Human Bio 2 Exam 1

Overview

Chemical Signaling

• Paracrine: cell → nearby cells via ECF

  • Chemical released from cell and has effects on nearby target cell

  • cell to cell, local signaling through extracellular fluid

  • ex. eicosanoids

• Autocrine: cell → itself via ECF

  • chemical released from cell to effect itself

• Endocrine: cell → distant cell via bloodstream

  • chemical produced by cell, hormone, released into bloodstream

  • effects distant target cell through interaction with target cell receptor

Intro to Endocrinology

• Endocrine Glands:

  • ductless glands (specialized epithelium)

  • release chemical messengers (hormones) into blood stream

  • act on distant target cells

  • effects on target cells via interaction with receptors

• Other organs beyond the classical endocrine and

  neuroendocrine organs also produce hormones

• primary endocrine organ:→ primary function to make and produce hormones

  • Hypothalamus

  • Pituitary gland

  • thyroid gland

  • adrenal glands

  • pineal gland

  • parathyroid glands

• secondary endocrine organ → organ that has its own function but also has ability to make a produce hormones

  • heart

  • kidney

  • digestive system

  • adipose (fat)

  • gonads

Classification of Hormones: Structure

3 types: Amines, Lipid derivatives, peptides

Hormones = chemical messenger through bloodstream

1. Amines: amino acid derivatives

• most derived from → tyrosine

• thyroid hormone, epinephrine, norepinephrine, dopamine

• melatonin (derived from triptifan)

2. Lipid Derivatives:

• Steroid Hormones: derived from → cholesterol

  • i.e. testosterone, progesterone, estrogen, aldosterone, cortisol, corticosterone, Vitamin D

• Eicosanoids: derived from → arachidonic acid (paracrines)

  • paracrine chemicals

3. Peptide Hormones: 3-200 amino acids

• majority of hormones

• may be glycoproteins

• divided into groups depending on size:

  • smaller amino acids chains → peptide hormones

  • larger amino acid chains → protein hormones

• First synthesized as prohormones (inactive protein form)

• undergo post-translational processing → activated

• stored in secretory vesicles

• released via exocytosis

Hormones in the Blood

• most hormones can travel through blood freeform (on its own) → eg peptides and amines

• some hormones are hydrophobic (eg. lipid derived hormones) → travel through blood via carrier protein

Transport

• hormones either circulate in blood either:

  • free form/unbound → most hormones

  • bound to carrier protein (some steroid hormones and some thyroid hormone)

Metabolic Clearance → how hormones are broke down

• uptake by target cell and degradation

• ideal → hormone interacts with target cell → cell degrades hormone

• metabolic degradation: liver and kidney break down hormone → metabolites (break down products)

• excretion of metabolites of hormone from blood:

  • urinary excretion

  • bile (feces)

• very small amounts of hormone excreted in intact (unmodified form) → most degraded into metabolites

Bioavailability

• amount of hormone available to bind and act upon target cell → ability to bind to target cell

Half-life

• time needed for concentration of hormone in blood to decrease to 50% its initial concentration

Hormone Receptors

Hormone Receptors:

• Cell must have appropriate receptor to be sensitive to hormone

• most receptors have high specificity → sensitive to specific hormones

• protein/glycoproteins

• bind to hormones even through concentration in blood is very small (10^-8 -10^-12) → major effects based on receptor binding ability

• Signal transduction: receptor binds to ligand → undergo conformational change → transduce signal to cellular response → signaling pathways

Types of receptors:

• Intracellular receptors (in cell): steroid hormones, thyroid hormone

  • bind to hormones that can diffuse through plasma membrane (small, nonpolar) → steroid, thyroid hormone

  • effects: acts as transcription factor → alter gene expression

  • slow acting: long lag time to cellular response

  • slow response

• Plasma Membrane Receptors: Peptide hormones, most amines

  • bind to hormones that can’t easily enter cell

  • amplification: second messenger systems

  • effects: alter activities of proteins in cell

  • fast acting: short lag time to cellular response

  • fast response

Intracellular Receptors

Steroid hormone receptors, thyroid hormone receptors

Steroid hormones

• diffuse through plasma membrane →

• bind to intracellular receptors in cytoplasm/nucleus →

• form transcription factor →

• moves to nucleus and binds to DNA →

• activate specific genes → change gene expression of cell

Thyroid hormones

• transported across plasma membrane into cytoplasm →

• binds to intracellular receptor in nucleus → act as transcription factor

• also bind to intracellular receptors on mitochondria → influence ATP production

Plasma Membrane Receptors: GPCRs (metabotropic)

include: peptide hormones, most amine hormones

GPCR: G protein coupled receptors (metabotropic)

• largest family of receptors

• Basic Structure:

  • n terminal → extracellular side (amino group exposed)

  • c terminal → intracellular (carboxyl group exposed)

  • integral protein with 7 transmembrane domains (made of alpha helixes)

  • G protein interact with c terminal and intracellular loops of transmembrane domains

• G proteins couple the hormone receptor to effector molecules within the cell

G Proteins:

• interact with GTP or GDP and intracellular region of GPCR

• polypeptide → quaternary structure (multiple proteins)

• made of 3 protein subunits (heterotrimeric proteins):

  • alpha subunit: only subunit that interacts/binds to GDP or GTP

  • beta subunit

  • gamma subunit

• Alpha subunit binds to guanosine diphosphate (GDP) or guanosine triphosphate (GTP)

• GTP binding to alpha subunit activates G Protein

General Mechanism of GPCRs

1. ligand binds to receptor

• G protein in inactive state

• hormone binds to receptor → activates receptor → creates conformational change to structure of GPCR

• G protein binds to receptor

2. receptor inieracts with G protein → conformational change and activate Alpha subunit (GDP→GTP)

• activated receptor interacts with G protein

• GDP replaced by GTP at alpha subunit of G protein → active form (with energy!!)

3. G protein dissociates from receptor

4. Activated Alpha subunit (with GTP) separates from beta-gamma dimer

5. Active Alpha subunit interacts with enzyme/effector molecule → utilize energy (GTP→GDP) → inactivated

• dissociated subunits interact with effector molecules, eg enzyme, which now becomes activated/inhibited

• Alpha subunit interacts with enzymes/effector molecules releasing energy via hydrolyzing GTP → GDP, becomes inactive again

• beta gamma subunits can interact but usually doesn’t do much

Signal Amplification (dont memorize not necccessary to know all steps)

1 signal molecule → 1 million activated enzymes

• protein phosphorylation (often but not always) important step

  • addition of phosphate group to protein by enzyme (kinase)

• each step of transduction activates a bunch of molecules

signaling pathway:

• reception

  • epinephrine bind to GPCR (activate 1 molecule)

• transduction

  • each activated GPCR → activate 10² G protein

  • each g protein → activate 10² of enzyme

  • each enzyme → 10³ conversion

  • bunch of steps

• response

  • activated enzyme → cleave millions of glucose molecules from glycogen

Receptor Regulation

Desensitization: Decreases a cell’s response to hormone

• prolonged exposure to hormone → may lead to desensitization

• decrease in # of receptors on plasma membrane

  • internalization of receptor:

    • receptor degraded in lysosomes or proteosomes

    • membrane holding receptors are pulled back into cell and degraded

  • downregulation of receptor number

    • making fewer receptors

Sensitization: Increases a cell’s response to hormone

• may occur in response to low amounts of hormone

• increase # of receptors on plasma membrane

  • stored receptors in vesicles fuse with membrane

  • upregulation: increase in number of receptors

• hormones can regulate other receptor expression

  • ie estrogen regulates progesterone receptor expression

• Phosphorylation of receptor

  • may lead to desensitization OR sensitization (depends on receptor and where its phosphorylated)

  • changing shape changes function

The Hypothalamus and Pituitary Gland

3 mechanisms of hypothalamus control over endocrine function

Anterior Pituitary: receive hormone → affect what hormone it releases

• neuroendocrine cells: neurons that release hormones into circulation

  • release hormones in hypothalamus → travel bloodstream → influence hormone release from anterior pituitary

