ANIMAL PHYSIOLOGY

Communication, Integration and HomeostasisHomeostasis• normal state of the body

• when body enters excited or depressed state

• body gets used to that particular condition after a while

4 basic processes of cell to cell communication (necessary for homeostasis to occur) 1. Direct cytoplasmic transfer (Gap Junctions)• Connexins from each cell form connexon (channel)

• Gate open 㲗 cytoplasmic bridges form functional syncytium

• Ions and small molecules can pass freely

• Transfer of electrical and chemical signals (ubiquitous, but particularly in heart muscle and smooth muscle of GI tract) 2. Contact dependant signals (Surface Molecules)

• Require cell-cell contact

• Surface molecules bind

• CAMs – Cell Adhesion Molecules

• Bidirectional Communication Possible 3. Short distance (local diffusion)

• Paracrines and Autocrines (Chemical signals secreted by cells)

• Para- = next to

• Auto- = self

• Mode of transport

• diffusion (slow)

• Histamines, cytokines, eicosanoids

• Many act as both paracrines and autocrines 4. Long distance (through either chemical or electrical signals)

• Body has two control systems:

• Endocrine system communicates via hormones

• Secreted where? Transported where and how?

• Only react with ____________

• Nervous system uses electrical (along the axon) and chemical (at the synapse) signals (APs vs. neurotransmitters and neurohormones [adrenal gland])

• makes use of PNS

Cytokines for BOTH Local and Long Distance Signaling• Act as paracrines, autocrines and/or hormones

• Comparison to hormones (sometimes blurry):

• Broader target range

• Made upon demand (like steroids, no storage in specialized glands)

• Involved in cell development and immune response

• Terminology: A zoo of factors in a jungle of interactions surrounded by deep morasses of acronyms and bleak deserts of synonyms

Signal Pathways• Signal molecule (ligand)

• Ligand = active messenger

• Receptor on target cell membrane, intracytoplasmic or intranuclear

• Intracellular signal

• Target protein

• Response

Three Receptor Locations• Membrane

• Cytosolic

• Nuclear

• Lipophilic ligands:

• enters cell and/or nucleus

• Often activates gene

• Slower response

• Lipophobic ligands:

• can't enter cell

• Membrane receptor

• Fast response

Membrane Receptor Classes 1. Ligand-gated channel• Direct Mechanisms via Ligand-gated Channel

• Nicotinic Acetylcholine (ACh) receptor

• change in ion permeability changes membrane potential 2. Receptor enzymes 3. G-protein-coupled 4. Integrin

Signal Amplification• Activates an Amplifier Enzyme to catalyze reactions

• Kinase

• Secondary messengers

Signal Transduction Activated receptor alters intracellular molecules to create response First messenger transducer amplifier second messenger➔ ➔ ➔Most Signal Transduction uses GProtein• G-Protein: membrane-associated protein that binds to GDP (guanosine diphosphate)

• Hundreds of types known

• Bind GDP / GTP and become activated

• Activated G proteins can

• Open ion channels

• Alter intracellular enzyme activity, e.g.: via adenylyl cyclase (amplifier)

• cAMP (2nd messenger)

• protein kinase activation

• phosphorylated protein

• Inositol triphosphate opens Ca2+ channels in ER➔• G-Protein Mediated Signal Transduction: Muscarinic ACh Receptor

Other Signal Molecules• Not all are proteins

• Ca2+ is a common cytosolic messenger

• Ca2+ channel blockers are common drugs

• NO (nitric oxide) is a neurotransmitter

• Lipids, esp. eicosanoids:

• Produced from arachidonic acid

• Leukotrienes cause contraction of bronchiolar smooth muscle

• Prostanoids have several communicative roles, e.g., inflammation

• NSAIDS inhibit COX enzymes

Cannon's Postulates (concepts) of properties of homeostatic control systems 1. Nervous regulation of internal environment 2. Tonic level of activity 3. Antagonistic controls (insulin/glucagon) 4. Chemical signals can have different effects on different tissues (e.g., α and β receptors) Failure of homeostasis?

Modulation of Signal Pathways Receptors exhibit:• Saturation, yet

• Receptors can be up- or down-regulated (e.g. drug tolerance)

• Change the number of or binding affinity of the receptor

• Specificity, yet

• Multiple ligands for one receptor: Agonists (e.g. nicotine) vs. antagonists (e.g. tamoxifen, finasteride)

• Multiple receptors for one ligand

• Competition

• Aberrations in signal transduction causes many diseases

• Many drugs target signal transduction pathway (SERMs, β-blockers etc.)

