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Physiology Unit 1 Study Guide
Dr. Walz – Hemostasis
Describe the components of blood. Relate the three red blood cell concentration estimates, red
blood cell count, hematocrit, and hemoglobin concentration.
Components: hematocrit (RBCs), WBCs (mostly neutrophils), and plasma (water with
dissolved ions and proteins)
Hematocrit: fraction of whole cell volume that consists of RBCs
RBC count: absolute # of RBCs/liter
Hemoglobin concentration: grams/deciliter
Describe hematopoiesis, the process by which blood cells are produced.
try to remember your histo
Describe the unique characteristics of red blood cells (erythrocytes).
histo again – heme, O2, funky disk shape, very compressible, no nucleus
Explain how red blood cell surface antigens account for typing of blood by the A B O system
and rhesus factor. Based on these antigens, identify blood type of a “universal donor” and a
“universal recipient.”
antigens are A and B; you make antibodies against what you don’t have – so if you’re Otype, you have antigens against both A and B, so you’re a universal donor; if you’re ABtype, you have antigens against neither, so you’re a universal recipient
rhesus factor is another antigen, you’re either positive or negative
so strictly speaking, O-negative is the universal donor, AB-positive is the universal
Understand the role of normal endothelium in preventing and how endothelial injury regulates
healthy endothelium prevents coagulation through the following mechanisms:
 production of NO, PGI2, and ADP dephosphatases, which inhibit platelet
 NO and PGI2 are also vasodilators
 heparin sulfate and similar proteoglycans activate anti-thrombin III, which
inhibits thrombin and activated coagulation factors VII, IX, X, XI, and XII
 heparin and dermatan sulfate activate heparin cofactor II, which inhibits
 thrombomodulin binds thrombin, which then activates protein C to activated
protein C (APC), APC inhibits activates factor V and VIII
 tissue factor pathway inhibitor binds and deactivates VIIa (extrinsic pathway)
 intact endothelium blocks blood-born coagulation factors from interacting with the
ECM, which is prothrombotic
injured endothelium promotes coagulation through the following mechanisms:
 no longer producing anti-coagulation factors
 no longer shields the blood from ECM – ECM very prothrombotic (see below)
 releases endothelin, a vasoconstrictor
 releases von Wilebrand factor, which binds to GPIb-IX-V on platelets (see
 pericytes specifically release tissue factor (TF), which activates factor VII and
initiates the extrinsic coagulation cascade (see below)
Describe the interactions between endothelium and platelets in regulating these coagulation.
after GPIb-IX-V is bound by vWf, platelets undergo the following:
 “activation”, in which the inactive form of the integrin αIIbβ3 is changed to the
activated form
 activated αIIbβ3 binds fibrinogen and other platelets, forming the primary platelet
 arachidonic acid is converted to TxA2, which promotes the release of dense
granules (and is also a vasoconstrictor)
 dense granules are released, containing:
o serotonin – minor vasoconstrictor
o ADP – activates platelets through the P2Y1 and P2Y12 receptors (
trigger internal release of Ca2+  αIIbβ3 activation)
o Ca2+ -- essential for many coagulation factors (see below)
 α granules are released, containing vWf, factor V and fibrinogen
why is the ECM prothrombotic?
 ECM is negatively charged, which activates the intrinsic coagulation cascade
 vWf is strongly bound by the ECM, and vWf activates platelets by binding GPIbIX-V
Diagram the enzymes and substrates involved in the formation of fibrin polymers, beginning at
prothrombin. Contrast the initiation of thrombin formation by intrinsic and extrinsic pathways.
Contrast the mechanisms of anticoagulation of a) heparin, b) EGTA, and c) coumadin.
heparin: activates anti-thrombin II and heparin cofactor II, which inhibit serine
proteases such as thrombin and factors VII-XII
EGTA: strong Ca2+ chelator; Ca2+ is required for the activity of coagulation factors VIIa,
IXa, Xa, and thrombin
Coumadin: inhibits vitamin K; vitK is a required cofactor for γ-glutamyl carboxylase,
which carboxylates the factors that require Ca2+: VII, IX, X, prothrombin, and
protein C
Describe the mechanisms of fibrinolysis by TPA (tissue plasminogen activator) and urokinase.
either tissue-type plasminogen activator (TPA) or urokinase-type plasminogen activator
(UPA) converts plasminogen to plasmin, plasmin breaks up fibrin clots into fibrin
degradation products. the conversion of plasminogen to plasmin is inhibited by PAI-1
and PAI-2; the action of plasmin is inhibited by anti-plasmin. APC (anticoagulant
produced by healthy endothelial cells, see above) inhibits PAIs.
Explain the role of the platelet release reaction on clot formation. Distinguish between a
thrombus and an embolus.
platelet release reaction – platelet activation; already covered above
thrombus – stationary blood clot along the wall of a blood vessel
embolus – a thrombus or fragment of thrombus that is moving through a blood vessel or
has moved and is now blocking a vessel somewhere else
Explain why the activation of the clotting cascade does not coagulate all of the blood in the
localized – healthy endothelium surrounding the break are still producing the anticoagulation factors (especially TPA and ADP-phosphatases). moreover, coagulation
factors are at too low a concentration in the blood to promote coagulation unless they
are bound on a negatively charged surface (and in the presence of required cofactors
such as Ca2+), which only activated platelets (for the intrinsic pathway) or membranebound tissue factor (for the extrinsic pathway) provide. thus coagulation is confined to
the area in which the prothrombic factors outweigh the antithrombic factors. ideally, at
any rate.
The asprin thing (ok this isn’t an official objective, but he talked about it a lot)
Asprin inhibits the enzyme COX, which converts arachidonic acid into eicosanoids.
Particularly relevant are TxA2, which is prothrombotic and produced by platelets, and
PGI2, which is antithrombotic and produced by endothelial cells. Asprin inhibits BOTH
EQUALLY. However, because platelets are anucleate and cannot make more enzyme,
once you’ve inhibited their COX, they’re done making TxA2 for the rest of their
(admittedly very short) lives. In contrast, endothelial cells are fully capable of making
more COX once the asprin goes away. Therefore, if you take subclinical doses of asprin,
you will be inhibiting platelet COX, and thus the production of TxA2, permanently, and
inhibiting endothelial COX, and thus the production of PGI2, only briefly. This tips the
balance away from coagulation. Key is that you have to take a very small dose of asprin,
though, or you’ll just knock everyone’s COX out and accomplish nothing (vascularly
Dr. Yingst – Cell Physiology
Necessary Equations
• Memorize the simplified version of the Nernst equation, so that you can calculate equilibrium
potentials for the common ions.