• these hormones regulate hormonal production by other endocrine glands

• anterior pituitary controlled by hypothalamic hormones (hypophyseal portal system)

Posterior Pituitary: synaptic terminals release hormone directly

• neuroendocrine cells:

  • cell bodies in hypothalamus → axons run through infundibulum → synaptic terminals in posterior pituitary

• hormones released from axon terminals in posterior pituitary → into general circulation

• neuronal tissue

Adrenal medulla

• release epinephrine and norepinephrine using SNS (already covered)

Posterior Pituitary

Release of 2 hormones: Oxitocin and Antidiuretic Hormone

Oxytocin: Peptide (9 amino acids)

• pair bonding and maternal

• Stimulus for release:

  • Breast → suckling of lactating breast

  • uterus → positive feedback mechanism with cervical stretch during labor

  • detected by sensory receptors in breast and uterus

• Target Organs:

  • smooth muscle within breast (ducts of mammary glands)

  • smooth muscle of uterus

• Effect: contraction of smooth muscle

  • milk let-down response

  • contraction of uterus

Antidiuretic Hormone (ADH) / Vasopressin: peptide (9 amino acids)

• reduces amount of pee → affects kidneys → reabsorb water → dilute osmolarity

• Stimulus for release

  • increased plasma osmolarity (hyperosmolarity >300 mOsm) → very sensitive

  • detected by osmoreceptors in hypothalamus

• Target Organs

  • distal part of tubules in kidney

• Effect: increased water reabsorption by distal part of kidney tubules → decrease osmolarity

• ADH release stopped once osmolarity recovered

• when ADH activated water pulled from urine when osmolarity is high, stopped when ADH is not released

Hypothalamus hormones regulate Anterior Pituitary

• GROWTH HORMONE release from anterior pituitary regulated by:

  • Growth Hormone Releasing Hormone (GHRH) → increase growth hormone

  • Growth Hormone Inhibiting Hormone (GHIH) (somatostatin (SS)) → decrease growth hormone

• PROLACTIN release from anterior pituitary inhibited by PIH

  • Prolactin inhibiting hormone (PIH) → decrease prolactin

  • trigger: pregnancy, breast suckling (decrease PIH

  • target: mammary glands

  • effect: growth and development of mammary glands, milk synthesis, inhibit GnRH

• THYROID STIMULATIMNG HORMONE (TSH) release regulated by:

  • Thyrotropin Releasing Hormone (TRH) → increase

• ADRENOCORTICOTROPIC HORMONE (ACTH) release regulated by:

  • Corticotropin Releasing Hormone (CRH) → increase

• LEUTINIZING HORMONE (LH) and FOLICLE STIMULATING HORMONE (FSH) regulated by:

  • Gonadotropin Releasing Hormone (GnRH) → increase

hormones regulated by hypothalamus

FLAPiG

GnRH→Fsh, LH

CRH→ increase ACTH

PIH → decrease prolactin

GHRH → increase GH

• THYROID STIMULATING HORMONE release from anterior pit. regulated by

  • Thyrotropin Releasing Hormone (TRH)

Anterior Pituitary

5 types of secretory cells produces 6 peptide hormones

• synthesis/release of anterior pituitary hormones → regulated by hormones from hypothalamus

• hypothalamic hormones delivered to anterior pituitary via hypophyseal portal vessel

hypothalamic hormones affect cell that produce hormones:

• GHRH/GHIH → Somatotrophs → growth hormone (GH)

• PIH → Lactotrophs → prolactin (PRL)

• TRH → Thyrotrophs → Thyroid Stimulating Hormone (TSH)

• CRH → Corticotrophs → adrenocorticotropic hormone (ACTH)

• GnRH → Gonadotrophs → follicle stimulating hormone (FSH) and Luteinizing hormone (LH)

Hypothalamic hormones influence → hormone producting cell in anterior pituitary → produce or inhibit hormone 2 → travel to target cells of endocrine organs → release hormone 3.

Anterior Pituitary: Prolactin

Prolactin: Peptide, tonic inhibitory control of PIH from hypothalamus

• prolactin usually inhibited → when breast feeding → PIH decrease

• PIH = Dopamine

  • prolactin release is stimulated by decreasing PIH (dopamine) release from hypothalamus

• stimulus for release:

  • pregnancy and suckling on breast (decreases PIH release)

    • sensory receptors in nipples send afferent signal to hypothalamus

• target organ:

  • mammary glands of breast

• effect:

  • stimulate growth and development of mammary glands (levels rise during pregnancy

  • stimulate milk SYNTHESIS

• Prolactin = feedback loop for GnRH → inhibits GnRH (gonadotropin releasing hormone) release from hypothalamus → inhibits FSH and LH

• hyperprolactinemia → menstrual cycle irregularities in females, infertility, low libido in males

males can lactate with a bunch of prolactin

Anterior Pituitary: Growth Hormone

Growth hormone (aka somatotropin): peptide (needs both inhibitory and releasing hormone)

• under stimulatory (GHRH) and inhibitory (GHIH) hypothalamic control

• stimulus for release:

  • circadian rhythm → peak in release in early hours of sleep (varies with age)

• target organs: most cells of body

• GH effects on target hormones via 2 mechanisms:

  • 1. Growth hormone binds to GH receptors directly on target cell (direct)

  • 2. Major effect: Growth hormone stimulates production of insulin-like growth factors (IGFs/somatomedins) from liver → IGFs bind to receptor cells (indirect)

• effect:

  • stimulates cell growth and division → increase protein synthesis

Effects of Growth Hormone

• Liver: GH → production of IGFs, increased protein synthesis, increased synthesis of glucose

• Muscle: GH → increased amino acid uptake and protein synthesis

• adipose: stimulate lipolysis

• visceral organs and glands: increased protein synthesis and cell proliferation

• connective tissue/bone: increased amino acid uptake and protein synthesis, increase in linear growth by proliferation of chondrocytes and protein synthesis in cartilage

Thyroid Gland: anatomy

• 2 connected lobes just inferior to thyroid cartilage (highly vascularized)

• follicle = smallest functional unit

  • fluid (colloid) filled sphere lined by simple cuboidal epithelial cells (follicle cells)

  • synthesis/release → thyroid hormone

• Parafollicular cells: “C cells”

  • synthesis/release → calcitonin hormone

• calcitonin released when there is too much Ca²⁺ in blood

  • inhibits osteoclasts

  • increase excretion of Ca²+ by kidney

  • prevent absorption of Ca2+ by digestive system

Thyroid Hormones: T₄ and T₃

• amine

  • derived from 2 amino acid tyrosine

• iodine = essential dietary element → required for synthesis of thyroid hormones

• 2 forms of thyroid hormones:

  • T₄ : thyroxine

    • 4 iodine atoms

    • most abundant form of thyroid hormone

  • T₃ : Triiodothyronine

    • contains 3 iodine atoms

    • most biologically active form of thyroid hormone

• T4 released into blood stream from thyroid gland can be diodinated into most active form T3 in some target cells including kidney and liver

Receptors→

• cytoplasmic → storage

• mitochondria → aTP

• nucleus → gene transport

Synthesis of Thyroid Hormones

thyroglobulin = globular protein secreted by follicle into colloid → contains many tyrosine residues

1. Capillary beds transport iodide ions from blood → follicular cells in response to TSH (active transport)

2. Iodide ions converted → iodine atoms by thyroid peroxidase → combine iodine with thyroglobulin (protein)

3. transferred into colloid → T3 and T4 formed in thyroglobulin

4. endocytosis of thyroglobulin → back into follicular cell

5. lysosomes degrade thyroglobulin → release T3 and T4

6. thyroid hormones diffused out follicle cell → plasma

7. transported in plasma via carrier protein

Regulation of Thyroid Hormone

Hypothalamus

• TRH: Thyrotropin Releasing Hormone

• Action: synthesis/release of TSH from anterior pituitary

  • Hypothalamus sends TSH → anterior pituitary via hypophyseal portal system → go to thyrotrophs → release TSH

