Functional Human Physiology for the Exercise and Sport Sciences Chemical Messengers and the Endocrine System

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Functional Human Physiologyfor the Exercise and
Sport Sciences Chemical Messengers and the
Endocrine System

• Jennifer L. Doherty, MA, ATC
• Department of Health, Physical Education, and
  Recreation
• Florida International University

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The Endocrine System

• Endocrine control of cell function
• Depends upon the secretion and action of chemical
  messengers or hormones
• Directly linked to the autonomic nervous system
• Endocrine glands
• Ductless glands that release their secretory
  products (hormones) directly into the
  extra-cellular fluid.
• Hormones then diffuse into capillaries and are
  carried throughout the body in the blood.

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• Specific Endocrine Glands
• Primary Endocrine Glands
• Hypothalamus, Pituitary, Thyroid, Parathyroid,
  Adrenal, Pineal glands, Thymus, Pancreas, and
  Gonads ( Testes and Ovaries)
• Secondary Endocrine Glands
• Several organs contain endocrine tissue and
  produce hormones
• Heart, kidneys, and others
• The Endocrine System is integral in Intercellular
  Communication

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Intercellular Communication

• Direct Communication through Gap Junctions
• Connexins (plasma membrane proteins) link
  adjacent cells forming connexons
• Connexons form channels that allow ions or small
  molecules to pass directly from one cell to
  another

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Intercellular Communication

• Indirect Communication through Chemical
  Messengers
• Ligands (chemical messengers) bind to proteins
  (receptors) on the target cells
• Chemical substances produced at one site cause an
  effect at a different site in the body.
• Regulate metabolism, maintain homeostasis, and
  are essential for reproduction.
• Binding between messenger and receptor results in
  a response in the target cell
• Response is called Signal Transduction

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Chemical Messengers

• Functional Classification (6)
• Paracrines
• Chemicals that communicate with neighboring cells
• Autocrines
• Chemicals that act on the same cell that secreted
  them
• Neurotransmitters
• Chemicals released from neurons into the
  interstitial fluid

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Chemical Messengers

• Functional Classification (6) cont.
• Hormones
• Chemicals released from endocrine glands
• Neurohormones
• Chemicals released from a special class of
  neurons called neurosecretory cells
• Cytokines
• A wide range of chemical messengers released from
  a variety of cells, especially WBCs

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Chemical Messengers

• Chemical Classification (5)
• Amino Acids (Lypophobic)
• Amines (Lypophobic)
• Peptides (Lypophobic)
• Steroids (Lypophilic)
• Eicosanoids (Lypophilic)

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Chemical Messengers

• Lypophobic messengers
• Water-soluble (hydrophilic)
• Pass through the cell membrane
• Function to
• Open or close Channel-Linked, Enzyme-Linked, or
  G-Protein-Linked Receptors
• Altering the permeability of the cell membrane
  leading to depolarization or hyperpolarization
• Activate membrane bound enzymes
• Activate the second messenger system (more later)

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• Types of lipophobic messengers
• Amino Acid Messengers
• Function as neurotransmitters in the central
  nervous system
• Examples include
• Glutamate, Glycine, Gamma amino butyric acid
  (GABA)
• Most Amine Messengers
• Substances derived from the amino acids
• Examples include
• Catecholamines (Both norepinephrine and
  epinephrine), secreted by neurons as
  neurotransmitters or by the adrenal medulla as
  hormones
• Peptide Messengers
• Short chains of amino acids
• Examples include
• Insulin, oxytocin, antidiuretic hormone (ADH)

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Chemical Messengers

• Lipophilic messengers
• Fat loving (hydrophobic)
• Do not pass through the cell membrane
• Bind with receptors in the cytosol or nucleus of
  the target cell
• Function
• Control protein synthesis

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• Types of lipophilic messengers
• Steroid Messengers
• Derived from cholesterol.
• Cholesterol is made up of hydrogen, oxygen and
  carbon molecules and is most recognizable because
  of its 4-ring structure.
• Examples include
• Sex hormones
• estrogen and testosterone
• Some Amine Messengers
• Derive from amino acids
• Thyroid hormones
• Thyroxine and triiodothyronine

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Signal Transduction Mechanisms