For a valance of +1:
𝐸𝑥 = −61 mV 𝑙𝑜𝑔
For aFor
a valance
of +2:
of -2:
𝐸𝑥 = −30.5 mV 𝑙𝑜𝑔 [𝑋] 𝑖
For a valance of -1:
𝐸𝑥 = −61 mV 𝑙𝑜𝑔
= +61 mV 𝑙𝑜𝑔
• Know how to calculate the driving forces for each of the ions and be able to determine how the driving
force on ions is affected by the membrane potential.
Ionic current:
𝐼𝑥 = 𝐺𝑥 (𝑉𝑚 − 𝐸𝑥 )
𝐺𝑥 = conductance for X ≈ 𝑃𝑥
driving force
• Know the units for osmotic concentration and how to calculate the contribution a given salt makes to
the total osmotic concentration based on its molar concentration. Do not memorize values for φ,
because this is a minor correction.
𝜑 = osmotic coefficient
𝑖 = # of particles formed by dissociation of solute
𝐶 = modal concentration
• Know how to predict the direction the membrane potential changes as a function of changes in the
permeability to ions, as described by the GHK equation.
𝑉𝑚 = −61 mV log (
𝑃𝐾 [𝐾 + ]𝑖 + 𝑃𝑁𝑎 [𝑁𝑎+ ]𝑖 + 𝑃𝐶𝑙 [𝐶𝑙 − ]𝑜
𝑃𝐾 [𝐾 + ]𝑜 + 𝑃𝑁𝑎 [𝑁𝑎+ ]𝑜 + 𝑃𝐶𝑙 [𝐶𝑙 − ]𝑖
𝑉𝑚 for most cells ≈ 𝐸𝐾 because 𝑃𝐾 ≫ 𝑃𝑁𝑎 + 𝑃𝐶𝑙
Remember :
positive current = flow of POSITIVE ions OUT of the cell
negative current = flow of POSITIVE ions INTO the cell
flow of negative ions is the other way
thus if INa = +60 mV, Na+ is going to flow OUT of the cell; if ICl = +60 mV, Cl- is going to flow INTO the cell
More general concepts that are good to know
Understand the physiological basis for how the young man became confused after his experience in the
sauna, as described in the article in the New York Times.
Drank too much pure (hypotonic) water  induced hyponatremia, relative increase of water
compared to Na+  fall in plasma tonicity  movement of water into cells, including brain cells
 cerebral edema  “drunk” presentation
(See UpToDate, “General principles of disorders of water balance” and “manifestations of
hyponatremia and hypernatremia” for more detail)
Know how drinking water containing sodium and glucose promotes rehydration faster than drinking
water alone.
Ingesting an isotonic solution allows water to stay in the ECF. As glucose is slowly transported
into cells, water will follow, thereby rehydrating the ICF as well (without causing edema). See
question #5 of the extra homework problems.
Understand which transport mechanisms that we studied will be affected by changes in the membrane
For anything that involves the movement of ions, the electric gradient is as influential as the
chemical gradient. (Vm – Ex = driving force)
Know how water is distributed throughout the body.
1/3 ECF, 2/3 ICF
ECF further broken down into: 31% interstitial fluid, 7% blood plasma
Know the concentrations of the major solutes in the major body fluid compartments.
Dude, seriously?
Know how the mechanisms by which the major solute gradients are formed across the plasma
membrane and across the capillary endothelium.
Na+ and K+: Na/K ATPase, aka the “Na/K pump”, 3 Na+ out and 2 K+ in
Ca2+: Ca-ATPase, Ca/Na exchange protein (uses the Na+ gradient to shuttle Ca2+ against its
gradient -- antiport)
glucose: Na/glucose cotransporter (uses the Na+ gradient to shuttle glucose into the cell –
Be able to explain how changing the concentration of extracellular potassium will have a significant
effect on the resting membrane potential, whereas changing the concentration of extracellular sodium
will not.
See the GHK equation: 𝑉𝑚 for most cells ≈ 𝐸𝐾 because 𝑃𝐾 ≫ 𝑃𝑁𝑎 + 𝑃𝐶𝑙
Know the physiological consequences of having soluble protein in the plasma, but not in the interstitial
fluid. What happens when soluble protein does accumulate in the ISF?
Proteins: occupy space  solutes are effectively more concentrated – molality (solutes per kg
water) is 7% higher than molarity (solutes per L solution)
are anionic  plasma has more + ions than the ISF
Obv. if protein accumulates in the ISF, it will throw off the ion balance (more + ions, fewer – ions
than should be)
Know how the lipid bilayer functions in terms of forming a barrier to the movement of solutes. What
solutes easily cross? Which do not?
Cross easily: hydrophobic or small, uncharged polar molecules
Require channels: large, uncharged polar molecules and ions
Know the difference between net flux and the two unidirectional fluxes.
flux: amount of solute which crosses a boundary per unit time (moles/cm2*sec)
influx: Jio; efflux: Joi
Net flux: efflux minus influx
𝐽𝑛𝑒𝑡 = |𝐽𝑜𝑖 − 𝐽𝑖𝑜 |
Know how the unidirectional and net fluxes through the major transport mechanisms are affected by
the concentration of the solute on both sides of the membrane and by the value of the membrane
Seriously, 𝐼𝑥 = 𝐺𝑥 (𝑉𝑚 − 𝐸𝑥 ) is kind of everything?
Understand the functional consequences of having a solute move by diffusion, by a carrier, by a channel,
and by active transport. Know in principle how each of these major transporters function and the
respective physiological roles each of these plays in cells.
Diffusion: free, slow, uncontrollable, unselective, only works if the solute is small and uncharged
Channel: fast and moves a large volume of solute; controllable; selectivity varies; usually free 
used for rapid response!
Carrier: slower than a channel; controllable; usually costs something (either ATP or an already
established electrochemical gradient); usually highly selective
What are the different ways in which carriers are classified?