Anterior Pituitary

• TSH: Thyroid Stimulating Hormone

• Action: Synthesis and release of thyroid hormones

  • TSH enter blood stream → transport iodide into thyroid gland

  • influence structure and growth of thyroid gland

Thyroid Gland

• Thyroid Hormones

  • 1. effects on target cells

  • 2. negative feedback on hypothalamus and anterior pituitary

    • higher levels of thyroid hormone → stop TRH production by hypothalamus → stop TSH release by anterior pituitary → decrease thyroid hormone production

    • mediated by levels of thyroid hormone

Actions of Thyroid Hormones

Stimulates Growth and metabolism

• Affect almost every cell in body

  • fast, strong, short increase in rate of cellular respiration → increase metabolism

• Specific actions

  • increased metabolic rate (heat production) → increased body temp for children (little/no effect on adults)

  • increased HR and BP

  • stimulate red blood cell formation in kidney→ increase oxygen delivery

  • accelerate turnover of minerals in bone

    • affect osteoclasts and osteoblasts

• 3 receptor locations in cell (intracellular receptors)

  • Cytoplasmic receptors: storage

  • Mitochondria receptor: increase rate of ATP production

  • Nucleus: act as transcription factor → increase gene transcription

    • upregulation of NA/K pump, glycolytic enzymes

Pathophysiology: Hypothyroidism

• deficient thyroid hormone

• most common cause → iodine deficiency

• symptoms of hypothyroidism (dont memorize)

  • tiredness weakness

  • dry skin

  • feel cold

  • hair loss

  • difficulty concentrating

  • constipation

  • weight gain and poor appetite

Hypothalamus release TRH → Anterior pituitary release TSH → but thyroid does not produce T4 and T3 because it does not have → produce more TRH and TSH

Pathophsyiology: Hyperthhyroidism

• excess thyroid hormone

• most common cause: grave’s disease (autoimmune disorder = body attacks itself)

  • antibody activates TSH

  • goiter and increased T4 and T3

• production of thyroid stimulating antibody → mimics TSH → binds to TSH receptor → produce too much thyroid hormone → feedback loop tries to stop TSH → antibody says nah

ectopic antibody bound to thyroid

Parathyroid Glands

4 small glands embedded on posterior surface of thyroid

• collection of parathyroid principle cells

• secrete Parathyroid Hormone (PTH) in response to decreased blood Ca2+ levels

• effects:

  • stimulates osteoclasts → eat bone → release Ca2+

  • enhances reabsorption of Ca2+ by kidney

  • stimulates formation of calcitriol (active vitamin D) by kidney → promotes absorption of Ca2+ from digestive system

• action release PTH

• trigger: low ca²+

• effect: stimulate osteoclasts → increase renal Ca²+ resorption, increase calcitriol formation

• calcium has multiple physiological roles (normal plasma levels → 8.8-10.2 mg/dL)

  • nerve and muscle excitation

  • muscle contraction

  • blood coagulation

  • bone mineral balance

  • intracellular signaling

Anatomy of Adrenal Glands

• Retroperitoneal (behind and above) above each kidney

• composed of:

  • outer cortex → produce corticosteroids (2 dozen steroid hormones)

  • inner medulla → produce epinephrine and norepinephrine

outer cortex layers:

superficial

• zona glomerulosa (release mineralcorticoids)

• zona fasiculata (glucocorticoids)

• zona reticularis (adrenal androgens)

deep

Hormones of Adrenal Cortex

All adrenocortical hormones are steroids → derived from cholesterol

• Mineralocorticoids: Zona glomerulosa

  • regulate sodium and potassium levels in ECF

  • aldosterone: released when Na+ levels are low

    • reabsorption of Na+ and water from forming urine in kidney, sweat glands, salivary glands at expense of K+

• Glucocorticoids: Zona fasciculata

  • Regulation of carbohydrate levels in ECF

  • anti-inflammatory properties

  • cortisol, corticosterone:

    • speed up rate of glucose synthesis (gluconeogenesis) and glycogen formation m

    • anti-inflammatory → reduces immune system function

Adrenal androgens: Zona reticularis

• produce low levels of “weak” androgens → useful as precursors for production of estrogen and testosterone by other tissues

• influence muscle mass and sex drive in adult women

Hypothalamic Pituitary Adrenal (HPA) Axis

• Release of CRH (corticotropin releasing hormone) increased by stressors

  • hypothalamus produce CRH → enter hypophyseal portal system → effect corticotrophs in anterior pituitary → release ACTH (Adrenal Corticotropic Hormone) → travel through blood stream → adrenal gland → release cortisol

• inhibition of release of CRH is initiated by cortisol (negative feedback loop)

  • cortisol → stop hypothalamus from CRH production → stop ACTH → stop cortisol production

• chronic high levels of cortisol desensitize receptor cells in brain (hypothalamus)

  • effect: continued release of CRH → excess production of cortisol

• Chronic stress → chronically high levels of cortisol

stress → CRH → ACTH → cortisol

1. gluconeogenesis

2. protein mobilization

3. fat mobilization

4. stabilize lysosomes

Short term and long term stress response

• stress from external environment change

• signals from sensory receptors → hypothalamus

• →

• short term stress (fight or flight/ alarm stage)

  • blood glucose increase

  • blood glycerol and fatty acids increase

  • HR and BP increase

  • air passage dilate

  • pupils dilate

  • blood flow redistribution

• long term

  • increase in blood concentration of amino acids

  • increased release of fatty acids

  • increased glucose formed from noncarbohydrates → amino acids (from protein) and glycerol (from fats)

Heart Wall

superficial

• parietal pericardium

  • outer membrane

• pericardial cavity

• epicardium (visceral pericardium)

• myocardium

  • contain most cardiomyocytes

• endocardium

  • inner lining of heart chambers

Cardiomyocyte Cells

cardiac muscle cells = cardiomyocytes

• striated (orientation of sarcomeres)

• 50-100 um long, diameter 20 um (shorter and thinner than skeletal muscle cells)

• branched at ends → contact other cardiomyocytes → create network of interconnected cardiomyocytes

• mono nucleated (vs multinucleated skeletal muscle cells)

• reduced sarcoplasmic reticulum system but extensive T tubule system

• large and numerous mitochondria → lots of ATP use

Unique feature: Intercalated discs → contact point between cardiomyocytes

• desmosomes: mechanical coupling → proteins holding cardiomyocytes together

• gap junctions: electrical coupling (ESSENTIAL FOR HEART CONTRACTION) → protein channels allowing flow between cardiomyocytes

Major types of Cardiomyocytes

contractile cells → normal cardiomyocytes

• bulk of atrial and ventricular tissue

• contraction and transfer of electrical signals

conductive cells → specialized cardiomyocytes

• generate and propagate its own electrical activity

• communicate with other cells via connected pathway → conductile pathway

• spread activity across contractile cells → induce contraction

skeletal vs cardiac muscle cells

• in common:

  • sliding filaments → produce contraction

  • regulation of contraction via increase in intracellular calcium

  • calcium bind to troponin → move tropomyosin → free myosin binding site on actin

• cardiac muscle only

  • influenced by autonomic nervous system

  • calcium from ECF AND SR

  • removal of calcium → Ca ATPase pump on SR AND plasma membrane Na/Ca exchanger

Blood Flow through the Heart

• Path of Blood Flow (chamber/destination, valve)

  • vena cava → right atrium → tricuspid valve (atrioventricular) → right ventricle → pulmonary valve (semilunar) → pulmonary trunk → left and right pulmonary arteries → lungs (oxygenate blood) → pulmonary veins → left atrium → mitral valve/bicuspid valve (atrioventricular) → left ventricle → aortic valve → aorta → body

• 4 chambers

  • Left/right atria (superior)

  • Left/right ventricles (inferior)

• 4 Heart Valves

  • goal → promote unidirectional blood flow (only lets pass one way)

