Exercise And Motion

Front 1

Primary measures of peak exercise capacity

Back 1

Max VO2 = maximal aerobic capacity (aerobic potential).
- effected by genetics, training, age, O2 supply
- usually increases linearly with workload in exercise
MET: metabolic equivalent; the multiple of basal metabolic rate occurring during exercise

Front 2

Organ systems integrated into normal cardiopulmonary response to exercise

Back 2

- respiratory (perform gas exchange with air and pulmonary circulation)
- circulatory (transfers oxygenated blood from the lungs to target organs, and returns deoxygenated blood to the lungs)
- musculoskeletal: receives oxygen and nutrients from the peripheral circulation and performs movement of exercise via generation of ATP in the mitochondria

Front 3

3 tiers of cardiovascular disease prevention

Back 3

- Primordial: before risk factors manifest; things addressed includes physical activity, healthy eating, weight management, psychosocial factors, genetics
- Primary: after risk factors manifest; goal is to reduce morbidity due to factors; includes lipids, hypertension, smoking, diabetes, lifestyle (primordial)
- Secondary: after disease has manifested, goal is to prevent further mortality, improve condition; includes ASA, ACE-I, Rehab, beta-blockers, plus other conditions/risk factors

Front 4

1st Law of thermodynamics

Back 4

"conservation of energy"
Total energy of a system and its surroundings must remain constant. Energy can neither be created nor destroyed but may be converted from one form into another.

Front 5

2nd Law of thermodynamics

Back 5

"Entropy increases"
The free energy of a system tends to decrease. The disorder or randomness in a system tends to increase. The entropy of a system tends to increase.

Front 6

Define Free Energy (G)

Back 6

Energy available to do work. All systems tend to change in such a way that free energy is minimized.

Front 7

Define Enthalpy (H)

Back 7

Heat content (chemical bond energy)

Front 8

Define Entropy (S)

Back 8

Degree of randomness (temperature-dependent)

Front 9

Equations relating to Gibbs Free Energy

Back 9

ΔG = ΔH - TΔS
ΔG = G(prod) - G (react)
ΔG = ΔG°´ + RT ln([prod]/[react])
ΔG°´= -RT ln Keq

Front 10

ATP: utility as an energy source and energy quantity

Back 10

- ATP is easy to synthesize and utilize.
- worth 7.3 kcal/mol
-contains less energy than 1-3bisphosphoglycerate, creatinine phosphate, phosphoenolpyruvate, which all contribute to ATP synthesis during metabolism

Front 11

Equations relating to Gibbs Free Energy

Back 11

ΔG = ΔH - TΔS
ΔG = G(prod) - G (react)
ΔG = ΔG°´ + RT ln([prod]/[react])
ΔG°´= -RT ln Keq

Front 12

Glucose transporters 1-4

Back 12

GLUT1: expressed in all cells, esp RBCs. Km = 1mM so saturated under normal conditions
GLUT2: low affinity, high capacity; allows liver to regulate plasma glucose independent of insulin; allows galactose to enter into
liver; (Km = 15 – 20 mM).
GLUT3: found in brain tissue, high affinity (normally saturated), Km = 1 mM
GLUT4: found in heart, muscle, and adipose; insulin dependent (insulin binding allows channel carrying vesicles to fuse to PM); Km = 5mM

Front 13

Priming reactions of glycolysis

Back 13

1: Glucose → G6P via hexokinase & ATP. Traps glucose in the cell; regulated step (can now be used for glycolysis, Pentose-phosphate pathway or glycogen synthesis)
2: G6P ↔ F6P via hexose phosphate isomerase
3: F6P → F1,6BP via PFK-1 & ATP; committed step, regulated by F2,6BP (PFK-2) and hormonal control by insulin/glucagon

Front 14

Splitting reactions of glycolysis

Back 14

4: F1,6BP ↔ glyceraldehyde-3P + dihydroxyacetone-P; via aldolase; 6 carbons split into two 3C molecules
5: dihydroxyacetone → gly-3P via tripose phosphate isomerase; now two gly-3P

Front 15

Payoff reactions of glycolysis

Back 15

6: (2)gly-3P → (2)1,3BP-glycerate + (2)NADH by G3P dehydrogenase.
7-9: (2) 1,3BPG ↔ (2) 3PG →(2) phosphoenolpyruvate + (2)ATP via phosphoglycerate kinase, PG mutase, Enolase
10: (2) phosphoenolpyruvate → (2) pyruvate + (2) ATP via pyruvate kinase; regulated step

Front 16

Total energy production of glycolysis

Back 16

Input: 2 ATP + 1 glucose
Output: 4 ATP, 1 NADH, 2 Pyruvate

NET: 2 ATP, 1 NADH, 2 Pyruvate

Front 17

Regulated steps in Glycolysis

Back 17

1: hexokinase is inhibited by its product G6P
3: PFK-1 is inhibited by ATP, citrate, and H+ and activated by F2,6BP and AMP (a sign of low energy). Insulin and glucagon can turn up and down, respectively, the formation of F2,6BP (via de/activation of PFK-2).
10: Pyruvate kinase is inhibited by ATP and alanine. Fructose-1,6-biphosphate is an activator.

Front 18

Acetyl-CoA production and uses in metabolism

Back 18

- formed from pyruvate in the matrix of mitochondria via pyruvate-DH, produces 1 NADH. Requires cofactors: Thiamine pyrophosphate (TPP/ Vit B1) in step 1, FAD (riboflavin/Vit B2) and NAD (from niacin) in step 3
- formed from catabolized fatty acids and amino acids
- Can be used in the TCA cycle or production of ketone bodies, sterols, and fatty acids

Front 19

TCA cycle: purpose and energy outputs

Back 19

- converts Acetyl-CoA into carbon dioxide while producing “reducing” energy
- produces 3 NADH, 1 GTP, 1 FADH2, 1 CO2 per acetyl-CoA

Front 20

Steps of TCA cycle

Back 20

1: Acetyl-CoA + oxaloacetate → citrate via citrate synthase
2: Citrate → isocitrate via aconitase (iron-containing enzyme)
3: Isocitrate → α-ketoglutarate + NADH + CO2 via isocitrate-DH and an intermediate
4: α-ketoglutarate → succinyl-CoA + NADH + CO2 via α-ketoglutarate-DH
5: Succinyl-CoA → succinate + GTP via succinyl-CoA synthetase
6: succinate → fumarate via succinate-DH
7: Fumarate → malate via fumarase
8: malate → oxaloacetate + NADH via malate-DH

Front 21

Regulation of the TCA cycle

Back 21

- regulated by products and substrate availability
- ATP and NADH are inhibitors of TCA cycle while Ca2+ and ADP signal a need for energy and activate the cycle. Most of the enzymes within the cycle are also regulated by their end products.

Front 22

Standard redox potential

Back 22

- a measure (in volts) of the affinity of a substance for electrons
- substances more electronegative than hydrogen have positive redox potentials
ΔG⁰' = -nFΔE⁰'

Front 23

Proteins in the ETC

Back 23

- linked in order of increasing (negative) redox potential
- NADH → Complex I ((4 H+)→ Co-enzyme Q
FADH2 → Complex II → Q
Q → Complex III (4 H+) → Cyt C → Complex IV (2 H+) → O2

Front 24

Proton motive force

Back 24

- the electrochemical and pH gradient created when protons are sequestered in the intermembrane space of the mitochondrion
- Used to synthesize ATP via ATP synthase (Complex V) or to generate heat

Front 25

ROS and mechanisms for their disposal

Back 25

- generated co-enxyme Q donates electrons directly to O2
- O2 + 1e- → ·O2- (can be reversed by manganese superoxide dismutase or Cu-Zn superoxide dismutase)
-  ·O2- + 1e- → H2O2 (degraded by catalase or glutathione peroxidase)
- H2O2 +1e- → ·OH (cannot be enzymatically neutralized)
- ·OH +1e- → H2O
- all can donate electrons to antioxidants

Front 26

Body water content, distribution, and ion differences/permeability

Back 26

- Total body water (TBW) = 0.6*weight
- intracellular fluid (ICF) = 0.67*TBW
- extracellular fluid (ECF, plasma + intercellular) = 0.33*TBW
- ICF is high in K+,Mg+, phosphate, proteins, and inorganic ions. Separated from ECF be semipermeable plasma membrane (with transporters, Hydrophobic and small uncharged polar molecules can diffuse)
ECF: higher in Na+, Ca+, Cl-, HCO3-

Front 27

Osmolality vs. tonicity

Back 27

Osmolality: physical property, give by moles solute over kg solvent
Tonicity: effective osmolality, only accounts for solute particles that are impermeable to the membrane

Front 28

4 main mechanisms of passive transport

Back 28

- simple diffusion occurs through the bilayer (only works for hydrophobic molecules and small uncharged polar molecules)
- simple diffusion through a pore
- gated diffusion through a channel
- facilitated diffusion through a carrier

Front 29

types of active transport

Back 29

Primary: Moving solutes against their electrochemical gradient, but the driving force comes from the favorable energy change that is associated with an exergonic (favorable) chemical reaction (e.g., ATP hydrolysis).
Secondary: Moving solutes against their electrochemical gradient, the driving force is provided by coupling the uphill movement of one solute to the downhill movement of one or more other solutes for which a favorable electrochemical potential difference exists.