• Binding between a messenger and a receptor
  resulting in a response in the target cell
• Produces (one or more) of four typical responses
• Changes the cell membrane permeability or
  membrane potential
• Increases the production of proteins or
  regulatory molecules (enzymes) within the cell
• Activates or deactivates enzymes
• Increases secretory activity

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Signal Transduction Mechanisms

• Relationship Between Receptor Binding and the
  Magnitude of the Target Cell Response
• Blood levels of the chemical messenger
• The relative number of receptors for the chemical
  messenger
• Affinity (strength) of the union between the
  messenger and receptor

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Signal Transduction Mechanisms

• Receptor Agonists and Antagonists
• Agonists
• Ligand binds to receptor and produces biological
  response
• Antagonists
• Ligand binds to receptor, blocking the agonist
• No biological response

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Signal Transduction Mechanisms

• Intracellular Receptor-Mediated Responses
• Lipophilic messengers affect protein synthesis of
  the target cell by direct gene activation
• Usually involves steroid and some amine (thyroid
  hormones) messengers
• These chemical messengers are lipid soluble.
  Lipids make up most of the cell membrane so they
  readily diffuse through the cell membrane.
• Once inside the cell, the steroid messenger
  combines with a protein receptor usually located
  in the nucleus.
• A messenger-receptor complex interacts with
  chromatin in the nucleus of cell and triggers
  transcription of specific genes causing
  production of specific mRNA for synthesis of new
  proteins

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Signal Transduction Mechanisms

• Membrane-Bound Receptor Mediated Responses
• Binding of a chemical messenger or ligand to a
  membrane-bound receptor initiates a chain of
  events inside the cell that changes the cell's
  activity or metabolism.
• Involves the amines (catecholamines), peptides,
  and amino acid (lipophobic) messengers
• These messengers are not soluble in lipids thus,
  they cannot diffuse through the cell membrane and
  bind to intracellular receptors.
• The messengers act through receptor proteins at
  the external surface of the cell membrane and
  depend on second messengers inside the cell to
  mediate the cellular response to the chemical
  messenger.

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Signal Transduction Mechanisms

• G-Protein Linked Receptors
• Involves the intracellular enzymes Cyclic AMP,
  Adenylate Cyclase, and Phosphodiesterase
• Cyclic adenosine monophosphate (cAMP)
• The best known second messenger
• Adenylate cylase
• Cyclic AMP is synthesized in the cell from ATP
  via the action of an enzyme attached to the inner
  surface of the plasma membrane, adenylate
  cyclase.
• Phosphodiesterase
• cAMP is inactivated by another enzyme present in
  the cell, phospho-diesterase.

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• G-Protein second messenger systems
• The hormone is the first messenger and it binds
  to receptor on the cell membrane, usually a G
  protein.
• The G-protein activates adenylate cyclase that
  generates cAMP from intracellular ATP (G protein
  is a transducer)
• cAMP is the second messenger
• It initiates a cascade of reactions by activating
  protein kinases which phosphorylate millions of
  proteins/enzymes, producing an amplification
  effect.
• Phosphorylation activates some proteins, but
  deactivates others. It is like an on/off switch
  thus, cAMP can lead to many different
  physiological responses.
• Different cells contain different proteins so
  that cAMP is able to produce different effects in
  different cells often with several different
  actions in one cell at the same time.
• cAMP is rapidly degraded by phosphodiesterase.
  This turns off the cellular response, unless new
  hormone molecules continue to bind to the
  membrane-bound receptor. There are other known
  second messengers, cAMP is the best understood.

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Signal Amplification in Chemical Messenger Systems

• The ability of small changes in the concentration
  of a chemical messenger to elicit marked
  responses in target cells
• A single kinase enzyme can catalyze thousands of
  reactions
• As the reaction cascades through enzymes, one
  intermediately after another, the number of
  product molecules increases dramatically.
• For example, one kinase enzyme can activate many
  G-proteins producing thousands of cAMP molecules

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Specific Endocrine Glands and their Hormones

• Control of Hormone Levels
• Negative feedback
• The concentration of each hormone in the body
  fluid is regulated precisely by negative feedback
  systems.
• In a negative feedback system, a gland is
  sensitive to the concentration of a substances it
  regulates.
• When the concentration of the regulated substance
  reaches a certain concentration, it inhibits the
  gland. As the gland secretes less hormone, the
  controlled substance also decreases.
• Feedback systems occur when a hormone level or
  its effect is fed back to the gland.
• The endocrine gland then responds in a manner
  that will return the system to homeostasis.
• For example
• Increased blood glucose concentrations stimulate
  insulin secretion by the pancreas. Insulin
  stimulates glucose uptake by cells decreasing the
  blood glucose concentration and inhibiting
  insulin secretion.