  • Atrioventricular valves → tricuspid, bicuspid/mitral

    • atria → ventricles

    • papillary muscles, chordae tendineae

  • Semilunar valves→ aortic, pulmonary

    • between ventricles and arteries

• Vessels

  • Vena Cava

    • superior vena cava → drain deoxygenated blood from head and neck to heart

    • inferior vena cava → drain deoxygenated from lower body to heart

  • pulmonary artery → deoxygenated blood from right ventricle to lungs

  • pulmonary vein → oxygenated blood from lungs to left atria

• Arteries → carry blood AWAY from heart

• Veins → carry blood TOWARDS heart

Order of valves mnemonic

• Try Pulling My Aorta

• Try → tricuspid valve

• Pulling → pulmonary valve

• My → mitral valve

• Aorta → aortic valve

Pattern of Cardiac Muscle Contraction

• contraction myocardium → sequence for efficient blood ejection

• electrical signals trigger myocyte contraction

• Conduction System → spread electrical signals in highly organized pattern

General events of cardiac contractions (Heartbeat)

1. deoxygenated blood returning to heart → AV valves (tricuspid and mitral) open, semilunar valves (pulmonary and aortic) closed

2. atria contract first so ventricles can “top off” fill with blood

3. ventricles contract (AV valves close to prevent backflow)

4. pressure builds in ventricles

5. semilunar valves open

6. blood ejected

Conduction System

Propagation of Electrical Signals

pathway of wave of electrical excitation

• SA node (normal pacemaker)

  • atrial activation begin

• → Atrial Internodal fibers (atrial contraction)

  • spread signal across atrial conductile cells to AV node

  • spread to atrial contractile cells → atria contracts

• → AV node (slowed transmission of impulse→ allow ventricles to fill)

• → AV bundle/ Bundle of His (only electrical link between atria and ventricles)

  • signal to interventricular septum

• → Right and Left Bundle Branches

• → Purkinje Fibers (rapid propagation→ contract ventricles)

Conduction System

Sinoatrial Node and Atrioventricular Node

• Normal Pacemaker of heart → SA Node (generates initial electrical signal)

  • Automaticity = ability to generate signals and contract on its own

  • spontaneous firing = 100/min (fastest rate of conduction)

  • overdrive suppression = the fast rate of firing of SA node suppresses other cells from acting as pace makers

    • prevent ventricles from contracting at the same time as atria

  • all conductile cells can generate signal → SA node has fastest rate → overrides automaticity of other conductile pathway → overdrive suppression

• Atrial Internodal Pathway→ connects SA Node to AV Node

  • Specialized conducting cells

  • ~50 msec to travel pathway

  • stimulus passed to contractile cells → spread across both atria → atria contract

  • stops at atria → myocardium of atria and ventricles are not connected

• AV Node

  • specialized smaller conductile cells → slows electrical signal

  • 100 msec to move through AV node

  • slow signals from atria to allow ventricles to fill with blood before contraction

  • normal firing rate 40/min

• AV bundle/ Bundle of His enters interventricular septum

  • spread electrical signal from atria → ventricles

  • only electrical connection between atria and ventricles

• Left and Right Bundle Branches

  • electrical signal travel towards apex along ventricles

  • left much larger → need to activate thicker muscle tissue in left ventricle → pumps blood to the whole body

• Purkinji Fibers

  • larger cells → speed up electrical signal rate

  • fight conduction system

  • signal move up from apex → base

  • signal to contractile cells → contract ventricles → push blood upwards

  • normal firing frequency 15-20/min

• if SA node not functioning → ectopic pacemaker → other pacemaker

Action Potential: conductile cells (SA Node and AV node)

Phase 1: Pacemaker potential (no resting membrane pot)

• Na+ leak channels are always open (rather than chemically gated channels → continuous increase of membrane potential)

• Voltage gated channels closed

• upward drift of membrane potential

• no resting membrane potential → always gradually increasing → -65mV minimum

Phase 2: depolarization

• threshold = -40mV

• voltage gated Ca²⁺ channels open → large influx of Ca²⁺ → membrane potential spikes

• Ca2+ plays role in contraction too → bind to troponin to move tropomyosin

Phase 3 - repolarization

• voltage gated Ca²⁺ channels close → stop Ca²⁺ influx

• Voltage Gated K⁺ channels open → K+ leaves cell

• membrane potential decreases until -65 mV → start to gradually increase again

• Ca2+ diffuse out gap junction→ neighboring atrial internodal fibers and contractile cells

Action Potentials: Contractile Cells

Phase 1: Rapid Depolarization

• resting membrane potential (stable) = -90mV

• Ca2+ from neighboring cells enter → increase membrane potential Threshold = -75 mV

• quick opening of voltage gated Na+ channels → rapid Na+ influx

• Membrane potential increases rapidly

Phase 2: Plateau

• Early repolarization

  • voltage gated Na+ channels close

• Plateau

  • Voltage gated Ca²⁺ channels open (long/L type CA2+ channels → open for long time)

  • → slow calcium influx throughout entire period

  • slow K+ efflux + slow calcium influx → plateau

  • Ca2+ channels close staggered → no clear repolarization point

  • Ca2+ also binding to troponin to move tropomyosin

Phase 3: Repolarization

• Voltage gated Ca²⁺ close

• Voltage gated K+ channels open → K+ leaves cell

• membrane potential decreases

Ca has 2 functions → aid in contraction (bind to troponin) and bind to ryamodine receptors to release more Ca

Refractory Periods: Contractile cells

• Absolute refractory period: LONG compared to skeletal muscle (200 msec)

  • no additional action potential at all

  • includes: depolarization, plateau, and initial period of rapid repolarization

  • because Na+ channels are open during depolarization and Ca2+ open during plateau → all channels doing all they can already

• Relative refractory period

  • difficult to initiate action potential → require more signal

  • includes: remaining repolarization

• Together → limit frequency of action potentials

  • prevent tetanic contractions (early contraction) → don’t want to mess up timing

  • prevent ectopic pacemaker from stimulating contraction (any pacemaker other than SA node)

  • → allows time for ventricles to fill

Excitation-Contraction Coupling: contractile cells

Contractile cells

• Calcium required for contraction:

  • 80% from SR (sarcoplasmic reticulum)

  • 20% from ECF

• Increase in Cytosolic Calcium

  • Calcium enters myocyte via L-Type calcium channels

  • this calcium binds to ryanodine receptors on SR → stimulates release of calcium from SR

  • Calcium Induced Calcium Release → Ca2+ signals SR to release more Ca2+

• Removal of Cytosolic Calcium (during relaxation)

  • calcium pumped back into SR (SERCA pump → Sarcoplasmic Endoplasmic Reticulum Calcium Pump)

  • calcium moved to ECF via Na/Ca exchanger

• Ca has 2 functions → aid in contraction (bind to troponin) and bind to ryanodine receptors on SR to release more Ca

Autonomic Regulation of SA node (conductile): increasing heart rate

• SA node signal 100/min normally

• sympathetic nerves → synapse on SA node → influence activity

• heartrate increased by sympathetic nervous system via norepinephrine binding to Beta-1 receptors

• Sympathetic regulation: norepinephrine → Beta-1 Receptors on SA node → increase heartrate

  • increased opening of Na+ and Ca 2+ ion channels → more influx of Na+ and Ca 2+

  • reduced repolarization → builds up more positive charge → steepens pacemaker potential (less charge difference from pacemaker potential → threshold)

  • effect: shorter time for SA node to reach threshold → increase heart rate

• POSITIVE CHRONOTROPIC EFFECT: INCREASES HEART RATE

Autonomic Regulation of SA node: decreasing heart rate

• Parasympathetic Regulation: ACh → Muscarinic Receptors on SA node

  • increased opening of K+ channels

  • efflux of K+ → lose more positive charge (larger charge difference from pacemaker pot → threshold)

  • hyperpolarization → decreases steepness of pacemaker potential

• effect: longer time for SA node to reach threshold → decrease heartrate

• NEGATIVE CHRONOTROPIC EFFECT: DECREASES HEART RATE

Blood Flow

• right side of heart → pump deoxygenated blood to lungs

• left side of heart → pump oxygenated blood to body

Pulmonary circulation

• vessels carrying blood to and from lungs

Systemic circulation

• vessels (arteries and veins carrying blood to and from body

Oxygenated Blood

• pump to body

Deoxygenated blood

• pump to lungs

Cardiac Cycle

• electrical and mechanical events that repeat with every heart beat

• duration (s/beat) = (60 sec/min)/ Heart Rate (beats/min)