Front 30

Types of active transport pumps

Back 30

1) P-type ATPases (Na-K pump, H-K pump, Calcium pump): include ATP hydrolysis and the resulting phosphorylated intermediates with conformational changes.
2) ABC transporters (MDR): characterized by 6 or 12 transmembrane ATP-binding cassette (ABC) domains. Able to recognize a broad range of substrates and distinguish the ones that are causing the stress.
3) V-type H pump: rotary-like pump that pumps protons into the vacuoles or lysosomes of cells (keeps them acidic)
4) F-type pump: ATP synthase. Uses proton gradient to synthesize ATP.

Front 31

Mechanisms to correct volume disturbances in the cell

Back 31

Short-term: changes in pressure activate transport pathways through which osmolytes are either gained or lost, to induce compensating osmotic water movements.
(ex: cell shrinkage activates Na-K-2Cl cotransporters,
Na-H exchanger, Cl/Bicarb exchanger, while stretching activates K-Cl co-transporter, K and Cl channels)

Long-term: Induce synthesis or degradation of osmotically active molecules (e.g., sorbitol, inositol, betaine, taurine)

Front 32

Relationship between pressure, flow, and resistance in a vessel

Back 32

- ΔP = QxR. ΔP is the change in pressure from one point in a vessel to another and Q is the flow (cardiac output)
- resistance can be summed in series or in reciprocal (for parallel veins)

Front 33

Poiseuille's Law

Back 33

Poiseuille’s law states that the resistance of a cylindrical vessel is proportional to the length of the vessel (L), the viscosity of the fluid (η), and the inverse of the radius of the vessel to the fourth power (1/r⁴)

R = 8ηL/(πr⁴)

Q = ΔP x πr⁴/8ηL

Front 34

Vascular resistance vs. compliance

Back 34

- Resistance determines how much flow occurs for a given driving pressure. Resistance is altered by a change any of the factors from Poiseuille’s law
- Compliance relates transmural pressure, or the difference in pressure on the walls of the vessel due to volume. Transmural pressure an intrinsic property of arteries and regulated by sympathetic tone in veins. Compliance = ΔV/ΔP

Front 35

Mean arterial pressure (MAP, Pₐ) and total peripheral resistance

Back 35

- MAP is set point at which the body tries to maintain pressure (but is not fixed)
MAP = diastolic pressure + 1/3 pulse pressure (the difference between systolic and diastolic pressures)

Pₐ = CO x TPR (where CO is cardiac output = SV x HR L/min)
--This equation is a simplification because CO and TPR are NOT independent b/c of reflexes

Front 36

Baroreceptors and MAP maintenance

Back 36

- baroreceptors are mechanoreceptors that are sensitive to pressure or stretch.
- Located at the carotid sinus (glossopharyngeal nerve) and aortic arch (vagus nerve)
- Changes in stretch/pressure are transduced as changes in firing rate of the neurons to the medulla, which increases/decreases the parasympathetic and sympathetic controls of HR and vasodilation, returning the BP to MAP
- this is a short-term reflex control (sense changes rather than absolute pressure). Long-term changes mediated by the renal system, changing the MAP

Front 37

Renin-Angiotensis-Aldosterone control of BP

Back 37

- Slower, long-term, hormonal control of BP via regulation of extracellular fluid
- Low MAP, results in low renal perfusion pressure, increasing plasma renin secretion, which split angiotensin I from angiotensinogen, and is then converted to angiotensin II by ACE
- Angiontensin II increases blood volume (& TPR) by triggering secretion of aldosterone, increasing Na/K exchanger activity, increasing thirst, and causing vasoconstriction

Front 38

Arteriole control of flow to capillaries

Back 38

- vasoconstriction of arterioles restricts flow to capillaries, constriction of precapillary sphincters can shut it off entirely
- metabolism of tissues surrounding the arteriole regulates resistance to match flow to need
- will vasodilate if low 02, high CO2, low pH, high adenosine, (high NO); due to either increased metabolism in tissues or low flow

Front 39

3 types of local control of blood flow

Back 39

1. Autoregulation: maintenance of a constant blood flow to an organ in the face of changing arterial pressure
• Myogenic hypothesis: When vascular smooth muscle is stretched, it contracts- therefore increased resistance of arteriole
• Decreased arterial pressure —a less stretch and vasodilation
• Thus maintains same flow even though arterial pressure changed
2. Active hyperemia: blood flow to an organ is proportional to its metabolic activity
3. Reactive hypermia: (rebound overshoot) increase in blood flow in response to a prior period of decreased blood flow

Front 40

Capillary Exchange

Back 40

- Resistance regulates capillary flow, and has a major influence on capillary pressure.
- Wall properties of the capillary determine solute flux between the vascular space and interstitial space
- In most tissues, capillaries are permeable to all small solutes (e.g. Na, Ca, glucose).
- Thus interstitial fluid and plasma have almost the same composition (except for proteins).

Front 41

Blood flow control to skeletal muscle

Back 41

- controlled both by local metabolites and sympathetic innervation of vascular smooth muscles
Neural control:
- PNS: sympathetic postganglionic neurons in skeletal muscle release norepinephrin which accumulates in the ECF and binds to α₁ receptors on vascular smooth muscle cells, causing vasoconstriction
- CNS: adrenal medulla secrete epinephrin in the blood, increasing plasma epinephrin which binds to both α₁ and β₂ receptors, causing vasoconstriction or dilation depending on the amount of receptors (lots of β₂ in skeletal muscle)
- during rest VC dominants, but during exercise epinephrin and local metabolite release causes VD an decreased resistance to the increased flow

Front 42

Starling forces

Back 42

- Gradients of transmural hydrostatic pressure (ΔP) and colloid osmotic pressure (Δπ) drive filtration and reabsorption respectively. Vary based on distance along capillary (more absorption toward venous end)
- Net filtration rate = Kf (ΔP — VΔπ) (Δ=inside - outside).
- On average ΔP is greater than Δπ
- Kf is very high in fenestrated capillaries, and still higher in discontinuous capillaries.
- σ= 1 for all but discontinuous capillaries.
-

Front 43

Events that regulate the net filtration rate in capillaries (Kf (ΔP — VΔπ)

Back 43

Events that increase filtration, and lead to edema if excessive include:
- ↑ Kf (leaky vessels)
- ↑ ΔP (arteriolar dilation or high venous pressure) (capillary pressure can never be less than pressure in the venule into which it drains)
- ↓ Δπ (low plasma protein or rapid loss to interstitium)
Events that promote absorption (less filtration):
- ↓ ΔP (arteriolar vasoconstriction)
- ↑ Δπ (elevated plasma protein)
33

Front 44

The lymphatic system

Back 44

- drains the interstitial fluid and protein (more fluid is filtered out than absorbed by the capillaries (4 L/day))
- lymphatic capillaries are composed of a single layer of endothelial cells on a basement membrane. These capillaries converge to form larger vessel, nodes, and eventually drain into subclavian vein.
- junctions have valves to prevent backflow and generates a negative interstitial pressure
- surrounding smooth muscle responds to stretch and propel lymph
- sympathetic neurons increase lymph flow

Front 45

Steps in the cardiac cycle

Back 45

- Late diastole: both sets of chambers relaxed. Passive ventricular filling
- Atrial systole: atrial contraction forces a small of additional blood into the ventricles
- End-diastolic volume (EDV): the max amount of blood in the ventricles at the end of ventricular relaxation ≈135mL
- Isovolumetric ventricular contraction (IVC): all valves closed, increasing ventricular pressure
- Ventricular ejection: rising pressure exceeds arterial pressure and opens semiluminar valves, blood ejected
- End-systolic volume (ESV): min amount of blood in venticles ≈65mL
- Isovolumetric ventricular relaxation: ventricles relax, semiluminar valves close

Front 46

Wigger's Diagram

Back 46

- Shows the cyclic changes of aortic pressure, atrial pressure, ventricular pressure, ventricular volume, ECG, and phonocardiogram (impulses received)
Of note:
- diastole is typically longer than systole, shortens during exercise
- electrical activity precedes contraction
- ventricular pressure oscillates between atrial and aortic pressures (possible due to large compliance)
- two phases of ventricle filling: diastasis (passive) the atrial contraction.
- P wave signals atrial contraction, QRS ventricle contraction, T ventricle repolarization

Front 47

Pressure volume loop

Back 47

- plot of ventricular volume vs. pressure
- pressure stays constant during filling between ESV and EDV (stroke volume).
- at EDV pressure increases up at constant volume
- During ventricular election pressure increases (to aortic) then decreases as volume falls
- at ESV pressure shoots down at constant volume.