Uncoupled, passive: driven by electrochemical gradient of the moving solute
primary: uses ATP
secondary (coupled): driven by an already established electrochemical gradient
Only active transport can create a concentration gradient!!
Know the different mechanisms by which glucose is transported across the plasma membrane by active
and passive transport mechanism and the respective physiological roles of each.
D-glucose carrier – passive transport; glucose moves down its conc. gradient
Na/glucose cotransporter – active transport; Na+ moves down its concentration gradient and
takes glucose with it – a concentration gradient for glucose can thus be established
outside of the normal “oh we ate all our glucose and now we need more” mechanism
Know how cardiac glycosides, such as digitalis, affects the Na,K-ATPase.
Bind the E2-P state, preventing it from changing conformation
Know the mechanism by which cardiac glycosides cause an increase in the strength of contraction in
muscle. This is especially important for strengthening the contraction of the heart.
Effectively decrease Na+ gradient by inhibiting the Na/K-ATPase  less Ca2+ is transported out
of cell by the Ca/Na exchange protein (which relies on the Na+ gradient to move Ca2+)  more
Ca2+ in muscle cells, more contraction
Know what the pump leak model of the plasma membrane is and how this concept is used to link
cellular metabolism with the creation and maintance of solute gradients.
Metabolic energy is stored in the form of ion gradients, which are then used by other
transporters to carry out specific functions
e.g., Na/Ca exchange protein moves Ca2+ against its conc. gradient by moving Na+ down its
conc. gradient
Membrane potential/depolarization/repolarization also an example of the work that can be
done by having established gradients!
Na+ tends to be super important here
Understand osmosis and how it drives the movement of water across plasma membranes.
All water equalizes
Know the theoretical factors that drive water movement across the plasma membrane and between the
plasma and the ISF.
across the plasma membrane, only ∆μH2O matters, because pressure is equal
across capillary endothelium, both ∆μH2O and ∆μH2O, pressure matter
What is the Starling-Landis equation and how does it account for the forces that move fluid between
plasma and ISF?
Know why differences in hydrostatic pressure do not play a role in determining the driving force for
water across the plasma membranes of cells, but does play a role in the direction at which water moves
between the plasma and the ISF.
osmolality of plasma is slightly higher than the ISF b/c of plasma proteins & associated excess
positive ions  difference produces the plasma colloid osmotic pressure, πc  πc is small (1
mOsm = 19 mmHg) but tips the balance towards osmosis into the plasma
Know how to calculate the concentration of water and the difference between osmotic concentration
and tonicity and why we need to distinguish between them.
concentration of water = 1/osmotic concentration
osmotic concentration = 𝜑𝑖𝐶 (see first page)
tonicity = relative to 290 mOsm (isotonic)
Know how to calculate changes in the osmotic concentration and volumes of the major body fluid
compartments as discussed in class.
see practice problems
Know how the membrane potential of cells is created. Understand how to define “membrane
potential,” “equilibrium potential” and “diffusion potential.”
Vm created by conc. gradients of ions – primarily K+
membrane potential: difference in charge across a membrane
equilibrium potential: value of Vm that exactly balances a concentration difference
diffusion potential: potential difference created across a membrane when a charged solute
diffuses down its concentration gradient
Know the Nernst equation and how to use it to calculate the equilibrium potential of an ion.
𝐸𝑥 = −61 mV 𝑙𝑜𝑔 [𝑋] 𝑖 etc. (see first page)
Know how to go about calculating the driving force acting on an ion. Know how to determine if the ion is
at equilibrium. If the ion is not at equilibrium, know how to calculate the size of the driving force and
how you would determine the direction of the driving force.
𝐼𝑥 = 𝐺𝑥 (𝑉𝑚 − 𝐸𝑥 ) (see first page)
if at equilibrium, driving force = zero, so Vm and Ex must be equal
Know the difference between a driving force, a flux, and a current.
driving force is a potential, a flux is a movement of solute, and a current is a movement of charge
i.e., a flux happens because of a driving force, and because of the flux, current is
Understand what extracellular solutes play critical roles in controlling cell volume and understand how
the permeability of the plasma membrane to these solutes is important in their ability to regulate cell
everything is Na+
Know the mechanisms by which cells regulate their volume under normal conditions and be able to
describe the contribution of the Na,K-ATPase to the regulation of cell volume.
seriously, it’s all Na+
Understand the mechanisms that account for the changes in red cell shape that we discussed in the
clinical problem on hereditary spherocytosis.
PNa was three times higher than normal, meaning that too much Na+ was getting into the RBCs.
because volume control is primarily due to Na+, that meant too much water was also getting
into the RBCs, resulting in the spherical shape.
What are electrotonic potentials and how are they different than action potentials? What are the
physiological roles played by each?
Electrotonic, aka graded potentials: decay over distance, decay with time, are proportional to
stimulus intensity
Action potential: all-or-nothing, independent of size of stimulus, propagate with constant
amplitude and shape over distance
APs are stimulated by graded potentials that pass a threshold
What triggers an action potential in nerves and skeletal muscle?
Depolarization that passes a threshold  opening of voltage-gated Na+ channels
How do voltage-dependent Na channels behave during the initiation of an action potential?
enough depolarization  opening of the activation gates  rapid depolarization (AP)
What are the individual steps in the opening and inactivation of Na channels during and action potential
and how do these account for the change in sodium conductance at the beginning of an action
1. at rest, activation gates are closed and inactivation gates are open
2. upon sufficient depolarization, activation gates open
3. when Vm becomes positive enough (at peak of AP), inactivation gates close
4. inactivation gates remain closed until cell is repolarized
key here is that the inactivation gates close after a short delay, stopping the Na+ influx and
letting GK take back over, which repolarizes the cell
because the inactivation gates WILL NOT reopen until cell is repolarizes  absolute
refractory period, during which the cell cannot be stimulated to produce another AP
What are some of the consequences of the fact that the opening and closing on individual channels is
accommodation – when cell is depolarized too slowly, only some voltage-gated Na channels
open (and then close) because cell must repolarize for the Na channels to reopen, there are
then not enough Na channels available to enable the cell to cross threshold
How does the driving force on Na and K change during the course of an action potential?