• Systole: contraction

• Diastole: Relaxation

Cardiac Cycle

• 22% atria in systole (contract)

• 88% atria in diastole (relax)

• 1/3 ventricle in systole

• 2/3 ventricle in diastole

Ventricular Diastole and Atrial Systole

• relaxation and filling of ventricles with blood

• atrial contraction

• SIMILAR EVENTS OCCUR ON RIGHT AND LEFT SIDE

• BLOOD FLOWS FROM HIGHER TO LOWER PRESSURE

ventricles just ejected blood to arteries → empty ventricles

Early Diastole → ventricles relax

• pressure drops

• isovolumetric relaxation: all heart valves closed (no blood volume movement) → pressure less than arteries, but more than atria

• Artery (aorta and pulmonary trunk) pressure > Ventricular pressure (because ventricles just pumped out blood) → semilunar valves (pulmonary + aortic) closed

• Ventricular pressure > Atrial pressure → AV valves (tricuspid + mitral) close

2. Late Diastole → continued ventricular relaxation

• ventricular pressure continues to drop

• Ventricular pressure < Atrial pressure → AV valves open

  • blood flow from atria → ventricles

• Rapid Ventricular Filling: “Passive filling” → 70% of blood pours into ventricles via pressure difference (blood travels from high → low pressure) and gravity

3. Atrial Systole

• ventricles “topped off” → push remaining 30% of blood into ventricles via atrial contraction

End Diastolic Volume → approx 150mL blood per ventricle

Ventricular Systole

• contraction of ventricles

• electrical signal by conductile cell purkinje fibers (apex up to→base) → contraction of ventricles up

• BLOOD FLOWS FROM HIGH TO LOW PRESSURE

ventricles are full of blood now

1. 1st Phase

• begin as atrial systole ends

• ventricles begin to contract → increase ventricular pressure

• Ventricular pressure > atrial pressure → AV valves close (1way valve)

• artery pressures > ventricular pressure → SL valves closed

• Isovolumetric contraction: ventricle pressure increase → all heart valves closed

• pressure rises steeply until → ventricular pressure > aortic pressure (artery) → SL valves open

2. 2nd Phase

• Semilunar valves open → blood ejected from ventricles to arteries

• Rapid ejection: ventricular pressure continues with big decrease in ventricular volume (big squeeze → blood ejected)

• Reduced ejection: less rapid ejection in ventricular volume (less pressure) → ventricular and aortic pressure begin to fall

Stroke Volume → approx 70mL blood ejected per ventricle

End-Systolic-Volume → approx 80mL remaining in ventricle

Heart sounds

auscultation: listening to internal body sounds

• S1 “lubb” → closure of AV valves

  • sound from blood hitting closed valve

• S2 “dubb” → closure of semilunar valves

  • early ventricular diastole

• murmur → regurgitation of ventricular blood back into atria

  • slight backflow→ malformed AV valve

• Bruit → abnormal sound as blood runs past obstruction through arteries

ECG →

• P wave

  • atrial depolarization → atrial systole

  • at end of ventricular diastole

• QRS complex

  • ventricular depolarization → ventricular systole

• T wave

  • ventricular repolarization → end of systole →beginning of ventricular diastole

Overlapping Electrical and Mechanical Activity e

• Ventricular Systole

  • QRS wave → ventricular depolarization → contraction

  • AV valve close when ventricular pressure > atrial pressure (1st heart sound) → both valves closed (artery pressure > ventricular pressure → SL valves also closed)

  • isovolumetric contraction → increase in ventricular pressure > artery pressure → SL valves open

  • ventricular ejection

• Ventricular diastole

  • T wave → ventricular repolarization → end of systole → relaxation

  • diastole when t wave is complete

  • drop in ventricular pressure < aortic pressure → aortic valve close (second heart sound

  • fall of ventricular pressure < arial pressure → AV valve opens

  • P wave → atrial depolarization → atrial contraction → small rise in ventricular pressure

Wigger’s Diagram (for left ventricle)

1. Ventricular Systole: QRS → ventricular contraction

• immediately after atrial contraction→ topping off → immediate rise of ventricular volume → increase in ventricular pressure > atrial pressure → AV mitral valve closes → 1st heart sound

• isovolumetric contraction w/ 2 closed valves (ventricular pressure < aortic pressure→ aortic valve still closed) → sharp increase in pressure, no volume change

• rapid ejection: ventricular pressure > aortic pressure → aortic valve opens → rapid decrease in ventricular volume and pressure

• reduced ejection: T wave → repolarization of ventricles → lower rate of decrease in volume and pressure

2. Ventricular Diastole (completion of repolarization): end of T wave → diastole start

• isovolumetric relaxation: decrease in ventricular pressure < aortic pressure → aortic valve close → 2nd heart sound

• both valves closed (ventricular pressure > atrial pressure → AV valve closed) → rapid decrease in pressure, no volume change

• Rapid refilling: drop in ventricular pressure < atrial pressure → AV mitral valve opens → 70% of blood passively pours into ventricle → large increase in volume

3. Atrial Systole (during ventricular diastole): P wave → atrial contraction

• slight increase in atrial/ventricular pressure (AV valves are open)

• atrium contract → slight bump in ventricular volume → last 30% topping off ventricle

Cardiac Output

Cardiac output: amount of blood pumped by each ventricle in one minute

• Cardiac output = (heart rate) x (stroke volume) = HR x (EDV - ESV)

  • stoke volume = volume of blood ejected every contraction

    • affected by preload, contractility, afterload

• EDV = end diastolic volume

  • max blood volume filling ventricle during diastole

• ESV = end systolic volume

  • remaining blood remaining in ventricle after contraction

• Stroke volume = EDV-ESV

  • volume of blood ejected from ventricles

• contractility

  • force of heart muscle contraction

    • more force → more blood ejected

• preload

  • degree of stretch of cardiomyocytes at the end of ventricular filling/diastole → use EDV to measure

• afterload

  • resistance ventricles must overcome to eject blood

  • ventricular pressure > SL pressure

Altering Heart Rate

• autonomic nervous system: cardiac centers of medulla oblongata

  • Sympathetic innervation

    • positive chronotropic effect → increase HR → increase cardiac output

    • norepinephrine → Beta-1 receptors → opening of Na+ and Ca2+ channels

  • Parasympathetic innervation

    • negative chronotropic effect → decrease HR → decrease cardiac output

    • ACh→ muscarinic receptors → openning K+ channels

• venous return

  • volume of blood veins return to heart

  • direct effect on SA node

  • larger volume of blood → stretch atria → stretch SA node fiber → increase rate of depolarization → increase HR

Altering Stroke Volume LEARN BETTER

• dependent on EDV (end diastolic volume) and ESV (end systolic volume

• increase stroke volume → increase cardiac output

• increase heartrate → increase cardiac output

• Factors influencing EDV → preload

  • preload = heart muscle stretch when ventricles are full → EDV

  • filling time → dependent on HR

    • longer fill time → EDV larger

    • increase in HR → shorten filling time → increase CO

    • body position and activity level

• Starling’s Principle of the Heart: higher preload → higher stroke volume

  • greater preload (stretch of cardiomyocytes during end of ventricular diastole) = higher EDV (more ventricular filling) → greater the contraction

  • related to tension levels produced in muscle

  • more blood in heart → potential to eject more blood

• Factors influencing ESV (end systolic volume):

  • afterload: ventricular pressure required to open semilunar valves (ventricular pressure > SL pressure)

  • proportional to amount of pressure present in aorta at time of ventricular contraction

    • amount of blood pressure present in aorta at time of contraction (HR)

    • if aorta is full, more pressure is required to open SL valves → decreased stroke volume and vice versa

    • vasodilation → vessels widen→ less pressure in aorta → lower afterload → easier to pump blood

    • vasoconstriction → vessels narrow → more pressure in aorta → higher afterload → more difficult to pump blood