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• Three types of stimuli affect endocrine glands
• Hormonal stimuli
• Produce responses in the same or other endocrine
  glands.
• For example, the hypothalamus secretes releasing
  hormones or inhibiting hormones to the anterior
  pituitary gland.
• Increased release of particular anterior
  pituitary hormone into blood stream tells the
  hypothalamus to decrease secretion of releasing
  hormones.
• Decreased secretion of the releasing hormones
  decreases the activity of the anterior pituitary.
• Humoral stimuli
• Refers to blood and other body fluids. This term
  refers to chemical changes in the blood that can
  influence endocrine gland activity.
• For example, changes in blood glucose
  concentration produces changes in insulin
  secretion by the pancreas.
• Neural stimuli
• Long-distance communication via the nervous and
  endocrine systems
• Some endocrine glands secrete in response to
  neural stimuli or nerve control.
• Neural stimuli results from nerve fibers
  signaling hormonal release from a gland.
• For example, the sympathetic nervous system
  stimulates the adrenal medulla to release
  catecholamines during periods of stress such as,
  exercise.

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Primary Endocrine Glands

• Main function is to secrete hormones
• Hypothalamus and Pituitary Gland
• Hypothalamus
• Master control of one of the most important
  endocrine glands, the pituitary.
• It contains centers for control of body
  temperature, appetite, thirst, blood nutrient
  concentrations, sexual behavior, and emotional
  state.
• Functions as an important link between the
  nervous and endocrine systems.

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Anterior Pituitary Gland

• Controlled by the hypothalamus.
• The hypothalamus controls the secretory activity
  of the anterior pituitary by producing releasing
  hormones (RH) and inhibiting hormones (IH).
• Releasing hormones produced by the hypothalamus
  cause hormone release from the anterior
  pituitary.
• Inhibiting hormones produced by the hypothalamus
  slow or suppress the release of certain anterior
  pituitary hormones.

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• Hypothalamic control is regulated via negative
  feedback
• When blood concentration of a particular hormone
  rises to a certain level, the hypothalamus either
  decreases production of releasing hormone or
  produces inhibiting hormone.
• Hypophyseal portal veins
• Connect the hypothalamus to the anterior
  pituitary
• Transports hypothalamic releasing and inhibiting
  hormones to the anterior pituitary gland.

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Anterior Pituitary Hormones

• Growth Hormone (GH)
• Protein hormone with target tissues throughout
  the body (bones and muscles being the primary
  target cells).
• General effect of growth hormone
• Promote cell growth and division (anabolic
  effect) by stimulating the uptake of amino acids
  and protein synthesis, while slowing protein
  catabolism.
• Increases the growth rate of skeleton and
  skeletal muscles during childhood and
  adolescence.
• In adults, growth hormone helps maintain muscle
  and bone size and promote tissue repair. It
  affects growth in target cells indirectly,
  through proteins called somatomedins.

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• Prolactin
• A protein hormone that initiates and maintains
  milk secretion by the mammary glands in women.
• Regulated by
• Prolactin inhibiting hormone (PIH) from the
  hypothalamus
• Prolactin-releasing hormone (PRH) also from the
  hypothalamus
• Normally, prolactin inhibiting hormone
  predominates over prolactin-releasing hormone
  (PRH) which suppresses milk production.
  Prolactin release-inhibiting factor from the
  hypothalamus restrains secretion of prolactin,
  while prolactin-releasing factor promotes its
  secretion.

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• Melanocyte stimulating hormone (MSH)
• The exact role in humans is unknown.
• Tropic hormones
• Regulate the activity of other endocrine glands.
• There are no hypothalamic inhibiting factors
  associated with the tropic hormones, only
  releasing hormones.
• Thyroid stimulating hormone (TSH) or thyrotropin
• Stimulates normal development and secretory
  activity of the thyroid gland.
• Stmulates synthesis and secretion of thyroid
  hormones.
• Adrenocorticotropic hormone (ACTH)
• Target organ as the adrenal cortex.
• Stimulates release of corticosteroid hormones,
  especially cortisol from adrenal cortex.
• Release is stimulated by corticotropin releasing
  hormone (CRH) from the hypothalamus.