Up- vs. Down-regulation• Up

• Receptors (e.g., exocytosis)

• Affinity for ligand

• Down (think: drug tolerance)

• Add competitors

• Desensitization of receptors

• Intracytoplasmic changes

Receptors Explain Why

• Chemicals traveling in bloodstream act only on specific tissues.

• No receptor, no activity

• One chemical can have different effects in different tissues.

• May have + or - effect

Control Pathways: Response and Feedback Loops• Maintain homeostasis

• Local

• paracrines

• autocrines

• Long-distance

• reflex control

• Nervous

• Endocrine

• Cytokines

Steps of Reflex Control Stimulus (internal or external)

Sensory receptor

Afferent path

Integration center

Efferent path

Effector (target cell/tissue)

Response

Receptors (or Sensors)• Different meanings for “receptor”:

• 1. Sensory receptor

• Peripheral

• Central

• 2. Membrane receptor

• 3. Endocrine cells act as receptor and effector

• Constantly monitor environment

• External or Internal

• Threshold (= minimum stimulus necessary to initiate response)

• Afferent → Integration → Efferent

Afferent Pathway• From receptor to integrating center.

• Same as the Reflex Pathway

• Endocrine system has no afferent pathway (stimulus comes directly into endocrine cell)

Integrating Center• Neural reflexes usually in the CNS; endocrine integration in the endocrine cell itself

• Receives info about change

• Interprets multiple inputs and compares them with set-point

• Determines appropriate response (→ alternative name: control center)

Efferent Pathway

• From integrating center to effector

• NS → electrical and chemical signals

• Action Potential

• ACh

• ES → chemical signals

• hormones

Effectors

• Cells or tissues carrying out response

• Target for NS:

• Muscles, glands and some adipose tissues

• Target for ES:

• Any cell with proper receptor

• May be + or -

Responses at 2 levels: 1. Cellular response of target cell, e.g.,

• opening or closing of a channel

• Modification of an enzyme etc... 2. Systemic response at organismal level

• vasodilation, vasoconstriction

• Lowering of blood pressure etc....

Feedback Loops Modulate the Response Loop• Response loop is only half of reflex! → Response becomes part of stimulus and feeds back into system.

• Purpose: keep system near a “Set Point”

• E. g., Household thermostat

• Circadian rhythms are changes in setpoint

• Two types of feedback loops:

• - feedback loops (homeostatic)

• + feedback loops (not homeostatic)

The Bodyʼs 2 Control Systems• Variation in speed, specificity and duration of action

• The two systems allow for 4 different types of biological reflexes

• 1. Simple (pure) nervous

• 2. Simple (pure) endocrine

• 3. Neurohormone

• 4. Neuroendocrine (different combos)

Mechanics of BreathingFunctions of the Respiratory System• Oxygen exchange

• Air to blood

• Blood to cells (?)

• Carbon dioxide exchange

• Cells to blood

• Blood to air

• Regulation of body pH

• CO2 + H2O 非 H2CO3 非 H+ + HCO3-

• Protection from pathogens, irritants

• Vocalization

Terminology• Inspiration = Inhalation

• Expiration = Exhalation

• Ventilation

• Exchange

Anatomy• Lungs: – thin walled, moist exchange surface (75 m2 )

• Alveoli

• Ribs & skin protect

• Respiratory muscles create the pressure gradient that moves air

• Diaphragm

• Intercostals

Gas Laws Partial Pressure = the pressure (in mm Hg) of a single gas in a mixture. An expression of concentration of a gas. Atmospheric Pressure = 760 mm Hg at sea level; often reported as 0 mm Hg

• Air is a mix of gases: Daltonʼs law

• Total P = ∑Ps of individual gases Calculate partial pressure of O2 in dry air at sea level

• Gases move down their pressure gradients

• Pressure-volume relationship:

• Boyleʼs law: P1V1 = P2V2

• Describes the collisions of the gas molecules with both other gas molecule and the walls of the chamber

Ventilation• = Breathing

• Pulmonary Function Tests use Spirometer

• Measure volume of air moved during ventilation

More Terminology• Tidal Volume: Volume moved during normal respiration

• Approx 500 ml

• Inspiratory Reserve Volume: The additional volume after a tidal inspiration

• Approx 3000 ml

• Expiratory Reserve Volume: The additional volume after a tidal expiration

• Approx 1100 ml

• Residual volume: Whatʼs left after Expiratory Reserve Volume is exhaled

• Harder to measure, approx 1200 ml

The Airways: Conduction of Air from Outside to Alveoli• 3 upper airway functions:

• Warming

• Moisturizing

• Filtration

• Mucociliary escalator depends on secretion of watery saline – note: Cystic Fibrosis (genetic disease) interferes with mucus clearance

• Effectiveness of nose vs. mouth breathing (Respirators!)