Stoke volume (SV) = EDV - ESV
Ejection fraction = SV/EDV (should be greater than 55% for left ventricle)

Front 48

Frank-starling mechanism

Back 48

- the more you stretch a muscle the greater contraction you get when stimulated
- of the plot: systole curve rises rapidly then slows, diastole is the reverse

Front 49

Contractility and how it changes cardiac output

Back 49

= how hard the heart muscle contracts at any given end-diastolic volume
- increased by sympathetic NE and Epi
- greater contractility ejects more blood and at a higher pressure, decreasing ESV and increasing SV
- this is independent of EDV, and therefore different then Starling's Mechanism

Front 50

Preload and how changes in it effect cardiac output

Back 50

= volume of blood in the ventricles prior to contraction, the EDV.
- if preload is increased there will be greater contraction force and stroke volume due to starlings mechanism

Front 51

Afterload and how changes in it effect cardiac output

Back 51

= the arterial pressure against which the ventricle pumps blood
- increasing the afterload does not change the ESV, but increases the pressure the heart has to generate to open the aortic valve. The valve will close earlier also resulting in large ESV and decreased SV (and CO)

Front 52

Matching cardiac output and venous return

Back 52

- Central venous pressure (filling pressure) must be appropriate to supply the right atrium, any changes in CO must be matched in CVP
- accomplished by co-regulation of cardiac performance (contractility and HR) and venous compliance

Front 53

Edema: what & why

Back 53

= the accumulation of a large amount of interstitial fluid
- occurs when there is an excessive (uncompensated) increase in capillary filtration; decrease in plasma protein or rapid loss to the interstitium; malfunction of the lymph system

Front 54

Cardiac refractory period

Back 54

- After an action potential initiates, the cardiac cell is unable to initiate another action potential for some duration of time that is slightly shorter than the "true" action potential duration. This period of time is referred to as the (absolute) refractory period. During the relative refractory period at the tail end of the action potential, another premature contraction/ AP can be elicited, but it will not be at full intensity.
- the refractory period is longer in heart cells than neurons to prevent the buildup of contractions that might result in muscle tetanus, or prolonged contraction.

Front 55

excitation-coupling in the heart

Back 55

- depolarizing action potentials are transmitted to the muscle fibers by t-tubules which opens voltage-dependent calcium channels in the T tubule membrane. Calcium entering the muscle fiber activates ryanodine receptor channels (RYR) in the SR membrane, which release calcium into the sarcoplasm. Calcium in the sarcoplasm then interacts with troponin to move tropomyosin and induce contraction.
- After contraction intracellular calcium is taken up by the SR ATPase pump into the sarcoplasm, or ejected from the cell by the sodium calcium exchanger or the plasma membrane calcium ATPase.
- The strength of cardiac contractions would be reduced considerably without this extra calcium release.

Front 56

Adrenergic (sympathetic) cardiac receptors and the effects of stimulation

Back 56

- Beta adrenergic/sympathetic stimulation increases contractility (ionotropic) and increases relaxation (lusitropic)
α1 i. activated by NE ii. may have a small increase in inotropic effect iii. most relevant in vascular vasoconstriction iv. works through coupled Gq-protein to produce physioligic actions
β1
i. Most abundant B-adrenergic receptor (75%)
ii. Activated by NE mostly, but also E
iii. Acts through Gs, PKA to activate cAMP which P's Ca++ channels (more Ca in cell) to increase HR & contractility, also P's troponin C (release Ca) and PLM (release SERCA pump) to speed Ca reuptake and increase relaxation
iv. Down-regulated in heart failure
β 2
i. Make up 25% of β -adrenergic receptors
ii. Activated better by E than NE
iii. Receptor may activate both Gs and Gi (works on Gs)
v. when under chronic sympathetic stimulation to speed up HR during Heart Failure, B1's are down-regulated, but not B2's, therefore have therapeutic potential

Front 57

Cholinergic (parasympathetic) cardiac recepors and effects of stimulation

Back 57

M2
i. Activated by Ach
ii. Acts through Gi
iii. Slows heart rate
iv. acetylcholine is released from the nerve terminal and binds to an inhibitory G-protein which has a couple of different effects to modulate a K current that sets the heart rate. A Gi subunit also inhibits adenylyl cyclase, which decreases levels of cAMP.

Front 58

Drugs that regulate cardiac contractions

Back 58

- cardiac glycosides (digoxin): inhibits the Na/K exchanger, increasing Na, slowing Na/Ca exchanger, slowing calcium eflux so more is taken up by SR and bigger contraction next time. Ionotropic.
- myofilament sensitizers (levoosimendan): enhances Ca++ binding to troponin C, allowing stronger contraction at lower [Ca++]. ionotropic.

Front 59

Force frequency response

Back 59

the strength of contraction increases as heart rate increases, independent of sympathetic stimulation. This is an intrinsic property of myocardium starting at infant age.
- mechanism: As you pace a cell faster, more action potentials are generated per unit time, so calcium channels open more often. The larger buildup of calcium in the cell allows more calcium into the SR. Increased pacing frequency also phosphorylates PLM which increases the activity of SR calcium ATPase (SERCA), increasing Ca reuptake and relaxation (lusitropic)

Front 60

Synchronization of contraction in heart muscle

Back 60

An electrical wave starts at the sinoatrial node (pacemaker) and triggers atrial contractions (diffuses through tissue to the left) and travels to the AV (atrioventricular) node then the Bundle of His, then the bundle branches and perkinje fibers. The Purkinjie fibers line the endocardial surface of the heart and propagates the wave to the ventricular cells which contract (gap junctions spread current), beginning at the apex up to the base.
- A delay of more than 1/10 of a second occurs in the AV node and bundle, which allows the atria to contract before the ventricle

Front 61

5 Phases of ventricular action potential

Back 61

0: Fast upstroke: the action potential (K+ efflux) opens voltage gated Na+ channel (influx) rapidly depolarizing the cell (~40mV)
1: notch: Na+ channel closes and transient K+ channel opens (efflux) causing repolarization
2: plateau: depolarizing (inward) Ca++ current, triggers Ca++release in the SR
3: repolarizing: delayed K+ (influx) retifying current returns the cell to the polarized resting state. Sensitive to drugs to increase AP duration (bad)
4: resting phase: voltage sensitive inward retifying K+ current maintains the cell at resting voltage. (turns off during AP).

Front 62

Sinoatrial node

Back 62

- Pacemakerof the heart
- Located in posterior wall of right atrium
- Controls the heart rate
- Rate of action potential firing is modulated by sympathetic and parasympathetic stimulation, but firing itself automatic
- action potential has 2 potentials:
--Pacemaker: If (funny current) brings the cell up to the voltage threshold; channels are permeable to Na and K, turn on by hyperpolarization (low potentials) and turn off at higher potentials
--action potential:depolarizing calcium current then repolarizing/hyperpolarizing K restoring current

Front 63

Sympathetic/parasympathetic stimulation of the SA node

Back 63

Sympathetic Stimulation:
- Increases I(f) and I(Ca,L)
⇒ Increases rate and amplitude of diastolic depolarization
⇒ Therefore, spontaneous action potentials occur with a shorter diastolic interval,thus a faster heart rate

Parasympathetic Stimulation:
- decreases I(f)
- activates I(k,ACh)
- decreases I(Ca,L)
⇒ Hyperpolarizes the membrane and slows diastolic depolarization
⇒ Therefore, spontaneous action potentials occurwith a longer diastolic interval,thus a slower heart rate

Front 64

Differences in ionic currents muscles cells vs nodal cells

Back 64

Muscles cells (atrial & ventricular)
- require external stimulation to fire
- I(Na) creates fast upstroke, I(Ca,L) maintains the plateau, I(k) repolarizes, I(K,1) maintains the resting potential
Nodal cells
- fire independently of stimulation, but rate can be controlled by external stimulation
- I(Ca) causes fast upstroke, no plateau, I(k) immediately repolarizes/hyperpolarizes the cell, I(f) depolarizes to threshold and is NE,ACh sensative, I(k,Ach) is stimulated by ACh to slow rate by K influx

Front 65

3 main factors determining action potential propagation velocity through cardiac muscle (not nodal cells)

Back 65

- number of Na+ channels: increasing channels results in more inward current and faster upstroke and propagation
- cell size: larger cells have lower resistance so current flows faster
- gap junctions (increased coupling): the more gap junctions the more current pathways, reducing resistance and speeding conduction

Front 66

Electrocardiogram

Back 66

- measures small electrical changes on the surface  of the skin resulting from the action potential as it travels down through the heart. this voltage is measured a`nd amplified by placing leads on the skin on either side of the heart.