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• Gonadotropins
• Hormones that stimulate the hormonal functions of
  the gonads (ovaries and testes).
• Follicle stimulating hormone (FSH)
• Females
• Stimulates the development of the follicle and
  egg in the ovaries and stimulates the follicles
  to secrete estrogen (female sex hormone). I
• Males
• This hormone known as interstitial cell
  stimulating hormone (ICSH)
• Stimulates the interstitial cells of the testes
  to release testosterone and stimulates sperm cell
  production.
• Luteinizing hormone (LH)
• Females
• Stimulates the maturation of the egg and its
  release from the ovary. This includes ovulation
  or expulsion of the egg from the follicle,
  development of the corpus luteum, release of the
  ovarian hormones estrogen and progesterone.
• Males
• Effects are not clinically important

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Posterior pituitary gland hormones

• Oxytocin
• A protein hormone with two target tissues, the
  uterus and breast.
• During childbirth, it stimulates the smooth
  muscle contractions in the walls of uterus.
  Also, stimulates ejection of milk from breast
  glands during lactation in response to the
  mechanical stimulation from suckling infant.
• Example of a positive feedback mechanism
• Antidiuretic hormone (ADH)
• Also called vasopressin
• Effects of antidiuretic hormone
• Decrease urine volume produced by the kidney (an
  antidiuretic) resulting in more fluid returned to
  the blood.
• This increased blood volume produces increased
  blood pressure.
• Also stimulates smooth muscle contraction in
  arterioles (small blood vessels) increasing blood
  pressure.

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Thyroid Hormones

• Thyroxine (T4 )
• Accounts for almost 95 of circulating thyroid
  hormone, although T3 is the more active form
• Triiodothyronine (T3)
• T3 and T4 function to
• Stimulate cellular metabolism
• Increased production of oxidative enzymes and of
  Na/K pumps
• Increased basal metabolic rate and metabolic heat
  production
• Increased heart rate and force of contraction
• Increased blood pressure from up-regulation of
  catecholamine receptors
• The thyroid hormones are important in normal
  tissue growth and development, maturation of the
  nervous system

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• Calcitonin
• A peptide hormone produced the thyroid gland.
• Functions
• Lower the blood calcium levels by inhibiting
  osteoclasts and stimulating osteoblasts.
• Bone-sparing effect
• Secretion of calcitonin is stimulated when blood
  calcium concentration is high such as immediately
  after a meal.
• Calcitonin works opposite (antagonist) of the
  parathyroid hormone in regulation of blood
  calcium levels

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Parathyroid hormone (PTH)

• A protein hormone secreted by the parathyroid
  glands
• Functions as a second messenger to
• Increase blood calcium and decrease blood
  phosphate by stimulating osteoclast activity
  and increasing bone resorption thus increasing
  blood calcium levels.
• Release is stimulated by decreased blood calcium
  levels
• Parathyroid hormone is the single most important
  regulator of calcium levels in adult humans.
• Important for normal transmission of nerve
  impulses, muscle contraction, and blood
  clotting.
• Abnormalities of blood calcium levels result in
  depression of the nervous system, abnormal
  reflexes, weak muscles, twitches, and formation
  of kidney stones

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Hormones of the Adrenal Cortex

• The adrenal cortex can be divided into three
  zones that produce different types of
  corticosteroid hormones.
• From superficial to deep
• Zona glomerulosa
• produces aldosterone, a mineralocorticoid
• Zona fasciculata
• produces cortisol, the most abundant
  glucocorticoid
• Zona reticularis
• produces the adrenal sex hormones, primarily the
  androgens and estrogens or the gonadocorticoids.

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Corticosteroids

• The collective term for the steroid hormones
  secreted from the adrenal cortex that are
  essential for life.
• The corticosteroids include the
  mineralcorticoids, glucocorticoids, and the
  gonadocorticoids.
• Mineralcorticoid
• Aldosterone
• Functions to maintain water and electrolyte
  homeostasis, especially blood sodium and
  potassium levels by stimulating sodium
  reabsorption (conservation) and potassium
  excretion by the kidneys.
• Sodium is returned to the blood (with water)
  producing decreased urine volume, increased blood
  volume, and increased blood pressure.