Breathing and Ventilation• Air flows due to pressure gradients (analogous

• to blood)

• Inspiration:

• Contraction of diaphragm (60-75%) of volume change

• External intercostals and scalenes (25-40%)

• Expiration

• Relaxation of inspiratory muscles

• Elastic recoil of pleura and lung tissue reinforce muscle recoil Flow Rate α ∆P/ R

Alveolar and Intrapleural Pressures• Lungs unable to expand and contract on their own

• During inspiration, intrapleural pressure becomes subatmospheric

• Lungs “stuck” to thoracic cage by pleural fluid bond and vacuum

• Pneumothorax?

More Terminology• Compliance: ability of lungs to stretch

• Low compliance in fibrotic lungs (and other restrictive lung diseases) and when not enough surfactant

• Elasticity (= Elastance): ability to return to original shape

• Low Elasticity in case of emphysema due to destruction of elastic fibers.

• Normal lung is both compliant AND elastic

Surfactant• Surface tension at all air-fluid boundaries due to?

• Surface tension opposes alveolar expansion

• Surfactant = detergent like complex of proteins & PL:

• Disrupts cohesive forces between water molecules ↓ surface tension Easier ⟹ ⟹inflation of alveoli ↓ work of breathing⟹Airways Resistance• Also influences work of breathing.

• Primary determinant: airway diameter

• Tracheal diameter is not “adjustable”

• Bronchiole diameter is adjustable

• Under nervous, hormonal and paracrine control

• Parasympathetic:

• Sympathetic:

• Epinephrine (β2 receptors):

• Histamine:

• CO2

Matching Ventilation with Alveolar Blood Flow (Perfusion)• Mostly local regulation

• Lung has collapsible capillaries Reduced blood flow at rest in lung apex (reserve ⟹capacity of body)

• ↑ [CO2] in exhaled air bronchodilation⟹• ↓ [O2] in ECF around pulmonary arterioles vasoconstriction of arteriole (blood ⟹diverted) – opposite of systemic circulation!

Gas Exchange and TransportDiffusion and Solubility of GasesFickʼs law furthers the principles of diffusion: Diffusion rate ƹ Surface area x conc. gradient x membr. permeability

Membrane thickness

• Diffusion most rapid over short distances

• At alveolar and systemic capillaries

• Concentration Gradient expressed as Partial Pressure

Partial Pressure 1. = P O2 = 100 mmHg at sea level 2. Since gases can diffuse/dissolve into liquids, partial pressure allows comparison between the two media.

• Determines concentration gradient 3. Solubility of gas depends on

• solubility of molecule in particular liquid

• pressure gradient

• temperature 4. Equilibrium not necessarily the same concentration

• CO2 is 20x more soluble than O2, explains the need for Hb

Daltonʼs Law: the total pressure exerted by a mixture of gases is equal to the sum of the pressures exerted by the individual gases.

Total atmospheric pressure at sea level = 760 mmHg

Gas Exchange in Lungs• 1o factor: Partial Pressure Gradient

• Alveolar PO2 = 100mm Hg

• Venous PO2 = 40 mm Hg

• Simple diffusion drives the transfer

• PCO2 has the opposite

• Diffusion from capillary to alveoli

• Running Problem

• Influence of altitude on PO2: Mt. Everest: atmospheric P ~ 250 mmHg PO2= ?⟹• Alveolar hypoventilation affecting gas exchange

• ↑ airway resistance (?)

• ↓ lung compliance (?)

• Resp. membrane changes affecting gas exchange

• ↑ membrane thickness (?)

• ↓ surface area (?)

