Physiology I

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How many K ions per Na ions are pumped by Na/K pump?: 3 Na out, 2 K in.
What do cardiac glycosides do to Na/K pump?: (ouabain, digitalis)

Inhibit Na/K pump by plocking K minding sites outside the cell
Why does cell swell when Na/K pump is inhibited by oubain or digitalis?: When it is not working, 3 Na come back in for every 2 K that leave. Cell becomes more positive, so Cl- comes in to counter charge change. This all increases osmolality of the cell. Water follows; swelling cell
Secondary active transport: Transpots an ion up a gradient using the energy of another gradient that was set up (say, by na/k pump)
What causes glucosuria in DM: too much DM in serum. the Na/glucose symporter gets saturated. So some glucose enters the urine.
Name an antiporter: Na/Ca antiport in cardiac muscle: Na comes in down gradient, Ca pumped out (up gradient).
How does digitalis work?: A ardiac glycoside.

1) Inhibits K binding site of NA/K ATPases. This stopes the pump from working.
2) This means that the Na concentration gradient is lower.
3) This means that the Na/Ca ANTIPORTER doesn't work as well, and less Ca is extruded from the cardiac myocytes
4) Ca goes up in cardiac myocytes and is stored in SR
5) this excess Ca can be used to increase the CONTRACTILITY of the cell
6) this can be good--but you don't want to stop ALL of the na/k pumps from working.
Isosmolar v. isotonic: Isotonic: same osmolarity of the blood

Isosmolar: same osmolarity of another soution
Normal ion levels in cell and out: INSIDE:
1) K+ = 120 mM
2) Na+ = 15 mM
3) Cl- = 20 mM

OUTSIDE:
1) K+ = 4 mM
2) Na+ = 135-45 mM
3) Cl- = 100-111 mM
K or Na: which ion do human cells have greater permeability for?: K
What is the Nernst equation?: Ex = -58 log ([X]1 / [X]2)

Where Ex is equilibrium potential and X1 and X2 are ion concentration on both sides of membrane
what is tetrodotoxin and what does it do?: Puffer fish toxin

Blocks voltage gated Na channel from the outside.
What do tetraethylammonium ions do?: Block voltage gated K channels from the inside to prevent their activation
Describe the structure of a voltage gated Na channel?: 1) 4 domains
2) each domain has 6 transmembrane regions (S1-S6)
3) Linker domain between S5 and S6 makes part of the ion channel or pore
4) voltage sensor thought to be in S4
5) Inactivation involves the intracellular linker between domains III and IV (ball and chain that plugs upo channel during inactivation phase
Describe voltage gated K channel structure: Like Na channel, but made of of a tetrametrr of 6-transmembrane-domained molecules
difference between AP propogation and current in copper wire?: No decrementation in AP propogation--amplitude of current stays constant.
how does the diameter of the axon relate to conduction velocity?: Larger the diameter, the lower the resistance to e- flow in local current, and the faster new action potentials can be initiated.
How does myelination relate to conduction velocity?: Conduction velocity is higher in a myelinated axon

It conservese the electronic current of the local current, decreasing decrement. This means that the current can trigger an AP even further away.
How does myelin conserve local current strength?: 1) decrease in loss of current (increased membrane resistance
2) decreased membrane capacitance--less current needed to discharge the membrane capacitance beforee depolarization can take place.
what causes the absolute refractory period?: First, early in an AP, all of the Na channels are open, so no more are available to trigger an AP.

Later: Na channels need to be activateable to trigger the fast voltage upswing. At depolarized MP, Na channels are inactivated. The do not REactivate until MP goes back down toward RMP. Until enough NA channels reactivate, there can be no trigger of a second AP.
What causes the relative refractory period?: 1) enough Na channels have lost their inactivation so they can be reactivated
2) But note: during afterhyperpoarization, conductance of K is elevated and you have to depolarize MORE to reach threshhold for second AP.
Why does the membrane briefly hyperpolarize after an AP?: Because you are in a period where gK, compared to gNA, is much higher than normal. When no voltage gated channels are open, gK>gNA and this is why rmp is closer to Ek. But after AP, the voltage gated NA channels have inactivated (they inactivate at AP peak), the slower opening K channels are open wide. This makes, temporarily, gK>>gNA. K rushes out, quickly repolarizing membrane. And it ends up overshooting, until all the voltage gated K channels are now closed again and gK is back to normal state.
Overview of steps of neuromuscular AP transmission: 1) AP reaches axon terminal
2) triggers voltage gated Ca channels--ca rushes in and depolarized terminal
3) Ca influx causes release of Ach-filled vesicles into synamptic cleft
4) Ach binds to Ach recepto in endplate region of mocyte
5) this opens a channel that is equally permeable to Na and K; net result is depolarization from rmp, as the new rmp (when gNA=gK) is near zero.
6) this depol triggers voltage gated Na channels, which triggers an AP
What are neostigmine an eserine? What do they do?: They are Acetylcholinesterase inhibitors. They increase half life of Ach in the NMJ and increase end plate potential. But if Ach gets too high, then you get synaptic blockade.
Describe LES: Lambert-Eaton myasthenic syndrome