Front 67

PQRST waves of the ECG

Back 67

P wave: Atrial depolariztiaon as the electrical signal passes from the sinoatrial (SA) node to the atrioventricular (AV) node, through the atria
- QRS wave/”complex”: Depolarization of the leg and right ventricles.
- T wave: Repolarization of the ventricles

Front 68

Why do the QRS and T waves have the same polarity?

Back 68

- T wave has the same polarity as the QRS wave because the cells that depolarize last repolarize first. -In depolarization of the ventricles (QRS wave) the  wave goes from the septum to the endocardial surface of the ventricles, up laterally and through the epicardial surfaces. If repolarization happened in the same order, then you’d get a negative T wave because the direction of the current be reverse. Instead the action potentials of the cells that depolarized last are quicker than those of the cells that depolarized first. Thus repolarization happens in the opposite order.

Front 69

ECG leads

Back 69

Frontal leads: give xy axis of charge (clockwise ⁰)
- I : 0⁰, right to left
- II: 60⁰, down, left
- III: 120⁰, down, right
- aVL: -30⁰, up, left
- aVR: -150⁰, up, right
- aVF: 90⁰, down
Prechordal leads: give xz axis of charge
- V1-6, straight forward to left.

Front 70

Cardiac output changes during exercise

Back 70

Cardiac Output (CO) = SV x HR
-Resting CO ~5 L/min, exercise CO ~20L/min (in elite athletes 35-40)
- During exercise, the circulatory system’s main goal is to adequately increase and adjust the cardiac output to satisfy the metabolic needs of skeletal muscles, while ensuring perfusion of vital organs, and preventing hyperthermia. To increase the cardiac output during exercise, the heart rate and stroke volume are increased.
- As CO is increased, systemic vascular resistance decreases because vessels in the muscles and skin dilate (to allow more flow there). Net effect is modest increase in systolic BP (40-50pts) with little/no change in diastolic BP.

Front 71

Heart rate changes during exercise

Back 71

- resting heart rate is 50-100bpm, max rate during exercise is approx 220-age
- During exercise, the heart rate increases to about 100bpm via withdrawal of parasympathetic vagal tone (vagus nerve), which innervates the SA node. (vagus nerve = "brake of the heart”)
- In continued/strenuous exercise, respiratory rate increases and pulmonary stretch receptors trigger the release of NE from sympathetic neurons, stimulating the SA node to fire faster, increasing HR to max (plateau) and increasing heart contractility
- increased HR is the main driver of increased CO

Front 72

Changes in stroke volume during exercise

Back 72

- SV at rest is 50-80mL, increases up to 50% (100bpm)
- SV increases via the Frank-Starling mechanism: the more blood that fills the ventricle, the greater the ventricles stretch, and consequently, the more blood the ventricles will pump out (stronger contraction). Increased preload creates a feed-forward mechanism, because the more blood that comes back into the ventricle (stroke volume), the greater the contractility, and the greater the overall cardiac output.
- Basically: stronger contractions reciprocally increase SV via increased preload in the ventricles
- Less significant effort of CO than HR, SV plateaus when CO is only half its max value

Front 73

Testing cardiac function with exercise tests

Back 73

- Important to test cardiac function at conditions of high O2 demand because problems will manifest that don't at rest.
- assess MET's (1 MET = 3.5mL O2 upstake/kg/min), should be 8-10 for healthy person (18-24 for elite athlete) (under five for any reason is a poor prognosis). The longer you can exercise the better your prognosis
3 protocols:
- Bruce: 3min stages w/ increasing pace & elevation until 85% of max HR or adverse symptoms
- modified bruce: starts slower, slower increases (better for older patients w/ less exercise capacity)
- Naughton: increases speed/incline at 4min intervals, less demanding than Bruce.
In all protocols, the patient is continuously monitored via blood pressure and EKG for heart rate, arrhythmias, and signs of ischemia. Sometimes, echo or nuclear imaging is also used to increase sensitivity for coronary artery disease assessment
- normal response is an increase in systolic BP, a drop in BO is bad
- flow-limiting stenoses will cause ischemia

Front 74

Causes of sudden cardiac death

Back 74

- can occur in otherwise healthy, asymptomatic young (< 35yo) athletes. Prevalence unknown (est. 1 death per 50,000 – 300,000 competitive
athletes annually)
- ~45% due to hypertrophic cardiomyopathy
- other causes include anomalous coronary artery, myocarditis, Marfan syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC), arrhythmias, and commotio cordis

Front 75

Hypertrophic cardiomyopathy

Back 75

- leading cause of sudden cardiac death in young athletes
- Autosomal dominant mutation in sarcomeric proteins (Beta myosin heavy chain, cardiac myosin binding protein C, or cardiac troponin T). Muscle compensates by thickening
- Left ventricular hypertrophy, usually involving interventricular septum → obstruction of LV outflow →
patients prone to ischemia
→ ventricular tachycardia (VT: ventricle beats v. fast independent of SA node) or ventricular fibrillation (VF: ventricle just quivers, fatal)
-Can sometimes display exertional symptoms like dyspnea, angina, and syncope (fainting)
-Histological changes (noted around age 20 – 30) = myocardial disarray, increased intracellular matrix
- TREATMENT: exclusion from competitive sports

Front 76

Anomalous coronary artery

Back 76

- Denoted by anomalous origin of a coronary artery from the aortic cusps
→ Most worrisome is when the LEFT coronary artery branches off the RIGHT aortic cusp, creating a serpentine vascular course → Increased likelihood that abnormal artery can become kinked during strenuous exercise
- Symptoms include chest pain, fainting, or sudden death
- Usually normal findings on physical exam, EKG, and stress test
-Ischemia leads to VT or VF
- Treatment: Surgical correction

Front 77

Myocarditis

Back 77

- Usually viral origin (Coxsackie B) and often comorbid pericarditis
- Histological changes = inflammatory cells and lymphocyte infiltration
- Inflammation leads to VT or VF

Front 78

Marfan Syndrome

Back 78

- Autosomal dominant mutation in fibrillin gene, leading to weakened vessels (particularly aorta)
- Patients are NOT prone to VF or VT; instead at risk for ruptured aorta
- Many physical findings suggestive of Marfan – tall, long limbs, hypermobility, scoliosis, detached lens/retina, etc

Front 79

Arrythmogenic right ventricular cardiomyopathy (ARVC)

Back 79

- Most common cause of sudden death in Italians from Veneto region
- Autosomal dominant mutation that causes fibro-fatty infiltration of right ventricle wall
- Prone to VT and VF

Front 80

Arrhythmias

Back 80

- electrical abnormalities associated with structurally normal heart
- Examples = Wolff- Parkinson White, Congenital Long QT, and Brugada syndromes
- prone to fatal heart rythms

Front 81

Commotio Cordis

Back 81

- VF due to a physical blow to the chest
- more common in young patients due to compliant chest walls
- must be struck in exactly the right place and the right time during the cardiac cycle (
- NO structural heart disease

Front 82

Screening for sudden cardiac death

Back 82

- Very difficult to screen for conditions causing SCD. Really only done based on family history or symptoms
- These are low prevalence conditions so will have high false positives in screening.
- Many conditions have no symptoms and are not detectable on routine exam
- ECG's have high false positives, ECHOs are expensive, etc
- normal modifications in the athlete's heart cause thickening increased volume that mimic pathology (need ECHO to detect changes in stiffness)

Front 83

Adaptations that occur in the hearts of athletes

Back 83

- many athletes experience normal physiological modifications to their hearts to accommodate for the strain of exercise, including:
- increased heart wall thickness
- increased cavity size
- reduced ejection fraction
The main difference from pathology is normal wall stiffness, and changes will regress after 6mo of cessation of exercise.