as the cell depolarizes, Vm approaches ENa (when the cell is at V0, driving force is very strong on
Na+; as the cell depolarizes, it lessens)
as it repolarizes, Vm approaches EK (similarly, when the cell is at V0, driving force on K+ is low,
because Vm ≈ EK, but as the cell depolarizes, driving force increases)
Which ion channels are involved in producing an action potential? How does the conductance of the
membrane to Na and K change during the course of an action potential? How do individual types of
channels contribute to these changes?
voltage-gated Na+ and K+ channels – v-g Na channels responsible for depolarization; v-g K
channels responsible for repolarization
types of K+ channels:
K+ leak channels – open most of the time; responsible for resting Vm
delayed outward rectifying K+ channels – K+ current during AP
transient A-type K+ channel – responsible for after-hyperpolarization  determines
frequency of APs
What is accommodation and how does it occur?
see above
What is the relationship between the strength and duration of a stimulus that can produce an action
to cross threshold, a stimulus must be either low strength and long duration, or high strength
and short duration
Know what the length constant and time constant are, what factors affect their values, and how these
constants are used to describe how far and how fast local currents flow.
length constant: initial depolarization decreases exponentially with distance
𝑉 = 𝑉0 𝑒
where 𝜆 = √ 𝑟𝑚 , 𝑟𝑚 = resistance across membrane; 𝑟𝑖 = internal resistance
and 𝜆 = √ 2𝑅𝑚, 𝑎 = axon radius; 𝑅𝑚 = resistance across membrane per unit area;𝑅𝑖 =
internal resistance per unit area
thus λ proportional to √axon radius
longer λ = farther a charge in voltage can travel
time constant:
𝜏 = (𝑟𝑚 ∙ 𝑟𝑖 )2 ∙ 𝐶𝑚
where 𝐶𝑚 = capacitance of membrane
shorter τ = faster propagation
Know how local currents are involved in the propagation of the action potential.
local currents initiate APs by depolarizing to threshold
Understand how myelin affects the rate at which action potentials are propagated and what occurs to
conduction velocity during multiple sclerosis.
increases membrane resistance (rm)  longer λ
decreases capacitance (Cm)  shorter τ
also saltatory conduction
multiple sclerosis is an autoimmune disorder wherein myelin in the peripheral nervous system is
destroyed  eventually, signals cannot be propagated to or from the periphery and
paralysis results
Be acquainted with the different pathologies that are associated with defects in the membrane
properties that we have discussed.
Know the basic mechanisms by which signals are transmitter across electrical and chemical synapses.
electrical synapses – mediated by gap junctions; ionic current is directly transmitted
chemical synapses – mediated by a neurotransmitter; signal inhibits (hyperpolarizes) or excites
(depolarizes) membrane of post-synaptic cell
Know the basic types of receptors for neurotransmitters and how neurotransmitters can either excite or
inhibit the postsynaptic membrane.
 ion channel is part of receptor
 rapid response!
 channel activation either depolarizes or hyperpolarizes post-synaptic membrane
 G-protein coupled
 activate α and β subunits, which then go do stuff in the cell
 response is slow (seconds to minutes)
Know what accounts for size and duration of a post-synaptic potential.
the post-synaptic potential triggered by a neurotransmitter is a graded potential, i.e. it is
proportional to the strength of the stimulus (the amount of neurotransmitter encountered) and
the duration of the signal; as with all graded potentials, it decays over time and distance
key here is that the neurotransmitter, itself, does not trigger an AP on the postsynaptic cell;
instead it triggers a local potential that then triggers the AP in the target cell IFF it is big and/or
long enough
Know the sequence of events that occur at the neuromuscular junction that results in the subsequent
production of an action potential in the associated muscle fibers.
1. AP travels to presynaptic terminal
2. depolarization opens Ca2+ channels  Ca2+ flows into cell
3. ACh released by exocytosis
4. ACh binds receptor on postsynaptic terminal
5. receptor opens nicotinic ACh receptor – this receptor is not selective: both Na+ and K+ can
flow through it, but the driving force for Na+ is much much higher than for K+
6. end plate potential IF SUFFICIENT  action potential
7. ACh degraded to choline and acetate by AChE
8. choline taken back up by presynaptic terminal
Know the mechanism by which an action potential in the presynaptic membrane causes the release of
neurotransmitter into the synaptic cleft.
depolarization  opening of voltage-gated Ca2+ channels  influx of Ca2+  stimulation of
Know the mechanism by which acetylcholine is synthesized and degraded at the neuromuscular
acetyl CoA + choline by choline acetyltransferase within axon terminal (note: not made in cell
body and transported to axon terminal – that’s too slow)
degraded to choline and acetate by AChE; choline is recycled
What is a miniature end-plate potential and how is it related to the concept of the quantal release of
a neurotransmitter (e.g. ACh) is released in “packets” corresponding to the vesicles it is
packaged in in the presynaptic terminal  one packet is one quantum of neurotransmitter
each packet produces a miniature end-plate potential
 it is the sum of MEPPs that is relevant as to whether the local potential reaches threshold
What is a major symptom of Myasthenia gravis? How is this disease treated?
patients have antibodies to the ACh receptor  unable to sustain prolonged contraction of
skeletal muscle
treated with anticholinesterases
What is Lambert-Eaton syndrome?
patients have antibodies to voltage-gated Ca2+ channels in presynaptic terminals  decreased
release of neurotransmitter  weakened skeletal muscle and diminished stretch reflex
Facilitation and post-tetanic potentiation are short term events that occur at the postsynaptic
membrane. What are they and how do they both occur?
 an increase in the size of the EPP produced in the post-synaptic cell per AP in the presynaptic cell
 occurs when pre-synaptic cell is stimulated in quick succession
 occurs DURING this rapid signal received from the presynaptic cell
 may be due to accumulation in intracellular Ca2+ in presynaptic cell  release of more
neurotransmitter per AP
post-tetanic potentiation:
 a similar increase in the size of the EPP produced in the post-synaptic cell due to rapid
APs from presynaptic cell
occurs AFTER serious of rapid signals from presynaptic cell – a subsequent signal from
the presynaptic cell within a window will produce a larger EPP
maybe same mechanism, who knows
What are the space and time constants and what do they measure?
you already asked that
What is the relationship between conduction velocity of an action potential and the diameter of an
excitable cell?