  • contractility: amount of force produced during contraction

    • dependent on inotropes: factors that influence contractility (dependent on levels of cytosolic calcium 80% from SR, 20% from ECF)

Starling’s Principle of the Heart

• strength of ventricular contraction increases with an increase in preload

• increased preload (more ventricular stretch) → higher EDV (ventricles filled with more blood) → more contractile force (like a filled balloon)

• linear relationship between EDV and Stroke volume

Length-Tension relationship of heart

• contraction is dependent on overlap between actin and myosin

• optimal overlap → maximum contraction → best stroke volume

• when EDV is too low (empty volume) → cells not stretched → too much overlap of actin and myosin → bad contraction

• as ventricles fill → better actin myosin overlap → better stroke volume

• connective tissues and pericardium prevent overstretching

Contractility

increased strength of contraction of ventricle due to increases in cytosolic calcium

• positive inotropic effect → increase Ca2+ levels → increase contractility

• negative inotropic effect → decrease Ca2+ levels → decreased contractility

• because more Ca2+ → more troponin binding → more free tropomyosin → more contraction

Factors affecting cytosolic calcium

1. heart rate

• during action potential of contractile cell → Ca2+ into cell

• more time between act pot → time to clear Ca2+

• increase heart rate → more Ca2+ leftover

2. Size of inward Ca2+ current during plateau of contractile myocyte action potential

• larger concentration difference between ECF and cytoplasm → higher rate of movement into cell

• SNS phosphorylates L-type Ca2+ channels → more efficient at moving Ca2+ into cell

3. Amount of Ca2+ stored in SR

• thyroid hormone → acts as transcription factor → increase transcription of SERCA (sarcoplasmic endoplasmic reticulum Calcium ATPase) → more Ca2+ into SR→ more Ca2+ out of SR (calcium induced calcium release)

Vascular Wall (blood vessel)

lumen → space

• Tunica intima (closest to lumen)

  • endothelium

  • epithelial cells → basement membrane separates intima from media

• Tunica Media

  • smooth muscle cells → contract and determine diameter of vessel

  • elastic fibers → flexibility

• Tunica Adventitia

  • connective tissue

Tunica Intima: Endothelium

• specialized epithelium (simple squamous)

• function: barrier and filtration → control what moves between blood and interstitial fluid

• plasticity:

  • help new vessel growth (angiogenesis) in response to injury and ischemia (lack of blood flow)

• secretory: regulate neighboring smooth muscle

  • vasodilators: nitric oxide (NO) and prostacyclin

  • vasoconstrictors: endothelin

  • anti-aggregatory for platelets

Tunica Media → Smooth Muscle

contractile cells → contraction and relaxation

• Vascular tone

  • baseline level of contraction

• Vasomotion

  • change in caliber (diameter) of blood vessel

    • contraction influenced by signals by endothelium/ nervous system

Heterogeneity of Vessels: different types

Artery

• carry blood away from heart

• thick walls

  • most elastic tissue

  • most smooth muscle

• highest pressure

• large arteries branch into → small arteries (arterioles) → capillaries → capillary beds

• lowest permeability between blood and ISF

• most smooth muscle in arterioles

• blood flow via smooth muscle contraction

• Structure: round, relatively thick wall

  Tunica intima→ endothelium (rippled due to

  vessel constriction), internal elastic

  membrane (present)

  Tunica media→ thick, smooth muscle cells,

  and elastic fibers, external elastic membrane

  (present)

  Tunica externa→ collagen and elastic fibers

  Function: Arteries move blood AWAY from

  the heart

  NO VALVES!

• HIGHEST PRESSURE, MOST ELASTIC SUBSTANCE

• LEAST PERMEABLE, LOWEST TOTAL SURFACE AREA)

Vein

• carry blood towards heart

• small veins (venules) → larger veins

• less smooth muscle

• less elastic tissue

• lumen of vein larger > artery

• blood flow via surrounding skeletal muscle contraction

• Structure: flattened or collapsed, relatively

  thin wall

  Tunica intima→ endothelium (smooth)

  Tunica media→ thin, lots of smooth muscle

  cells and collagen fibers

  Tunica externa→ collagen and elastic fibers,

  smooth muscle cells

  NO INTERNAL OR EXTERNAL ELASTIC

  MEMBRANES

  Function: Veins move blood TOWARDS the

  heart

  HAVE VALVES!!

Capillary

• site of product exchange

  • allow for nutrient/oxygen and waste exchange between the blood and surrounding cells

• only endothelium without tunica media or tunica adventitia

• narrow lumen

• low pressure

• connect to arteries and veins

• highest permeability

• GREATEST TOTAL SURFACE AREA, MOST PERMEABLE

  (Additionally, LEAST MUSCLE + ELASTIC TISSUE… bc only consist of tunica intima)

Veins and Arteries connect at Capillary beds

Arteries

• smaller lumen (hole)

• thick tunica media → thick smooth muscle walls → control over diameter

• abundant elastic fibers

• high pressure

• low permeability

• blood flow via smooth muscle contraction in tunica media

• no valves

Veins

• less tunica media → less muscle contraction

• less elastic fibers than arteries

• more permeability than arteries, far less than capillaries

• blood flow via surrounding skeletal muscle contraction

• has one way valve system

  • pressure higher on one side → valve open → pressure higher on other side → valve closed

Blood distribution

• 70% blood in venous system

• 7% blood in heart

• 7% in capillaries

• 13% in arteries

Capillaries

• capillary structure

  • endothelial tube inside thin basement membrane

  • no tunica media or adventitia

  • diameter ~ 1 RBC

  • higher permeability than veins and arteries

  • higher pressure than veins, far less than arteries

Continuous Capillaries

continuous capillaries:

• little permeability

• found in all tissue except epithelia and cartilage

• complete endothelial lining → endothelial cells packed tightly

• allow diffusion of:

  • water, small solutes, lipid soluble materials

• prevent diffusion of:

  • blood cell and plasma protein

• specialized tight continuous capillaries in CNS and thymus (BBB)

Fenestrated Capillaries

Fenestrated capillaries

• greater permeability

• pores in endothelial lining

• allow rapid exchange of water and larger solutes

• found in

  • choroid plexus → nutrients into CSF

  • endocrine organs → hormones into blood

  • kidneys → filter blood

  • intestinal tract → absorb nutrients

Sinusoidal capillaries

sinusoids

• greatest permeability

• gaps between adjacent endothelial cells

• allow free exchange of water and large plasma proteins

• found in

  • liver

  • spleen → passing of RBCs

  • bone marrow →blood cells into blood stream

• phagocytic cells monitor blood at sinusoids

Starling Forces (for blood) RELEARN !!!!

• movement of fluid in capillary beds

  • Blood colloid osmotic pressure (BCOP) → osmolarity of blood

    • solute move from high → low concentration

    • arteries and veins have similar blood osmolarity (similar amount of albumins) → because albumins are plasma proteins and can’t usually pass through capillaries

  • Capillary hydrostatic pressure (CHP) → volume of blood

    • water move from high → low concentration

• arterial end: CHP>BOP

  • arteries have higher pressure → CHP pushing fluid out overcomes BCOP drawing fluid in

  • filtration → push fluid out of capillary

• venule end: CHP < BOP

  • venules have low pressure → the BCOP drawing fluid in overcomes CHP

  • reabsorption → bring fluid into capillary

Microcirculation

Flow through a region is determined by pressure and resistance of microcirculation

Key terms Circulation

• Blood Flow (Q)

  • volume of blood flowing through vessel per unit of time (eg capillary, organ, system)

• Resistance (R)

  • force opposing flow

  • vascular resistance determined by diameter and length of vessel

• Total peripheral resistance (TPR)

  • resistance of entire cardiovascular system

Blood flow Relationships

• Q ∝ P

• Q ∝ 1/R

• Q ∝ P/R

• Q ∝ BP/PR

• R ∝ 1/ r⁴

Blood Flow

Q = ΔP/R

• blood flow from high → low pressure

  • pressure difference high → blood flow high

  • pressure difference low → blood flow low

• resistance prevents blood flow

  • resistance high → blood flow low

  • resistance low → blood flow high

Blood Pressure

• Blood pressure:

  • measure of force of circulating blood exerted on arterial walls during systolic and diastolic heart pulses

  • arterial pressure highest and most dynamic

  • normal - 110mmHg/70mmHg (systole/diastole)

• dependent on

  • cardiac output (volume of blood)

  • vasomotion (size of vessel)

    • vasodilation → BP decrease

    • vasoconstriction → BP increase

Blood pressure regulation systems overview

Autoregulation (local level) → 1st line of defense

• vasodilators/vasoconstrictors

  • at tissue level

  • sphincter control in capillary beds

Neural Regulation → 2nd line of defense

• Cardiovascular centers

  • vasoconstriction and vasodilation

  • baroreceptor reflex

  • chemoreceptor reflex

Hormonal Regulation → long term effects

• Renin-Angiotensin II - Aldosterone System (RAAS)

  • immediate/long term effects

• Atrial Natriuretic Peptide (ANP)

  • long term regulation of ECF volume

  • opposite effect of RAAS

Autoregulation: local blood flow

• 2 mechanisms regulating blood pressure locally

• endothelium:

  • in response to friction (shear stress) → release vasodilators (NO and prostacyclin)

  • too much pressure → friction/sheer stress → release vasodilators to reduce pressure → sent to smooth muscle

• smooth muscle:

  • in response to excessive stretch → smooth muscle constricts → myogenic regulation

  • important to maintain systemic flow in relation to gravity and body position

    • sudden change in pressure (eg stand up → blood rush down → arteries stretch → arteries constrict (push blood back up) → increase BP in upper body

• vasomotion

  • at rest precapillary sphincters normally open/close

  • vasodilators → in response to abnormal tissue constriction → trigger vasodilation → higher rate of capillary closing

    • eg decreased O2, increased CO2

  • vasoconstrictors → thromboxane (reduce flow to damaged vessel), prostaglandins (pain), endothelin (released by endothelium

neural regulation

• Cardiovascular control center (medulla oblongata)

  • vasomotor center:

    • directs vasomotor responses in blood vessels

  • cardiac centers:

    • cardioacceleratory center → increase cardiac output via SNS

    • cardioinhibitory center → decrease cardiac output via PNS

• Supramedullary regulation

  • hypothalamus and cortex connect with cardiovascular control center to alter its activity → eg during exercise, emotional response, etc

Change in blood flow locally vs systemically

Q = P/R → increase pressure → increase resistance

Systemic blood flow (through whole system)

• constrict artery → increase pressure → increase blood flow

• pressure is more important systemically

Local blood flow

• dilate vessels → decrease resistance → more blood flow

• resistance more important locally

Sympathetic Regulation of Vessels

BP = CO x TPR

• BP= blood pressure, CO = cardiac output, TPR = total peripheral resistance

• WIDESPREAD arteriolar vasoconstriction → increase Total Peripheral Resistance (TPR) → increase preasure (Q = P/R) → increase blood flow

• decrease in BP → key stimulus to activate SNS

• most arterioles are richly innervated with sympathetic nerve fibers

• norepinephrine will stimulate arteriolar VASOCONSTRICTION in most organs

  • sympathetic nervous system activation → most arteries constrict → increase total peripheral resistance → increase pressure

  • automatic tone = background of sympathetic activity

  • decrease in sympathetic activation → vasodilation → decrease in resistance → decrease pressure

  • increase in sympathetic activation → vasoconstriction → increase in resistance → increase in pressure → increase blood flow

• important exceptions: cerebral vessels, coronary blood vessels, pulmonary vasculature

Baroreceptors: definition and location

• Baroreceptors: respond to changes in stretch

  • increased stretch → increased firing of sensory nerves

  • decreased stretch → decreased firing of sensory nerves

• located at 2 major sites

  • 1. wall of aortic arch → sensory nerve = vagus nerve

  • 2. carotid sinus → sensory nerve = glossopharyngeal nerve

    • all sensory input going to the medulla oblongata

Baroreceptor reflex feedback loop

• detectors = baroreceptors in carotid sinus and aortic arch

• afferent pathways (sensory info → brain) = Cranial nerve IX (glossopharyngeal) for carotid sinus and X (Vagus) for aortic arch

• integration center = medulla: cardiovascular control center

  • cardioinhibitory/ cardioacceleratory centers

  • vasomotor centers

• efferent pathways (brain to effector organ) = sympathetic and parasympathetic nerves

• Effector organs:

  • heart (conduction system and myocytes)

    • cardiac output

  • blood vessels (vascular smooth muscle)

    • vasodilation/vasoconstriction

• BP increased → more stretch in baroreceptors → increase signal → send info back via cranial nerve → medulla oblongata: vasomotor center inhibited (dilate vessel), cardioacceleratory center inhibited, cardioinhibatory center stimulated (slow down heart rate decrease cardiac output) → stimulate PNS → reduced BP

• BP decreased → less stretch in baroreceptors → decreased signal → info travel up cranial nerve → Medulla: vasomotor center stimulated (vasoconstriction), Cardioacceleratory center stimulated (speed up heartrate → increase cardiac output), cardioinhibitory center inhibited, → stimulate SNS → increased BP

Chemoreceptor Reflexes

• Specialized receptors

  • respond to pH levels in blood

    • elevated CO2 → decrease in pH (CO2 = acidic)

    • → increase blood flow → increase gas exchange with lungs

  • respond to O2 levels in blood

    • increase blood flow through lungs to bring more O2 in

• Receptors in sensory neurons of carotid sinus and aortic arch

• decrease pH and decrease in O2 → (want to increase blood fllow and blood pressure) → medulla: vasomotor centers stimulated (vasoconstriction), cardioacceleratory centers stimulated (increase CO), cardioinhibitory centers inhibited → increase BP and Q

Renal Regulation of Blood Pressure: RAAS (IMPORTANT!!!) (increase BP)

Renin-Angiotensin-aldosterone system

• long term effect

• kidneys release RENIN (hormone) in response to

  • decrease in BP (stretch receptors in kidney tubules → renal baroreceptors)

  • sympathetic activation (kidney tubules innervated by sympathetic nerves)

  • decreased flow of sodium through kidney tubules

• in blood, RENIN converts ANGIOTENSINOGEN → Angiotensin 1 (prohormone)

• in lung, ACE enzyme converts Angiotensin 1 → angiotensin 2

Effector organs of angiotensin 2 (ANG II) → more effective than norepinephrine for vasoconstriction

1. Blood vessels → vasoconstriction (increase TPR→ total peripheral resistance)

2. Heart → increased cardiac output

3. Adrenal Cortex → aldosterone release

• increase Na+ reabsorption by kidney → reabsorb water → increase blood volume → increase BP

4. Hypothalamus

• ADH release → increase water reabsorption by kidney → increase blood volume → increase BP

• stimulate thirst

RAAS feedback loop

• Kidney sensitive to BP decrease

• → increase release of RENIN

• → Renin converts Angiotensinogen → Angiotensin 1

• → in lungs ACE converts Angiotensin 1 → Angiotensin 2

• → Ang II affects all the stuff:

  • Blood pressure → vasoconstriction

  • heart → increased CO

  • adrenal cortex → aldosterone release

  • hypothalamus → ADH release and increased thirst

• → kidneys also increase red blood cell formation

• → increase oxygen carrying capability

Natriuretic Peptides (decrease BP)

ANP → atrial natriuretic peptides

• Detectors: baroreceptors in walls of right atrium

• hormonal response to atrial stretch:

  • when atrium stretch → atrial myocytes release ANP (atrial natriuretic peptide)

• effects of ANP → decrease BP

  • vasodilation

  • increased sodium and water excretion

    • decrease blood volume → decrease BP

  • block: ADH, aldosterone, norepinephrine

    • block all the effects

• increased blood in atria → increased atrial stretch → increased ANP release → increased sodium and water excretion → decreased blood volume → decreased BP

Chemoreceptor reflexes

• detect O2 and pH in aortic arch are carotid sinus

• CO2 + H2O → H2CO3 → H+ + HCO3-

special circulations

coronary circulations

• supply heart with blood

• normally 60ml/minute/100g of heqrt

• w/ exercise > 250mL/minute/100g of heart

• max blood flow = coronary reserve

• ATP metabolites → vasodilation

Regulation of coronary blood flow

• coronary circulation = blood supply to heart.