Front 84

Major functions of the respiratory system

Back 84

1. provide O2 to the tissues
2. eliminate CO2 from the tissues
3. short term regulation of blood pH (kidneys do long term)
4. defend against inhaled microbes (via mucus escalator)
5. Form speech sounds (in the larynx)
6. influence arterial concentrations of chemical messengers (removes/produce/add some to the blood)
7. trap and dissolve blood clots from systemic veins if not too large

Front 85

Functions of the conducting zone in the lung

Back 85

- consists of the tubes of the lung: trachea, bronchi, bronchioles, terminal bronchioles
- these are unable to do gas exchange, but provides low-resistance pathway for airflow to alveolar space. (has volume of ~150mL)
- tubes are more rigid and do not collapse during exhalation. Smooth muscles around these tubes helps control bronchodilation/constriction
- warms air to 37° and humidifies it to 100% saturation.
-mucus layer with cilia move particles up and out of the respiratory system
- houses laryns which forms vocal sounds

Front 86

Functions of the respiratory zone

Back 86

- includes respiratory bronchioles, alveolar ducts, alveolar sacs (huge elaboration of surface area). All are capable of doing gas exchange
- responsible for gas exchange (most occurs in the millions of alveolar sacs)
- normally filled with ~350mL air
- respiratory bronchioles have no cartilage so collapse on exhalation, allowing for sufficient exhalation and ability to get rid of waste gases-

Front 87

Relationship between alveoli and pulomonary capillaries that allows for efficient gas exchange

Back 87

- The majority of the lung is alveolar space and airways, but 10% is circulatory/lymphatic
- Pulmonary capillaries weave extensively through clusters of alveoli--more than 50% of alveolar surface is covered by capillary
- thin walls of both alveoli and capillaries (0.3 microns) promotes rapid gas exchange, very efficient

Front 88

Difference in arterial pressure in pulmonary and systemic circulation

Back 88

- In the aorta, normal pressure reaches 120/80mmHg, while in the pulmonary artery it's 25/8mmHg.
- The difference is because there is far less resistance in the pulmonary system
- Cardiac output from both ventricles is the same volume.
- In heart failure, the pulmonary pressure increases, forcing fluid out of the capillaries, causing pulmonary edema
- pulmonary system can accomodat 4-7x increase in CO w/o significant BP increase by opening and distending all the capillaries

Front 89

Factors that prevent alveoli from filling with water

Back 89

Normally, the alveolar surface is very leaky to water, proteins, and ions, and pressures in the capillaries favor fluid movement into the interstitium ("negative" relative pressure). Relies on mechanisms to keep the alveoli free of fluid:
1. evaporation: occuring at all times but not that significant
2. Surface tension: enough to restrict flow at most pressures.
3. lymphatic pumps: generate a negative pressure and carries fluid out of interstitium (malfunction can cause edema)

Front 90

Pulmonary edema

Back 90

= the accumulation of fluid in the interstitium and/or the alveoli of the lungs which impairs gas exchange.
- results when the left ventricle fails to pump blood to the same extent as the right ventricle. This increases left atrial pressure and the pressure in the pulmonary capillaries which drives fluid into the interstitium.
- Edema occurs when the flow of fluid into the interstitium exceeds the capacity of the lymphatics to remove it.
- left atrial pressure can rise to high levels before the ability of the lymphatics to remove the fluid is exceeded.

Front 91

Relationship between the chest wall and lung surface that prevents the lung from collapsing

Back 91

- the lungs don't attach to the chest wall, but are held in place by pressures (in the surrounding pleural sac) (connected by CT)
- the lung doesn't collapse b/c the atmospheric pressure is greater than the intrapleural pressure
- the opposing forces on the lungs (the elastic recoil of the chest wall, pulling the chest outward, and the elastic recoil of the lung’s connective tissue, pulling the lungs inward) create a negative pressure in the intrapleural space. That negative pressure in the intrapleural space keeps the lungs from collapsing
- changes in the interpleural pressure during breathing cause lungs to inflate/deflate

Front 92

Main muscles that mediate lung inspiration and expiration

Back 92

Inspiration
- Diaphragm: major muscle of inspiration; when it contracts, it moves down, expanding the lungs
- External intercostal muscles: used for more forced inspiration; contraction pulls the ribs upward
- Sternocleidomastoid: Also more for forced inspiration than in normal, relaxed breathing. Contraction raises the sternum
- Scalene muscles: Forced inspiration; contraction raises first two ribs
Expiration (Not required for normal, relaxed breathing)
- Internal intercostal muscles: Contraction pulls the ribs together and back toward the spine
- Rectus abdominus: Helps in forced expiration
- External oblique:  Helps in forced expiration

Front 93

Pressure changes in the lung that mediate inspiration and expiration

Back 93

Inspiration
- Inspiration begins when the skeletal muscles contract, expanding the chest cavity. This increase in volume causes a decrease in intrapleural pressure and a decrease in alveolar pressure. Alveolar pressure goes below atmospheric pressure, so air rushes into the lungs.
Expiration
- The skeletal muscles of inspiration relax (and  contraction of the expiration muscles if needed.) The chest cavity contracts in size. Intrapleural pressure returns to 
preinspiration level (still subatmospheric, but less so). Air in the alveoli gets compressed by the shrinking volume, increasing the alveolar pressure and forces air out of the lungs.

Front 94

Pneumothorax

Back 94

= when air enters the intrapleural space, eliminating the negative pressure, so there is no force to keep the lung expanded, and the elastic recoil of the lung causes it to collapse. The chest wall on that side will expand due to unchecked elastic recoil of the chest wall (will see one side of the chest raised)
- can happen as the result of disease (cancer, infection,  etc.) or trauma.
- usually happens only one side since each lung has it's own pleural sac
- treatment is to suction out the air

Front 95

Lung compliance (in health and disease)

Back 95

= the magnitude of the change in lung volume (VL) produced by a given change in transpulmonary pressure:
C(L) = ΔV(L)/ΔP(tp), P(tp) = (P(alv) – P(ip))
Determined by:
a) the “stretchability” of the lung (related to the elasticity of the lung tissue)
b) surface tension at the air‐water interface on the surface of the alveoli
- Low compliance: occurs in fibrosis (or infant respiratory distress syndrome where no surfactant is made), lung is stiffer so will have less expansion for pressure increase (work harder to inhale)
- high compliance: occurs in emphysema, alveoli are destroyed so less tissue/elasticity; more expansion for pressure (less work to inhale [but less gas exchange b/c fewer alveoli])

Front 96

Role of surfactant/surface tension in lung inflation

Back 96

- alveolar surface tension contributes to lung compliance. H-bonds between water molecules inhibit expansion/inhalation.
- type II alveolar epithelial cells secrete surfactant (mix of phospholipids & proteins) which disrupts H-bonds in water, lowering surface tension
- the amount secreted varies based alveolar size to all alveoli have equal resistance and receive equal inflation pressure (w/o surfactant P=2Tension/radius)

Front 97

Affect of airway resistance on airflow in lungs

Back 97

Airflow in lungs is determined by:
- lung/atmosphere pressure difference
- airway resistance: Air Flow = (P(atm) – P(alv))/R, R α 1/r⁴
small changes in radius greatly effect resistance
- radius effect is greatest in the respiratory bronchioles (no cartilage so radius is dependent on pressure). Inhalation: ↑radius, ↓resistance, air flows in. Exhalation: ↓radius, ↑resistance, bronchiole collapses so there is a limit to speed of exhalation
- airway resistance is also effected by chemicals: ex: histamines trigger allergic asthma by constricting airways, especially on exhalation (compounds w/ bronchiole collapse)

Front 98

"Work" of breathing

Back 98

Muscle is always required for inspiration. Working against:
- Compliance work: against the elastic tissues and surface tension of the lung
- Tissue resistance work: to overcome friction associated with tissue-tissue sliding (especially pleural surfaces)
- airway resistance work: overcome the frictional movement of air in the airways
Overall can consume ~3% (normal) to ~50%(pathological) of body energy

Front 99

Lung volumes measured by a simple spirometer

Back 99

- Tidal volume: the volume of air inspired or expired in normal resting breathing
- Inspiratory reserve volume: the volume of air inspired above tidal volume if a maximum breath is taken
- Expiratory reserve volume: the volume of air expired below tidal volume if a maximum expiration is performed.
- (Can't measure the residual volume or an capacities including it)

Front 100

Lung capacities and their associated lung volumes

Back 100

- Inspiratory capacity: max volume of air inhaled after a normal exhalation (tidal volume + inspiratory reserve)
- Vital capacity: max exhalation after a max inhalation (tidal + inspiratory + expiratory reserve volumes)
- Functional reserve capacity: lung volume remaining after normal exhale (expiratory reserve + residual volume)
- Total lung capacity: Difference between min and max lung volume (tidal + inspiratory reserve + expiratory reserve + residual volume)

Front 101

Minute ventilation rate vs. alveolar ventilation rate

Back 101

- minute inspiration rate: total ventilation per minute (V(E) = tidal volume(Vt)*respiratory rate (f)) (Vt = ~500mL)
- alveolar ventilation rate: the rate of air reaching the alveoli (air available for gas exchange), the tidal volume (minus dead space) per minute. V(A) = (Vt - dead space (Vd))*f (Vd= ~150mL)
- Dead space is the conducting zone (anatomical) plus alveoli not perfused by blood (together: physiolgical), so any air in it is not available for gas exchange and so is not included in the alveolar ventilation rate.