velocity of conduction of an AP increases with diameter b/c:
increases length constant: 𝜆 = √ 2𝑅𝑚
decreases cytoplasmic resistance (ri)  increases λ and decreases τ
What is membrane capacitance and how does it affect the rate at which the membrane potential can
capacitance (C) is a measure of how much charge (Q) is stored per volt (E) between surfaces that
can store charge, i.e. 𝐶 = 𝑄⁄𝐸
the capacitance of the membrane determines how much charge must move in order for Vm to
change  when current begins to flow, the time course is determined by the time it
takes the charge to redistribute on the capacitor
with an initial difference in voltage of V0, the charge stored on a capacitor is:
𝑄 = 𝐶𝑚 ∙ 𝑉𝑚
when a channel first opens, the initial voltage change is:
𝑉 = 𝑉0 𝑒 ⁄𝑅𝐶
and τ = time required for V0 to fall to 37% of its initial value (t = RC)
Dr. Cala – Muscle Physiology
3 types of skeletal muscle
How does skeletal muscle produce movement of the skeleton?
concentric contraction of the agonist (and any synergists)
eccentric contraction of the antagonist
What is the difference between anatomical and physiological cross-section?
anatomical: orthogonal to the length of muscle
physiological: orthogonal to muscle fibers
pennate muscles have greater physiological cross-section  this allows for greater muscle
mass in the same area = more force
Muscle tension
tension is orthogonal to contractile force
not exerted on tendon, simply squeezes the muscle!
Wall stress
thickness of muscle
How does hypertrophy reduce wall stress?
hypertrophy – increase in number of sarcomeres  thickens muscle
The sarcomere
thin filaments: actin, tropomyosin, troponin-T, -I, -C
thick filaments: myosin (heavy and light chains)
tintin: provides resting tension and acts as a spring
actinin & nebulin: stability, passive resistance, active recoil force
morphological relationship of sarcoplasmic reticulum to the contractile machinery
What is a muscle cell twitch?
contraction and relaxation of a single muscle cell in response to depolarization
How is a twitch produced? (excitation-contraction coupling)
1. AP  depolarization of T-tubules
2. depolarization  change in dihydropyridine receptor (DHPR)  opening of ryanodine
receptor (RyR) in SR  Ca2+ release from SR
3. Ca2+ binds to troponin-C  cross-bridge cycling  contraction
4. SERCA pumps Ca2+ back into SR  Ca2+ release from troponin-C  relaxation
How does the Ca2+ release differ in the 3 muscle types?
How do L-type Ca2+ channels differ between muscle types?
skeletal: voltage-induced Ca2+ release
cardiac: Ca2+-induced Ca2+ release
smooth: not really dependent on RyR-activated Ca2+ release
The actinomyosin ATPase cycle
1. myosin is bound to actin (rigor). ATP binds  release of myosin from actin
2. ATP hydrolysed to ADP+Pi, which remains attached to myosin
3. myosin + ADP+Pi reattaches to actin
4. ADP+Pi is released  myosin returns to rigor state
Which molecular change produces the actual power in muscle contraction?
the dissociation of ADP from myosin
Active vs. passive force
active force is produced by the cross-bridge cycling
 proportional to # of cross-bridges formed
 is maximal at optimal sarcomere length (maximum overlap between thick and thin
passive force is the force exerted by the “rubber band-like” proteins (tintin, nebulin) to return
the sarcomere to its resting position
 does not require ATP or Ca2+!
 see the cardiac lectures for more detail – this is preload!!!
What is the relationship between force and velocity?
velocity of muscle contraction slows exponentially with increased load
maximum load + maximal tetanic tension  velocity = 0
load = 0  maximum velocity
How do the properties of force and velocity reflect the structure of myofilaments?
force  # cross-bridges
What are the major types of muscle fiber changes?
hypertrophy – increase in sarcomeres (myofibrils)
hyperplasia – increase in fibers
atrophy – decrease in fibers
How do slow APs and non-striated contractile proteins lead to the uniqueness of smooth muscle?
slow waves are important in rhythmic contractility of smooth muscle; similar to cardiac slow APs
in that they are regulated by pacemaker cells (interstitial cells of Cajal in the intestines)
and prevent tetanus
myofibrils of smooth muscles are tangled up in intermediate filaments  the entire cell
contracts when the myofibrils contract (instead of shortening along one axis like striated
muscle cells)
dense bodies connect smooth muscle cells so when one contracts, its neighbors are pulled along
with it
What is the role of myosin light chain phosphorylation in SM force generation and the latch state?
myosin light chain cannot interact with actin unless phosphorylated
 light chains remain attached (cell contracted) unless de-phosphorylated!!!! (latch state)
NO acts on dephosphatase to relax smooth muscle (remember that PS innervation triggers the
release of NO rather than acting on the muscle cell itself)
What proteins are affected by the genetic disorders malignant hyperthermia, CPVT, and muscular
dystrophy, and how do their dysfunctions cause disease?
malignant hyperthermia
 cause: RyR1 point mutation  chronic SERCA activation
 symptoms: increased body temperature, smooth muscle rigidity, lactic acidosis
 treatment: dantrolene (inhibits RyR)
 cause: RyR2 point mutation  inappropriate triggered release of Ca2+
 symptoms: PVCs and fatal arrhythmias
 treatment: flecanide
muscular dystrophy
 cause: mutations in dystrophin (protein that couples myofibrils to cell membrane so
that contraction in the myofibril produces contraction of the cell)  necrosis
What is a motor unit?
collection of muscle fibers innervated by a single motor neuron
all fibers of a motor unit are of the same type
How does the size of a motor unit vary among skeletal muscles? Why does it matter?
small motor units: precise control, faster reactions, more expensive
large motor units: coarse control, slower reactions, less expensive
What are the three most common ways to classify motor units?
rate of twitch – fast or slow
both dependent on myosin heavy chain isoform
metabolism – aerobic or anaerobic
What are the types of motor units, and how do they differ?
I – slow twitch, non-fatigable (aerobic)
IIa – fast twitch, non-fatigable (anaerobic)
IIb – fast twitch, fatigable (anaerobic)
Why does increasing the frequency of alpha motor neuron frequency increase force?
frequency summation – Ca2+ is being released faster than SERCA can pump it out  cell
remains contracted (this is tetanus)
How can skeletal muscle fibers increase the level of force generation by recruitment of additional fibers?
increase in voluntary force  more motor units activated
recruited by the size principle – in increasing size, i.e. type I, then type IIa, then type IIb
How can both frequency summation and fiber recruitment occur in exercising muscle?
we probably recruit more fibers before we increase the frequency of stimulation. probably.