• Hypoxia and hypercapnea

Oxygen Transport in Blood• > 98% carried by Hb

• Rest dissolved in plasma

• O2 poorly soluble in plasma

• O2-Hb dissociation curve demonstrates relationship between PO2 and Hb binding of O2

• Other factors affecting O2-Hb dissociation curve

Hemoglobin (Hb)• Four protein fractions

• Four heme groups with Fe

• 70% of Fe in the body is in heme

• Binds reversibly to O2

• HbO2 or oxyhemoglobin

• 100% binding = saturation

• Pulse Oximeter

• Binding increased by many different conditions:

• ↑ Plasma PO2

• Alveolar PO2 determines plasma PO2

• ↑ pH

• ↓Temperature

• ↑ CO2

• ↓ 2,3-DPG

• ↑ by hypoxia, e.g., high altitude

• ↓ in stored blood

• HbF

O2 - Hb DissociationCurve• Binding is expressed as a %

• Amount of O2 that is delivered is dependent on available Hb

• Range 70-98%

• Easily measured with pulse oximeter

CO2 Transport in Blood• 7% directly dissolved in plasma

• 70% transported as HCO- dissolved in plasma (acts as a buffer)

• CO2 + H2O 非 H2CO3 非 H+ + HCO3-

• Carbonic Anhydrase in RBC

• 23% bound to Hb Carbaminohemoglobin

• Excess CO2 in blood = Hypercapnia Leads to acidosis, CNS depression & coma⟹

• At the alveoli, CO2 removed via PP gradients

Regulation of Ventilation Respiratory centers in brain stem integrate input from cortex, limbic & both central and peripheral chemoreceptors Carotid & aortic chemoreceptors for O2, CO2 & H+ Medullary chemoreceptor for CO2 Phrenic and intercostal nerves ⟹inspiratory muscles When neurons cease firing muscles relax expiration Low ⟹ ⟹[O2], high [CO2] & high [H+] ↑ ventilation CO2 + H2O ⟹ 非 H2CO3 非 H+ + HCO3-

Blood and Blood Gas TransportA. Composition of Blood 1. plasma• water + electrolytes (Na+, Cl-, K+, HCO3-, Ca2+), plasma proteins, glucose, urea, etc. 2. formed elements

• erythrocytes (RBCs) ~ 5,000,000/μL

• leukocytes (WBCs) ~ 5,000-10,000/μL

• platelets RBCs are anucleated cells, filled with hemoglobin

• hematocrit = % by volume of RBCs (normally ~ 45%) Blood cells are produced in red bone marrow from hematopoietic stem cells

• erythropoietin - hormone produced by kidneys, stimulates production and differentiation of RBCs

• polycythemia - high RBC count (high hematocrit)

• anemia - low O2 carrying capacity of blood (low hemoglobin concentration)

B. Hemoglobin Structure and Function• protein composed of 4 polypeptide (globin) subunits (2 α, 2 β)

• each subunit contains a heme group with iron (Fe2+) at the center

• each heme reversibly binds O2 (→ 4 O2 binding sites)

C. Oxygen Transport by Blood 1. O2 Dissolved in Plasma• low solubility of O2 in plasma at PO2 = 100 mm Hg, plasma: 3 mL O2 / L blood 2.

O2 Carried by Hemoglobin whole blood: 200 mL O2 / L blood

• ~ 99% of O2 in blood is carried by hemoglobin O2 carrying capacity of blood depends on hemoglobin concentration Hemoglobin-O2 Binding:

• deoxyhemoglobin (Hb) + O2 oxyhemoglobin (Hb O2)

• binding and release of O2 depends on: a. PO2 of the blood b. affinity of hemoglobin for O2 3. Oxygen-Hemoglobin Dissociation Curve

• relationship between PO2 of blood and percent O2 saturation of hemoglobin

• S-shaped curve results from interactions among hemoglobin subunits → promotes loading of O2 in the lungs and unloading of O2 in the tissues Normal values (resting, sea level):

• arterial PO2 = 100 mm Hg, 98% O2 saturation

• venous PO2 = 40 mm Hg, 75% O2 saturation

• In lungs (PO2 = 100 mmHg): flat part of curve → nearly 100% saturated

• In tissues (PO2 < 60 mmHg): → rapid unloading of oxygen as PO2 decreases

• During exercise, tissue PO2 ↓→ more O2 released from Hb → ↓ O2 sat. of venous blood

• Pumonary disease → ↓ arterial PO2 → ↓ O2 sat. (hypoxemia)

• At high altitude, ↓ arterial PO2 → ↓ O2 sat. 4. Factors That Affect O2 Affinity of Hemoglobin a. ↑ temperature → decreases affinity (rightward shift of O2 dissociation curve) b. ↓ pH (↑ [H+] ) → decreases affinity - (Bohr shift) c. ↑ PCO2 → decreases affinity