Front 102

Dalton's Law

Back 102

= total pressure of a solution is the sum of the partial pressures individual gases
- gases will diffuse from an area where its partial pressure is higher to a lower one.

Front 103

Changing partial pressures of gases in the lungs

Back 103

Atmospheric: at 760mmHg, ~79% N2, ~21%O2
Inspiration: water content increases from atmospheric to ~100% saturation, diluting other molecules but not changing pressure (changes volume)
Alveolar air: 45.3mmHg O2 is removed from the air and 40mmHg CO2 is added, N and H20 remain constant. The difference in O2/CO2 decreases the volume, concentrating N2 slightly
Expiration: alveolar air mixes with dead spaces air, which increase the PO2 (more in deadspace air), decreasing PN2 and PCO2 (less in dead space air), PH2O is constant

Front 104

Relationship between solubility and pressure of gasses

Back 104

- the amount of dissolved gas in a solution is directly proportional to the partial pressure of the gas in the gas phase: [gas]soln = solubility*P(gas)
- this means that you can have different concentrations of gases in solution even if their partial pressures are the same.

Front 105

Rate of diffusion of gases in water

Back 105

- diffusion coefficient, D, determines the rate of a gas diffusing in water.
D α solubility (S)/√MW
- gas will diffuse from high to low concentration/partial pressure
- CO2 is 20x more soluble that O2 and nitrogen is half as soluble as O2

Front 106

Carbon dioxide and oxygen circulation and exchange between the lungs and tissues

Back 106

- Atmospheric air has PO2 of 160, PCO2 of 0.3. After exchange in the alveoli this changes to PO2 of 105 and PCO2 of 40 (diffuses through 5 membrane, thin though)
- Blood returning to the lungs has PO2 of 40 and PCO2 of 46. After exchange O2 diffuses in and CO2 out. The resulting pressures are PO2 of 100 and PCO2 is 40
- in the tissues the PO2<40 and CO2>46 so the capillary pressures: PO2 100→40, PCO2 40→46...and back to the lungs!

Front 107

Respiratory quotient

Back 107

= ratio of CO2 produced/O2 consumed
- diet dependent: all sugars RQ=1, fats and proteins are more reduced so require more O2 so fat diet RQ = 0.7, all protein RQ =0.8, Normal diet RQ=~0.8

Front 108

Effect of hydrostatic pressure on ventilation and perfusion in the lung

Back 108

Apex:
- V: more negative intrapleural pressure → greater transmural pressure gradient → alveoli are larger, less compliant → less ventilation
- P: lower intravasuclar pressures → less recruitment, distension → higher resistance → less blood flow
Base:
- V: intrapleural pressure is less negative → smaller transmural pressure gradient → alveoli are smaller, more compliant → more ventilation
- P: Greater vascular pressures → more recruitment, distension → lower resistance → greater blood flow

Front 109

Blood flow in zones of the lung relative to the heart

Back 109

Because arterial pressures in the lung are lower than systemic (120/80 vs 25/8) gravity contributes to BP in the lung.
- Zone 1: (pathological) would occur at the apex of the lung where BP is less, so alveolar pressure is greater than the capillary and it collapses
- Zone 2: Top 1/3 lung, above the heart, diastolic pressure is below the alveolar P, so will collapse then open during systole.
- Zone 3: Bottom 2/3 of heart, gravity increases BP so will always be greater that alveolar pressure and always open.

Front 110

Matching of ventilation and perfusion

Back 110

- Gas exchange is most efficient when alveoli are equally perfused with blood and oxygen to allow for complete equilibration. Lungs can self-regulate this
- Decrease airflow in a region → low blood PO2 → vasoconstriction of pulmonary vessels → decreased blood flow (diverted to healthy/functioning areas). (this the opposite of what happens in the rest of the body)
- Low blood flow to region → low alveolar PCO2 → bronchoconstriction → decreased airflow → diversion of air to healthy/functioning areas
-→ Ventilation and perfusion are matched by sensing changing partial pressures

Front 111

How hemoglobin increases the total oxygen content of blood

Back 111

- O2 diffuses into the blood based on the pressure difference between the alveolar O2 and free blood O2.
- Disolved, free O2 is only 3% of total O2 in the blood, the rest is bound to hemoglobin so does not establish the gradient. Therefore hemoglobin lowers the PO2 of the blood, allowing more to dissolve.

Front 112

Bohr and Haldane Effect

Back 112

- binding of oxygen to hemoglobin is dependent on temperature, pH, and [BPG]. High temp, low pH, high [BPG] all occur in metabolizing muscles releasing O2 from Hb.
- Bohr effect: deoxy-Hb binds H+ (from CO2) better than oxy-Hb. H-Hb binding inhibits O-Hb binding (right shift in O-Hb curve), reducing O2 from being taken up in low pH tissues (muscles). This facilitates the O2 release (extra 2%) and CO2 transport back to the lungs (by buffering the H+).
- Haldane effect: O2-Hb binding inhibits H-Hb binding. In the lungs at high [O2] (left shift), O2 will bind Hb releasing (extra) CO2

Front 113

Henderson-Hasselbalch equation for bicarbonate

Back 113

pH= 6.1 + log([HCO3]/0.03PCO2)
- Normal [HCO3] = 21-28mM, PCO2=40mmHg, so blood pH is normally 7.4

Front 114

Negative feedback loop to regulate blood pH by the lungs

Back 114

↑ alveolar ventilation → ↓PCO2 → ↓[H+] → ↓ alveolar ventilation → ↑PCO2 → ↑[H+]→ etc
- The lungs regulate pH on the short term by changing ventilation to control CO2 levels.
- Hyperventilation: ventilation has exceed O2 demand and removed more CO2 (raising pH, respiratory alkalosis) → compensated by lowering ventilation
-Hypoventilation: increased blood PCO2 decreases pH (respiratory acidosis)
-chemoreceptors in the lungs and medulla are used to detect blood gases
- Kidneys do longterm regulation

Front 115

acidosis and alkalosis

Back 115

- both refer to an inbalance in the blood bicarbonate causing a change in pH
- metabolic alkalosis: ↑HCO3 from excess metabolism
- metabolic acidosis: ↓HCO3 in the tissue, insufficient metabolism for the normal respiration
- respiratory acidosis: ↑CO2, insufficient respiration (hypoventilation)
- respiratory alkalosis: ↓CO2 excessive respiration (hyperventilation)
- calculate changes in pH using the Henderson-Hasselbalch equation

Front 116

CNS controls of respiration

Back 116

- expiration is controlled in the ventral respiratory center of the medulla. Inspiration is controlled by both ventral and dorsal (since it involves more muscle coordination)
- receive inputs from peripheral (carotid sinus, aotic arch) and central (brainstem, monitor CFS) chemoreceptors
- the phrenic nerve (diaphragm) and spinal nerves (intercostal & abdominal muscles) exit originate there.
- can regulate respiration to maintain pH via feedback mechanism
-Bötzinger complex in the ventral group drives pattern of respiration

Front 117

Peripheral and central chemoreceptors of pH in respiratory control

Back 117

Peripheral:
- located on the carotid bodies and the aortic arch where they are in contact with blood.
- Change firing rate based on changes in pH and PO2 (esp decrease), relay info to the medulla
Central
- located in the medulla, monitor CSF for CO2 and pH changes.
- Stimulated by increased PCO2/decreased pH. More sensitive than peripheral receptors, don't respond to O2

Front 118

Negative feedback control of respiration by blood gases and pH

Back 118

- Changes in blood gases change (lower) the pH which is sensed by peripheral and central chemoreceptors which is relayed to the medulla, which stimulates inspiratory muscles (diaphragm, external intercostals), stimulating contraction, inhalation, and increased O2 absorption.
Stretch receptors in smooth muscle around the lung will prevent overinflation of lungs (Hering-Breuer reflex)

Front 119

Kidney cortex

Back 119

- contains the glomeruli (juxtamedullary and cortical) and the lowest glomerulus defines the end of the cortex (or the corticomedullary border).
- contains most of the kidney’s vasculature and so receives about 75% of the blood flow to the kidney.
- The interstitial space is isosmotic with plasma.