Peripheral vs. central muscle fatigue
central – CNS fatigue (decreased neural stimulation) – maybe through inhibitory afferents?
peripheral – in muscle cells of motor units
Ca2+ transients are reduced somehow
Anerobic vs. aerobic metabolism, and relative roles for ATP production
 phosphocreatine  creatine + PO3- and glucose  lactic acid
 12X faster than aerobic, but must get rid of byproducts
 3X as much phosphocreatine stored as ATP, payback is 4X faster
 glucose, fatty acids + O2  CO2 + H2O
 glycogen is most important, restoration requires ingesting glucose
What is oxygen debt?
buildup of anaerobic byproducts while aerobic metabolism is ramping up
What are the subcellular events that lead to the release of Ach from the neuromuscular junction?
see cell physiology notes, above
How does Ach activate contraction?
see cell physiology notes, above
How do common drugs prevent neuromuscular signal transmission?
D-tubocurare – competes with ACh
anti-AChE – prevents degradation of ACh
succinylcholine – receptor agonist
Clostridium toxins – inhibits release of synaptic vesicles (the difference in the paralysis produced
by C. botulinum and C. tetanus is due to which nerves they act on)
What are the afferent nerves of proprioception, and how do they sense the contractile state of the
Golgi tendon organs – sense tension, located in series on tendons
muscle spindles – sense stretch, located in parallel with extrafusal, receive both afferent and
efferent innervation
What are gamma motoneurons?
efferent γ-motoneurons regulate the gain of stretch reflex by adjusting level of tension in the
intrafusal muscle fibers
α-motoneurons innervate extrafusal muscle fibers (“normal” muscle cells)
Dr. Laisley – Cardiac Physiology
Ion currents and when they occur in fast and slow cardiac APs
Depolarization vs hyperpolarization
JFC that’s like three lectures
Fast AP:
Phase 4 (resting Vm):
 Vm ≈ -90 mV
 due to K+
 not quite EK (-94 mV) b/c of Na+ leak
 net driving force for K+ still outward (+4 mV)
 [] gradients maintained by Na/K ATPase
Phase 0 (rapid depolarization):
 due to fast opening of Na+ channels (1-2 ms)
rapidly altering Vm of a neighboring cell to  -65 mV causes depolarization b/c gap junctions
GNa decreases towards end of phase b/c of channel inactivation  absolute refractory period
!!! the SLOW RECOVERY of the inactivation gates are key to preventing tetanus in cardiac muscle
Phase 1 (early repolarization):
 returns Vm to  +10 mV (plateau voltage)
 due to:
o inactivation of fast Na+ channels
o slowing of inwards Ca2+ current
o voltage-dependent transient outward K+ current (Ito1)
Phase 2 (plateau):
 balance between inward and outward currents
 maintains cell in depolarized (+10 mV) state for a few 100 ms
o this determines strength and duration of contraction
 primary current is slow inward Ca2+ current
 Ca2+ channels:
o L-type:
 primary channels
 long-lasting
 activated @  -20 mV (last part of phase 0)
 slowly inactivate during phase 2
o T-type:
 transient
 open @  -70 mV
 balancing outward current: IK1
 delayed rectifier currents (smaller than IK1): IKr and IKs
 atrial myocytes have very rapid IKur
Phase 3 (repolarization):
 progressive decay of inward Ca2+ current
 increase in outward K+ (IK1)
 Na/K balance restored by Na/K pump
 intracellular Ca2+ reduced by Na/Ca exchanger & sarcolenmal Ca2+ ATPase
Slow AP:
Phase 4 (resting Vm):
 slow diastolic depolarization
o due to LACK OF IK1!!
 mediated by:
o pacemaker current, If
o Ca2+ current, ICa
o outward K+ current, IK
 If:
o non-specific cation channel
becomes activated during repolarization of previous AP @ -50 mV  autoexcitation!!
Phase 0 (depolarization):
 caused by inward Ca2+ flow
o channels become activated @ 55 mV (end of phase 4)
no phase 1 in slow response fibers; phase 2 cannot be distinguished from phase 3
Phase 3 (repolarization): mediated by outward K+ current IK
Ligand-gated Ion Currents
 activated by ACh
 shortens AP in atrial myocytes
 hyperpolarizes Vm in SA and AV nodes
 inhibited by normal ATP levels
 activated with decrease in the ATP/ADP ratio
 shortens AP in atrial and ventricular myocytes
The basic cardiac conduction system and where fast vs slow APs are located
SA node atria, AV node  DELAY!!  bundle of His  left and right ventricles
fast APs: atrial and ventricular myocytes, Purkinje fibers
slow APs: SA and AV nodal cells
Regulation of cardiac conduction by the autonomic nervous system
SS stimulation:
activation of β-adrenergic receptors  stimulation of all three currents BUT greater
stimulation of If and ICa  more rapid depolarization, increases repolarization time 
more rapid and shorter APs in the SA node  increased heart rate
PS stimulation:
ACh activates ligand-gated IK(ACh) channel  decreased Vm (hyperpolarization) 
increased threshold  slower depolarization
ACh also decreases If and ICa  slower depolarization
resting heart rate is primarily controlled by PS
Components of the ECG and “relative interval durations”
What it is
P wave
Atrial depolarization
PR interval
Depolarization propagated through AV node  AV
bundle  branches
QRS complex
Depolarization of ventricular myocardium
Q: depolarization of interventricular septum
R: primary depolarization of left ventricle
ST segment
All regions of ventricles depolarized – plateau phase
!! ST elevation or depression occurs during myocardial
T wave
Repolarization of ventricles
QT interval
Ventricular AP duration
Normal duration
80-100 ms
120-200 ms
<120 ms
<400 ms
Basic rules of how ECG waves on the ECG are generated – positive vs negative
a positive deflection indicates an approaching wave of depolarization
a negative deflection indicates a receding wave of depolarization
!! remember that depolarization moves downward and to the left
The location of and polarity of all 12 leads
aVR – right arm +, left arm and leg – (thus waves are inverted compared to other leads)
aVL – left arm +, right arm and left leg –
aVF – left leg +, right and left arm –
V1 and V2 – primarily right ventricle (but usually obscured by larger left ventricle depolarization)
large S waves because LV depolarization moves away
V5 and V6 – primarily left ventricle
large R waves because LV depolarization moves towards
How to estimate/calculate MEA; left vs right axis deviation
two best signals to use:
 lead with the greatest net positive amplitude of R is most parallel
 lead with the smallest difference between R and S is most orthogonal
vectors usually between -30° and +110°
Basics of ECG interpretation:
Heart rate (HR) – R to R
Chamber hypertrophy
Left ventricle hypertrophy
Large increase in QRS amplitude
T wave inverted and asymmetric
Left axis deviation
Split P waves
Right ventricle hypertrophy
Tall R waves in RV leads
Deep S waves in LV leads
T wave inverted and asymmetric
Right axis deviation
P wave amplitude increased in right chest leads
Myocardial ischemia/infarction
mostly observable through changes in the S and T waves
 ST segment is full depolarization
 T wave is repolarization
  inhomogeneities in AP propagation affect S & T
subendocardial ischemia – increased QT interval and/or T amplitude
subepicardial ischemia – T wave inversion
severe subendocardial ischemia – ST depression
severe subepicardial ischemia – ST elevation
Basics of cardiac EC coupling and effects of sympathetic stimulation
EC coupling same as for skeletal muscle; see Dr. Cala’s muscle section
SS stimulation of β-adrenergic receptors does the following:
1. increase Ca2+ flux across SR by phosphorylating Ca2+ channels
2. increase SR Ca-ATPase activity
3. decrease Ca2+ sensitivity of myofilaments
 shorter and stronger contractions
The 3 factors that affect cardiac function and how they differ
 force within cardiac muscle at rest
o this is PASSIVE FORCE remember that?