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• Glucocorticoid
• Cortisol, the most abundant.
• The effects of cortisol are
• Glucose sparing effect
• Stimulates metabolism of lipids, and proteins
• Stimulates gluconeogenesis, by facilitating
  lipolysis and proteolysis for gluconeogenic
  precursors
• Provides resistance to stress by insuring
  adequate blood glucose levels for ATP production
  such as between meals, during starvation, during
  prolonged exercise, etc.
• Anti-inflammatory effect
• Decreases capillary permeability
• Reduces histamine release
• Stabilizes lysosomal membranes
• In excess, cortisol slows connective tissue
  regeneration and may decrease immune function
• Regulated by adrenocorticotropic hormone (ACTH)
  from the anterior pituitary.

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Hormones of the Adrenal Medulla

• Catecholamines
• Production and secretion is regulated by the
  sympathetic division of autonomic nervous system.
  
• Epinephrine (epi) and norepinephrine (NE) are
  secreted in a 41 ratio.
• At rest, catecholamines are secreted continuously
  in small amounts.
• During stress, catecholamines produce the fight
  or flight response.

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Fight or Flight Response

• Increased heart rate and contractility (force of
  contraction) resulting in increased blood
  pressure
• Increased bronchodilation and respiration rate
• Decreased digestive activity
• Increased blood glucose levels
• Increased fatty acid mobilization from adipose
  tissue
• Rerouting of blood flow to essential organs so
  that blood vessels to the skin and kidneys are
  constricted while those to the brain, skeletal
  muscles, lungs and heart dilate
• The effects of epinephrine and norepinephrine are
  similar however, the response actually generated
  at target cells depends on the type of receptor
  available

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Pancreas

• Located in the abdominal cavity posterior and
  inferior to the stomach.
• Both endocrine and endocrine functions
• Exocrine (acinar) cells produce digestive enzymes
• Endocrine cells are the Islets of Langerhans
• Millions of small clusters of cells scattered
  throughout the pancreas.
• Three distinct types of cells in the Islets of
  Langerhans
• Alpha cells that secrete glucagon
• Beta cells that secrete insulin, comprise about
  70 of islet cells
• Delta cells that secrete somatostatin, the same
  growth hormone inhibiting hormone produced by
  hypothalamus. The physiological function in the
  pancreas is probably to inhibit secretion of both
  insulin and glucagon. This hormone will not be
  discussed further.

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Hormones of the Islets of Langerhans

• Insulin
• A protein hormone produced by the beta cells of
  the pancreas.
• Widespread metabolic effects
• Primary effect is to decrease blood glucose
  levels by
• Stimulating glucose uptake by muscle cells
  (cardiac and skeletal)
• Stimulating storage of excess carbohydrates as
  adipose tissue
• Stimulating glycogenesis, formation of glycogen
  from glucose in muscle and liver
• Inhibiting gluconeogenesis in liver

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• Glucagon
• A polypeptide hormone produced by the alpha cells
  of the Islets of Langerhans.
• Primary effect is to increase blood glucose
  levels by
• Stimulating glycogenolysis, breakdown of glycogen
  to glucose in the liver
• Stimulateing by gluconeogenesis
• Stimulating the liver to release stored glucose
  to bloodstream
• Stimulates lipolysis for gluconeogenic precusors

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Regulation of Insulin and Glucagon Secretion

• Negative feedback mechanism
• Insulin and glucagon are antagonists regulated by
  changes in blood glucose levels
• Insulin secretion is stimulated by high blood
  glucose levels
• Glucagon secretion is stimulated by low blood
  glucose levels

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Thymus gland

• Located in the thoracic cavity, deep to the
  sternum.
• Atrophies with age
• Large in infants and children and decreases in
  size throughout adulthood. By old age, it is
  composed primarily of fatty and fibrous
  connective tissue.
• Hormones of the thymus gland
• Thymosins
• Thymopoietin and thymosin
• Peptide hormones
• Essential for normal development of T-
  lymphocytes directly affecting the immune
  response

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Secondary Endocrine Glands

• Produce hormones in addition to other functions
• Heart
• Atrial Natriuretic Peptide (ANP)
• Regulates sodium reabsorption by the kidneys
• Kidneys
• Erythropoietin
• Stimulates red blood cell production in bone
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