Front 120

Kidney medulla

Back 120

- seperated into the inner medulla (deeper) and outer medulla (next to cortex, contains the thick loop of Henle)
- contains the loop of Henle and the descending osmolarity gradient in the intersitial space (also has the vasa recta which maintains the gradient)

Front 121

Renal Pelvis

Back 121

- connects the kidneys to the ureters
- nephrons drain filtrate into the collecting ducts which connect to the minor calyxes and the the major calyx and the renal pelvis.

Front 122

Functions of the glomerulus

Back 122

= a bundle of capillaries fed by an afferent arteriole (drained by and efferent arteriole), sitting in the Bowman's capsule.
- first filtration step in the kidney: Filters based on size (also charge), allows small molecules (ions, glucose, water) to be pulled out of the plasma into the Bowman's space (RBC's and proteins do not pass)
- Filters an average of 180L/day of blood

Front 123

Functions of the proximal tubule

Back 123

- connects the glomerulus to the loop of Henley (located in the cortex). Has a brush border for max surface area, associated with the peritubular capillaries
- responsible for the bulk of material reabsorption: 65% Na & Cl (but doesn't change [Na]), 65% H2O, 50% of K, Ca, & urea, 90% HCO3, 100% organic nutrients (glucose)
- will secrete foreign substances and drugs

Front 124

Functions of the loop of Henle

Back 124

- located in the medulla, recieves isoosmotic fluid from the proximal tubule and delivers hypoosmotic fluid to the distal convoluted tubule, associated with the vasa recta (together establish interstitial gradient)
- Water escapes in the thin descending limb from aquaporins
- Thick ascending limb is impermeable to water but allows diffusion/pumping of Na
- Main transporter of Na in the ascending limb is NKCC (moves Na, K, 2Cl in on apical side), Na/K exchanges on basal side (K, Cl diffuse through channels)

Front 125

Functions of the kidney

Back 125

1. Regulation of water and electrolyte balance.
2. Excretion of metabolic waste.
3. Excretion of foreign substances.
4. Regulation of ECF volume (and indirectly
blood volume and pressure).
5. Regulation of red blood cell production.
6. Regulation of the active form of Vit. D.
7. Regulation of acid/base balance.

Front 126

Salt and water reabsorption in the proximal tubule

Back 126

Step 1 - Passive apical entry of Na+. Active Na+ exit at basolateral membrane (recycle K+ at basolateral membrane). Movement of cations establishes lumen negative potential.
Step 2— Potential drives movement of anions from lumen to interstitium and establishes an osmotic gradient.
Step 3- Osmotic gradient drives water movement from lumen to interstitium.
Step 4— Accumulation of water and salt in interstitium and Starling’s forces promotes bulk flow of water and salt
into the peritubular capillaries.

Front 127

Functions of the distal convoluted tubule

Back 127

- Receives slightly hypoosmotic filtrate from the loop of Henle, delivers it to conducting duct
- Na/Cl symporter pumps small amounts of Na & Cl out of the filtrate, further diluting filtrate

Front 128

Functions of the collecting duct

Back 128

Cortical collecting duct: receives filtrate from DCT
- reabsorbes some Na+ (ENaC channel) and H2O, secretes K+
Medullary collecting duct
- involved in the secretion of acids and bases, reabsorption of water and urea (based on hormone stimulation).
- Delivers fluid for excretion to the calyxes

Front 129

Components of the glomerular filtration apparatus

Back 129

- Endothelial cells: line the capillaries in the in glomerulus. They have fenestrated pores that selectively filter plasma (~70nm)
- Basement Membrane: spongey, mesh of proteins secreted by endo & epithelial cells. Has a slight negative charge that confers minimal fitration based on charge
- Podocytes: specialized epithelial cells (sit on basement membrane) with large nuclei and foot processes which interdigiate to form slit diaphragms which filter according to size.

Front 130

Factors affecting the net filtration pressure in the glomerulus

Back 130

Pressure in:
- main force is the hydrostatic pressure of the afferent capillary (~60mmHg)
Opposing pressures: (net ~45mmHg)
- plasma oncotic: proteins cannot filter, so become more concentrated and pull water back into the plasma (30mmHg)
- capsule hydrostatic pressure: pressure from fluid in the Bowman's capsule forces fluid back into capillaries (15mmHg)

Net filtration pressure = capillary hydrostatic pressure - (capillary osmotic + capsular hydrostatic pressures)
NFP = 15mmHg

Front 131

Glomerular filtration rate

Back 131

GRF = amount of fluid filtered by glomerulus per unit time, proportional to net filtration pressure; GFR = K*NFP (where K is glomerular capillary filtration coefficient)
- maintained relatively constant over a wide range of blood pressures
- overall GFR is 125mL/min or 180L/day in a normal adult. This decreases with age and renal disease

Front 132

Regulation of the GFR

Back 132

Regulation mostly concerned w/ resistance of afferent arteriole (which matches pressure changes). Goal is to keep pressure almost constant
3 Mechanisms:
1. Autoregulation: intrinsic to the kidney; mechanical stretch in the arterial smooth muscle causes secretion of signaling molecules that change SM tone and lower resistance
2. Autonomic regulation: sympathetic neurons innervating the arteriole induce SM contraction during severe BP changes (vasoconstriction reduces GFR, keeping fluid in circulation).
3. Tubuloglomerular feedback: the macula densa (part of the TAL of Henle) sits in between the arteries and senses salt/water balance. Changes in salt in the distal nephron stimulates changes in blood flow or mesangial cell size in the glomerulus

Front 133

Renal Clearance

Back 133

= removal of a substance from the blood and excretion in urine; excretion rate; volume per unit time.
- helps measure GFR experimentally: if a substance is freely filtered, not secreted or reabsorbed then filtration rate = excretion rate; GFR = urine flow rate x [sub](urine)/[sub]plasma
- inulin used in labs, creatinine used in humans (gives over estimate of GFR b/c of secretion)
- Most solutes have clearance < GFR b/c not freely filtered or lots of reabsorption: glucose clearance = 0, Na ~0.01GFR, Urea ~0.5GFR

Front 134

How to secrete dilute urine

Back 134

Goal: excrete more salt and water. Max output: 20L/day, min [urine] = 50mOsm/L. Total amount of solute remains fairly constant
- Glom: little change, unless BP has gone up dramatically (>200mmHg)
-Prox T: little change, reabsorb water and solutes, isoosmolar
- LoH: Little change, H20 & Na reabsorb based on osmol differences
DCT & CD: Most change: will simply let fluid go with little reabsorption. ADH will be low, so DCT impermable to H2O (can still reabsorb solutes). Also interstitial medulla gradient will be weaker (dilute filtrate) so less gradient to filter in CD.