 force developed by contracting cardiac muscle depends on preload prior to onset of
contraction – Starling’s Law of the Heart, see below for more detail
 weight a muscle senses and must work against
o in a normal heart, this is equal to the aortic pressure
 as afterload increases:
o rate of shortening decreases
o extent of shortening decrease
o onset of shortening increases
o time to maximal shortening is UNCHANGED
 biochemical potential of muscle to perform work that is independent of preload and
 e.g., SS stimulation bringing in more Ca2+
The Frank Starling mechanism
increased stretch during diastole  increased force of contraction during systole
i.e., more blood in, more blood out
PASSIVE TENSION  independent of ATP and Ca2+
Where the 4 cardiac valves are located and how they regulate the different phases of the cardiac cycle
S1 vs S2; systolic vs diastolic murmurs
 closure of tricuspid and mitral valves
 onset of systole
 peak of R wave
 closure of pulmonic and aortic valves
 end of systole
 end of T wave
systolic murmurs occur between S1 and S2
diastolic murmurs occur after S2
The basics of the Wiggers diagrams
are you seriously fucking kidding me this diagram is the worst
The components of ventricular function:
Cardiac output
heart rate (bpm) x stroke volume (mL/beat)
Stroke volume
end diastolic volume (EDV) – end systolic volume (ESV)
Ejection fraction
Stroke work
stroke volume (mL) x mean aortic pressure (dynes/cm2)
The 4 factors that determine stroke volume
 heart rate
 ventricular compliance
 preload or EDV (venous return)
 afterload or arterial blood pressure
How the law of LaPlace applies to the heart
𝜎 = 𝑃 ∙ 𝑅⁄𝑊
where σ = wall stress, P = pressure, R = radius of curvature of the wall, and W = wall thickness
 when R increases (such as when heart dilates), more stress is needed to produce a given
How to interpret PV loops – load effects vs contractility
IVVR – isovolumic ventricular relaxation
IVVC – isovolumic ventricular contraction
as preload increases, capacity of LV to generate P increases
stroke volume increases
as afterload increases, stroke volume decreases
but this increases end-diastolic volume (preload)
so stroke volume increases again
increased contractility  increased SV & SW w/constant load
increased rate of ejection of blood from ventricle
You need to know the 4 types of murmurs – focus on aortic insufficiency vs stenosis
Cause & Effect
aortic stenosis
LVP during ejection >> aortic P due to
narrowing of aorta
 SV due to  afterload  LV
aortic insufficiency
blood leaks back into LV after ejection
 EDV   EDP   preload   SV
 blood flow between LA and LV
  LAP & LA hypertrophy
  LV filling   EDV & EDP   SV
blood leaks across MV during ejection
  LAV &  LAP   LV filling
  EDV &  EDP   SV
mitral stenosis
mitral insufficiency
for reference, normal sound graph is:
What you are not responsible for on the exam
You do not need to memorize specific numbers
You do not need to know the specific locations and differences in IKr vs IKs
You will not need to discriminate between similar types of arrhythmias, but you need to know where to
look on the ECG for these arrhythmias
You do not need to know the exact location of specific valve auscultation sites
You do not need to memorize the 3 waves or peaks from the jugular vein pulse
You do not need to know anything after the mitral insufficiency slide/page in the notes
Dr. O’Leary – Cardiovascular Physiology
Describe the relationship between pressure, flow and resistance.
𝑃1 − 𝑃2 = flow × resistance
where P1 = aortic pressure, P2 = central venous pressure, resistance = total peripheral
resistance (TPR)
if resistance, 𝑅 = 𝜋𝑟4 , where η = viscosity, l = length, and r = radius
then flow =
(𝑃1−𝑃2)(𝜋𝑟 4 )
the radius r becomes the most important factor for determining resistance (and hence flow)
 arterioles are most important for establishing TPR b/c of ++ smooth muscle in walls
also flow = velocity x cross-sectional area, just to confuse things
Compare and contrast the anatomy of blood vessels at the different levels of the vascular tree.
remember your anatomy
Compare and contrast the changes in pressure, velocity, area, and blood volume at different levels of
the vascular tree.
  from aorta to IVC
 biggest  across arterioles (b/c  resistance)
  from aorta to capillaries,  on venous side
 dependent on cross-sectional area
o cross-sectional area – area of all blood vessels at any level
% total blood volume
 dependent on pressure and compliance
 arteries have high pressure and low compliance, veins have low pressure and high
o 70% of TBV is in venous system
Understand the concept of compliance.