  • L and R coronary arteries take blood to heart

• at rest: blood flow through coronary arteries → 60mL/min per 100g tissue (dont need to remember)

• exercise: increases to >250 mL/min per 100 g tissue → “coronary reserve”

• increase blood flow to heart (local)

  • vasodilate artery → reduce resistance (resistance more important for local) → increase blood flow

• breakdown products (metabolites) of ATP production → vasodilation of coronary arteries

  • heart uses ATP → break down ATP into metabolites → metabolites serve as potent vasodilators

• SNS → release epinephrine from adrenal gland → causes vasodilation of coronary arteries (opposite of most vessels)

• increased work of heart → higher rate of ATP breakdown → increased vasodilation → increased epinephrine → further vasodilation → increased coronary blood flow

• Angina = coronary spasms which temporarily block blood flow

• Myocardial Infarction (heart attack) = total blockage of part of coronary circulation → death of cardiomyocytes

  • left coronary artery is most commonly blocked → descending into anterior ventricular septum

Cerebral Circulation

• autoregulation → brain is least tolerant to ischemia (lack of blood flow)

  • brain dependent on oxygen and glucose

  • death of cells within minutes of ischemia

• Brain receives blood through 4 source arteries

  • 2 internal carotid arteries (branch off common carotid)

    • external → blood outside of skull

    • internal → blood to brain via carotid canal

  • 2 vertebral arteries

• blood supplies 15% of resting cardiac output to the brain

• brain is least tolerant organ to ischemia (reduction of blood flow)

  • cell death within minutes

• Cranial cavity is fixed space → limits volumetric changes

  • too much blood flow → hemorrhage → extra pressure against brain damages neurons

Autoregulation of Cerebral Blood Flow

• Blood flow to brain is maintained at constant level over wide range of pressures (mean arterial pressure) → constant brain blood flow

• Autoregulation:

  • prevents increase in blood flow and intracranial pressure when blood pressure increases

  • maintains adequate blood flow when blood pressure decreases

• Process: vasoconstriction/vasodilation as needed

  • metabolic mechanisms (increases in demand or waste→ act as metabolic vasodilators)

  • myogenic mechanism (increased stretch in smooth muscle of of arterioles → contracts in response)

• autoregulatory range = 50 -150 mmHg

Splanchnic Circulation

• blood flow through GI tract: stomach, intestines, pancreas, spleen, liver

• hepatic portal system:

  • substances absorbed in GI tract travel first to liver → detoxify before going to heart

• Splanchnic circulation can serve as blood reservoir

  • receives 25% of resting cardiac output

  • mobilize blood from splanchnic circulation when needed (like in fight or flight) → redirect

• splanchnic circulation heavily regulated by autonomic nervous system

  • increased SNS activity → vasoconstriction

  • less output to splanchnic → to SNS

• hormonal and local metabolite regulate blood flow with change activity of gi tract

Characteristics of Blood

• homogenous connective tissue

Blood:

• temperature = 100 F (higher than body temp → transfers heat)

• pH = 7.35 - 7.45

• viscous: more viscous than water due to solid elements

• average blood volume = 5 Liters

Components of blood:

• Plasma: Extracellular fluid

• Formed Elements: blood cells

  • red blood cells

  • white blood cells

  • platelets

• serum → fluid left after natural clotting

• plasma → fluid left without clotting

• hematocrit → % of RBC

Plasma

• ECM of blood

91% water

Proteins (7% of weight)

• Albumins:

  • regulate osmotic pressure → creates osmotic gradient to draw water

  • transport steroid hormones → act as carrier proteins sometimes

  • buffer

• Globulins (round protein)

  • immunity → produced by immune cells

  • transport steroid hormones and thyroid hormone → carrier protein

• Fibrinogen

  • facilitates blood clotting

  • serum = plasma without clotting factor → no fibrinogen

Other solutes (2%):

• ions

  • sodium, potassium, calcium, magnesium, chloride, iron, phosphate, hydrogen, hydroxide, bicarbonate

• Nutrients: glucose, amino acids, triglycerides, cholesterol, vitamins

• Waste products

  • protein breakdown → urea, uric acid, creatine

  • RBC breakdown → bilirubin

  • lactic acid → product of anaerobic respiration

• Gases: O2, CO2, N2

• regulatory substances: enzymes and hormones

Formed Elements

• Erythrocytes (RBCs) (99.9%) → oxygen and CO2 transport

• Leukocytes (WBCs) (<0.1%) → immune responses

• Thrombocytes (platelet) → clotting

Red Blood Cells (erythrocytes)

Function: transport of gases (oxygen and carbon dioxide throughout body)

• Numbers (affected by testosterone)

  • Females (4.2 - 5.5 million per uL)

    • usually menstruate → lower blood

  • Males (4.5 -6.3 million per uL)

    • testosterone → more RBC

• Shape/Function relationship

  • lack organelles

  • biconcave disc shape

  • have bunch of protein → hemoglobin (95% of RBC)

  • flat →

    • higher surface area to volume ratio

    • function of RBC → diffusion of oxygen → easier to diffuse over large SA

    • stackable → fit through capillary beds (almost same size)

• Lifespan:

  • 120 days

  • no organelles → no repair mechanism

  • constantly move → damage easily

Hemoglobin

Function: Gas transport → majority of oxygen in blood is bound to hemoglobin

• hemoglobin quaternary structure (multiple proteins) made of

  • 4 hemes and 4 globin proteins

  • each globin gets 1 heme

    • 2 alpha chains

    • 2 beta chains

    • heme

• each RBS contains 280 million hemoglobin molecules → carry 1 billion oxygen molecules

• Heme = iron containing pigment complex

  • oxygen reversibly binds to iron in heme

    • Oxyhemoglobin → oxygen bound to hemoglobin (bright red)

    • Deoxyhemoglobin → oxygen removed from hemoglobin (darker red)

Life Cycle of Red Blood Cells

• 120 days

• synthesized in red bone marrow in epiphysis of long bone and in flat bone via erythropoiesis

• body constantly monitors RBC → don’t want to lose RBC contents to hemolysis (RBC exploding)

• RBCs constantly degraded and replaced → macrophages in sinusoidal capillaries monitor RBC in spleen, liver, lymph nodes

• if macrophages see RBC is at end of life → eat and recycle materials

• globin broken down into amino acids and recycled

• Heme Breakdown:

  • iron recycled

  • heme without iron converted → Biliverdin (green)

  • Biliverdin converted → Bilirubin (yellow/orange)

  • bilirubin excreted in bile to large intestine

    • bacteria break bilirubin → stercobilin → urobilin

    • stercobilin brown → poop is brown yippee

    • urobilin reabsorbed from digestive system → blood stream → kidney → pee

jaundice: accumulation of bilirubin causing yellowing of skin and eyes

The Spleen

• 5 inch organ in upper left of abdominal cavity

• sinusoidal capillary beds allow for free exchange of blood cells

• red pulp: filtration of RBC → red blood cells and macrophages for RBC monitoring and recycling

• white pulp: lymphoid tissue housing T and B lymphocytes

Regulation of Erythropoiesis (RBC synthesis)

• synthesis of erythrocytes (RBC) regulated by hormone Erythropoietin (EPO)

  • excreted by Kidneys

  • EPO released when O2 levels are low → stimulates production of RBC → more RBC to carry oxygen → increases carrying capacity of oxygen

  • Testosterone release more EPO

• Signal for release of erythropoietin (EPO)

  • HYPOXIA = low oxygen

  • androgens

Hematocrit

Percent volume of RBC in blood

• normal range → 40-50%

• 55% plasma

• buffy coat (WBC and platelets)

• 45% RBC hematocrit

Elevated Hematocrit from:

• increasing RBC

• decreasing plasma

Decreased hematocrit

• low RBC

• excess plasma