Front 135

How to secrete concentrated urine

Back 135

Goal: retain salt and H2O. Min output: 0.5L/day, Max [urine]= 1200-1400mOsm/L (4-5x plasma osmolarity)
Mediated by 3 factors:
1. high ADH (vasopressin): increases DCT and CD permeability by moving AQP2 channels to the luminal membrane
2. High osmolarity of the medullar interstitial fluid: provides gradient to move H2O in the presence of ADH
- Medulla interstitium is concentrated by: active transport of Na/K/Cl out of TALoH creating gradient by counter current multiplication (distributed and maintained by vasa recta; counter current exchange); active transport of ions out of CDs; facilitated diffusion of urea from the CDs; minimal H2O diffusion into the medulla

Front 136

Counter current exchange & multiplication

Back 136

- exchange of osmolarity between the tubes of the LoH because they run antiparallel and have different permeabilities
- Na/K pumps in the TAL dilute the filrate, and induce H2O diffusion from the TDL, concentrating it. As the fluid moves through the loop, these effects are multiplied, creating the gradient. (the longer the loop the greater the concentration)
- the vasa recta also uses these mechanism to absorb and redistribute Na, maintaining the gradient (no active transporters), has slow flow allowing equilibration at different levels (fast flow would dissipate gradient)

Front 137

Urea recycling

Back 137

- urea is pumped out of the lower collecting duct by the uniporter (impermeable at the top), concentrated in the medulla, and reabsorbed at the bottom of the loop of Henle.
- Contributes 50% of the medulla concentration gradient (allows salt to be excreted)

Front 138

ADH action in the nephron

Back 138

- ADH = antidiuretic hormone/vasopressin.
- pituitary peptide hormone, secretion stimulated by high plasma osmolality (mainly) or by very low blood volume/pressure
- acts on principle cells of the cortical and medullary collecting ducts to upregulate water reabsorption by triggering the fusion of AQP-2 containing vesicles with the luminal membrane (ADH receptor binding activates cAMP, PKA which P's AQP2 initiating transport)
-ADH also enhances hyperosmotic medullary interstitium by increasing urea reabsorption (acts on transporters in CD) and Na reabsorption in CDs/TAL

Front 139

Potassium movement in the nephron

Back 139

- K needs to be maintained in a narrow range because [ECF] is so low, even small changes can have a big effect (especially on cells that use electric gradients)
- K is freely filtered in the glom. 65% is reasorbed passively in the Prox T, 25% in the TAL, and 5-10% in the CD
- in case of low [K], transporters int the CD are upregulated to reabsorb more
- for high [K], K is secreted into the DCT (stimulated by high flow or aldosterone), and CD transporters are minimized. Can excreted up to 100%

Front 140

Calcium movement in the nephron

Back 140

- Ca is controlled hormonally outside the kidney PTH (breaks down bone) and calcitriol (stimulates GI absorption, mediates bone formation)
- Kidneys produce calcitriol (active form of Vit. D after D2 intermediate) via PTH stimulation and excretes phosphate (prevents over secretion of PTH)
- Most Ca in blood is bound/complexed
- free Ca is reabsorbed passively in the Prox T (60%) ane LoH (30%). Active Na/Ca antitransporters in the DCT are stimulated by PTH (absorb 5-10% more)
- normally <1% is excreted, if levels are too high a large Na load facilitates excretion b/c ions are coupled in the DCT

Front 141

Phosphate movement in the nephron

Back 141

Regulated by 2 mechanisms:
- conversion to calcitriol (with Ca) or break down from it in bone
- renal modulations:
--5-10% is protein bound, of free 75% get actively reabsorbed in the Prox T via Na sympoter (Tm limited system)
--Normal filtered load is higher than Tm (saturated) so the rest is excreted. PTH inhibits this reabsorption
---will act as a buffer for H+

Front 142

Glucose movement in the nephron

Back 142

- Gets freely filtered in the glom
- 100% gets reabsorbed in the Prox T via Na-Glu symporters (SGLT) on the luminal membrane. Then diffuses out via GLUT channels into the interstitium
- no normal regulation, but in high load (diabetes) the transport can be overwhelmed and glucose will be excreted

Front 143

Renal response to high volume/pressure

Back 143

- High BP/volume is sensed at the afferent arteriole as an increase in pressure across the golmerulus:
↑NFP → ↑GFR → ↑Filtrate load → Prox T. can't reabsorb as efficiently → ↓ Na reabsorption
- In the distal nephron:
↑ Na (osmotic + weaker gradient) + ↑ Filtrate load + ↓ ADH (pituitary) → ↓ H2O/Na reabsorption + ↑ urine volume
- Overall response: pressure naturesis (excess Na excretion) and pressure diuresis (excess H2O excretion) lowing blood volume and BP

Front 144

3 mechanisms that regulate Renin release

Back 144

1. Sympathetic nervous stimulation: low pressure in arterial & cardiopulmonary baroreceptors causes CNS to stimulate renal nerves, releasing NE which acts on β1 adregenic receptors on granular cells (around afferent ateriole) which secrete renin
2. intrarenal baroreceptor: granular cells sense mechanical changes in flow, secrete renin if pressure is low
3. Salt & flow sensors: macula densa (btwn arterioles & glom) senses tubular flow rate & [salt]:
- ↑GFR → ↑Flow/Na → detected by MD cilia in TAL → MD secretes signals that inhibit renin release & constrict afferent arteriole
- ↑GFR → ↓Na/flow → MD senses ↓Na at TAL → stimulates renin release by granular cells & relax afferent arteriole (so bad waste still excreted)

Front 145

Renin & Angiotensin

Back 145

Renin = enzyme that converts angiotensinogen (made in liver) to angiotensin I (then converted to active angiontensin II by angiontensin converting enzyme, ACE)
- Angiotensin then acts to conserve Na+ (therefore H2O) and increase BP
1. stimulates Prox T to increase Na reabs.
2. Acts directly on arterial/vascular SM to increase total peripheral resistance
3. Stimulates secretion of aldosterone

Front 146

Renal response to low blood pressure/volume

Back 146

- low pressure and/or afferent arteriole constriction is sensed as ↓glomerular pressure → ↓GFR → ↓Filtered load → ↑Prox tube efficiency (more time/area) → ↑Na reabsorption
- In the distal nephron: ↑ADH (pituitary) + ↓Na (stronger gradient) → ↑Na reabsorption + ↑H2O reabsorption → (secrete renin) → ↓urine volume

Front 147

Baroreceptors comminucating with the kidney

Back 147

Baroreceptors = physiological pressure gauges
- High pressure: in carotid sinuses and aortic arch; sense arterial pressure.
- Low pressure: in cardiac atria and pulmonary vessels; sense fullness of vasculature.
- Intrarenal: in afferent arterioles; sense renal artery pressure.

Front 148

Aldosterone Action and regulation

Back 148

= mineralocorticoid produced by adrenal glands (via renin/angiotensin stimulation). Acts on principal cells of CD's to increase Na reabsorption (H2O retention) (also excrete K)
Upregulated by: ↑[Angiotensin II], ↑[K], ↓[Na] (↓vol/P mostly by AngII), ↑ACTH (stims adrena medulla)
Mechanism of action: receptor inside cells, binding Aldo it travels to nucleus as a Tx factor, increases proteins for Na reabs (ENaC channel). [Other steroid hormones can bind, 11B-HSD is competitive receptor to prevent wrong activation)
Action corrects:
↓Na/BP: ↑H2O reabsorption, ↑BP
↑[K]: ↑K transport from ECF via Na/K exchanger, ↑K excretion by luminal channels

Front 149

Bicarbonate reabsorption in the kidney

Back 149

- kidney must reabsorb nearly all bicarbonate (diet usually leaves acid surplus)
Prox tubule: 75% abs; Na/H+ exchanger channel put H+ in lumen where it binds HCO3, CO2 diffuses into cell, degraded via carb.anhyd., HCO3 moved to interstitium by Na symporter. No effect on pH
- In CD: type A intercalated cells excrete H/reabsorb base (type B to opposite). CO2 inside cell is split via C.A., H+ pumped to lumen via H/K channel + H-ATPase; HCO3 reabsorbed by Cl/HCO3 transporter. This increases urine pH --Mechanism flipped to excrete HCO3
- HCO3 can be "generated" whenever a different buffer is available to accept H+ in the lumen

Front 150

Renal response to acid/alkali load

Back 150

Acid load: surplus of H+ so kidney will work to secrete it (utilize type A cells in the CD)
Alkali load: surplus base, so will excrete it (bicarbonate); utilize type B cells in CD. (CO2 diffuses in, split, HCO3 to lumen via Cl swapper, H+ to interstitium by K swap)

Front 151

Phosphate as an alternate renal buffer

Back 151

- At normal pH, 80% exists in the conjugate base form (HPO4)
- Total filtered load is about 160mmol/day. Most (75-90%) is reabsorbed in the PT and about 40mmol is available for buffering.
- Each H+ that combines with a P04 releases a molecule of HCO3 into the bloodstream.

Front 152

Ammonium in renal buffering

Back 152

- formed in the liver from protein catabolism. At high pH converted to urea and excreted, at low pH bound w/ HCO3 as glutamine
- glutamine converted back in PT--net gain HCO3, NH4 travels to the lumen and is excreted
- 59mmol/day available to buffer (in acidic conditions)
- In the medulla, NH4 travels to interstitium via NKCC, converted to NH3, reabsorbed by Rhcg/Rhbg transporters in CD to accept H from HCO3