i.e., how much volume changes due to a change in pressure
Discuss the effects of posture on transmural and perfusion pressures.
transmural pressure – pressure across the walls of blood vessels
perfusion pressure -- ∆P across tissue (arterial P – venous P)
upright posture: p = height of column x density of fluid x gravity
 hydrostatic pressure dependent on distance above and below heart
Mean Arterial Pressure (MAP) ≈ diastolic pressure + 1/3 pulse pressure
Understand the concepts of local control including:
reactive hyperemia –  in blood flow after a period of no flow
active hyperemia – when metabolic rate , blood flow 
 actively metabolizing tissue produces vasodilators (H+, K+, lactate, etc.)  
metabolism =  vasodilation
 no flow = constituent vasodilators not carried away  when flow resumes,  local
concentrations of vasodilators
autoregulation – ability of tissue to maintain constant blood flow despite changes in perfusion
 range over which autoregulation is effective is the autoregulatory range (duh)
 hypothesis 1: metabolic --  P causes  in blod flow, which  local concentration of
vasodilators   vasoconstriction
 hypothesis 2: myogenic – when smooth muscle is stretched, it contractions  when  P,
 recoil by smooth muscle walls  vasoconstriction
mechanical (tissue pressure) effects – compression of blood vessels, e.g. in endocardium during
 because perfusion is ∆P across tissue, if P ≈ across tissue, ∆P ≈ 0
Understand the concepts of remote control, effect of activation of alpha, beta, V1, and AII receptors.
neural – control by autonomics (primarily SS)
 norepinephrine (NE) release causes vasoconstriction
 except in some skin & muscle vessels – vasodilation
 PS in genitals, heart, brain – ACh  vasodilation (via NO)
circulating factors:
 vasopression  vasoconstriction
o via pituitary
 renin/angiotensin  vasoconstriction
o via kidney (renin) and lungs (angiotensin I  angiotensin II)
 norepinephrine & epinephrine (via adrenal medulla)
o blood vessels with β-2 receptors  vasodilation
o  [] or blood vessels without β-2 receptors and with α receptors 
o cardiac β-1 receptors   HR and contractility
Understand the concepts of basal tone and resting tone.
basal tone – vascular smooth muscle tone when all remote and local factors are removed
but….not physiologically possible, as basal levels of SS activity, etc., so:
resting tone is somewhat higher than basal tone (varies by tissue)
Differentiate between active and passive vasoconstriction/vasodilation.
active vasoconstriction is mediated
when this relaxes (to basal tone), it is passive vasodilation
active vasodilation is mediated
when this is removed (to basal tone), it is passive vasoconstriction
Describe the forces controlling fluid movement across the capillary.
πt – oncotic pressure in tissue interstitium – pulls fluid out of capillary
πc – oncotic pressure in capillary – pulls fluid into capillary
Pt – hydrostatic pressure within tissue – pushes fluid out of capillary
Pc – hydrostatic pressure within capillary – pushes fluid into capillary
net force for filtration = (𝑃𝑐 + 𝜋𝑡 ) − (𝑃𝑡 + 𝜋𝑐 )
for fluid OUT of capillary
net filtration = 𝐾𝑓[(𝑃𝑐 + 𝜋𝑡 ) − (𝑃𝑡 + 𝜋𝑐 )]
where Kf varies by tissue
Describe the role of the precapillary resistance in controlling hydrostatic pressure within the capillary
changes in precapillary resistance inversely effect Pc
 if R , Pc , if R , Pc 
Describe the role of compliance in regulating venous volume.
active: due to changes in vascular smooth muscle, result in changes in entire venous compliance
passive: changes in position on same compliance curve due to changes in transmural pressure
Describe a feedback control system
sensor – mechanism to detect the level of the parameter
integrator – analyzes info from the sensor and decides if adjustments are necessary; effects
adjustment by means of the:
effector – mechanism to affect the variable under control
Discuss the factors affecting baroreceptor nerve activity
 arterial baroreceptors – located in walls of carotid sinus and aortic arch
 cardiopulmonary baroreceptors – located in atria, ventricles, and pulmonary vessels
o arterial and venous
 much more sensisitive to small changes in P than arterial
 reinforce SS triggered by arterial
 atrial cells release atrial naturiuretic peptide, which does… something
o ventricular
 tend to reinforce arterial
 except…may be responsible for “vicious cycle” (see below)
carotid and aortic chemoreceptors – respond to changes in CO2 and O2
central chemoreceptors – if O2 delivery to brain becomes too compromised,  in SS
activity – cerebral ischemic pressor responses
o  vasoconstriction to shunt blood to brain
o responsible for hypertension associated with head injuries
integrator – probably the vasomotor center in the medulla
effectors – PS and SS autonomics
 basal state is SS, PS!!
o that is,  in baroreceptor activity INHIBITS vasomotor center  SS, PS
Discuss the compensatory responses to hemorrhage.
Discuss the "vicious cycle"
orthostatic intolerance – inability to stand without fainting
 probably due to dramatically  blood volume (bed rest and space flight)
o more susceptible to the blood volume shifts that accompany upright posture
prolonged orthostasis  contractility , preload   reflex bradycardia & SS  
cardiac output & vasodilation
oxygen consumption = blood flow x (arterial – venous)O2
 can  O2 consumption by  blood flow or extraction of O2 (or both)
response to exercise
 central command
o volition or “will” to exercise   in PS activity
 arterial baroreflex
o reset to higher level  reinforce  in pressure
o how? no one knows
 skeletal metaboreflex and mechanoreflex
o metabolites accumulate  stimulate afferent nerves   in arterial pressure and HR –
o some of these afferents are mechanosensitive & stimulate with contraction –
o works via SS & vasopressin
activity during graded exercise
 initially
o PS tone    in cardiac output
o small  in SS  muscle metaboreflex
 as exercise progresses
o PS  due to central command and resetting of arterial baroreflex
o SS  due to resetting of arterial baroreflex and muscle metaboreflex
 majority of cardiac output directed to the skin
o in cardiac output & redistribution of blood flow
 vasodilation due to SS (PS not present in limbs)
 exercise more difficult in hot environment because you only have so much blood, has to be
divided between muscle (actively metabolizing) and skin (heat loss)