (polydipsia), often tired since sleep interrupted by urination urges, clear, odorless and has low ccn of particles in urine Lead to severe dehydration

Sources “Antidiuretic Hormone (ADH) Test” http://www.healthline.com/health/adh#Purpose3 “Aquaporins: The renal channels” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813137/ “AVPR1A arginine vasopressin receptor 1A [Homo sapiens (human)]” https://www.ncbi.nlm.nih.gov/gene/552 “AVPR1A Gene (Protein Coding)” https://ghr.nlm.nih.gov/gene/AVPR2#resources “AVPR2 Gene” https://ghr.nlm.nih.gov/gene/AVPR2#resources “Definition of Antidiuretic Hormone (ADH)” http://www.medicinenet.com/script/main/art.asp?articlekey=7000 http://images.slideplayer.com/29/9441578/slides/slide_13.jpg Human Physiology, McGraw Hill “Vasopressin” http://www.healthline.com/health/adh#Purpose3 “Vasopressin (Antidiuretic Hormone)” http://www.cvphysiology.com/Blood%20Pressure/BP016.htm