1) symptoms: muscle weakness
2) cause: impaired release of ACh
3) reason: autoimmunity to presynaptic Ca channels; ABs block Ca channels and impede necessary Ca influx that would trigget Ach release
4) NOTEL large fraction of LES patients also have SCCL (small cell carcinoma of the lung)--this may be where the bad ABs are coming from
What kind of ACh receptors are foundi in the motor end plate?: Nicotinic
What happens when receptors bind ACh repeatedly over a short period of time?: You get receptor desensitization

That is, you get a change in conformation such that ACh receptor can still bind ACh, but it does not open a ion channel when it is binding Ach.
Why does nonspecific Ach ion pore lead to depol? Other, better answer: Outward driving force on K is less than inward driving force on Na. K is pressured out due to concentration gradient, but is opposed by voltage gradient. Na comes in due to concentration gradient, AND the electrical gradient of negativity draws it in too.
Is EPP an all or none event?: NO! It depends on the amt of ACh released into synaptic cleft, which influences the number of ACh receptors that are occupied and open, which influences amt of EPP.
what does curare do?: Plant poison that blocks ACh-activated channel in a closed position.
what does alpha-bungarotoxin do?: It binds irreversibly to closed AChR and blocks synaptic trasmission
What does succinycholine do?: Blocks channel in an OPEN state

But the resulting constant depolarization causes the voltage gated channels adjacent to the endplate to INACTVATE, leading to muscle relaxation after an initial depol
What is Myasthenia gravis? What treats it?: 1) MG is where you have a decrease in the number of functioning ACh receptors due to autoimmunity that degrades the AChR too fast.

2) you can treate with acetylcholinesterase inibitors, which maximize the the ACh concentration in the synaptic cleft and ensure that all available and functioning AChR are being used.
Name 2 key proteins in the endfeet of the triad?: 1) Dihydropyridine (DHP) receptor/voltage sensor (in the triad membrane)

2) ryanodine receptor/calcium release channel in the SR membrane
Does excitation-contaction in skeletal muscle cell require extracellular Ca?: No.
What does DHP receptor do in skeletal muscle?: IN response to triad membrane depol, DHP receptor changes its conformation, which causes a change in the ryanodine receptor in the SR membrane. The Ryanodine receptor acts as a Ca channel; when it opens, Ca from SR rushes out.
Is reuptake of Ca back into SR active or passice?: Active. Against concentration gradient. Requires ATP
What does Calsequestrin do?: it is an SR protein that binds Ca ions and increases storage capacity of SR by as much as 40-fold.
Overview of steps in excitation-contraction coupling in skeletal muscle: 1) depol of sarcolemma spreads into t-tubules
2) depol at triad causes conformational change in the DHP voltage sensor
3) conformational change is transmitted to the ryanodine receptor via direct interation
4) change in ryanodine receptor causes release of Ca from SR thru the receptor channel
5) intracellular Ca causes interaction betwee actin and mysin filaments
6) primary active pumps pump Ca back into te SR membrane
what are series elastic components?: Filamentous molecules in series along length of muscle fiber. They oppose contraction of the fiber, and make it so that maximal contractoin of fiber cannot be achieved with just one "twitch"
what is summation?: Because Ca release can be triggered before series elastic components have fully relaxed after one twitch, then multiple quick releases can cause further stretching of the SECs, and more stretching-->more actin/myosin overlap, which means greater contraction. Eventually, this leads to full SEC stretch, or TETANUS.

Note: summation is NOT due to steadily rising intracellular Ca.
in what order are motor units recruited to effect stronger contraction?: small motor units first, then larger ones as more tension is need ("size principle")
Efferent sympathetic innervation of the heart: 1) preganglionic efferents synapse in cervical ganglia and paravetebral ganglia. Release AcH into nicotinic AChR.
2) postganglionic neorons innervate SA and AV node cellsa s well as Atrial and Ventricular myocytes
3) release Norepinephrine (NE) (ADRENERGIC).
4) NE binds to B1-adrenergic receptors
What does NE binding to B1-adrenergic receptor do?: 1) increases HR via action on SA node cells
2) increases conduction velocity thru AV node and ventricular conductile system (shortening QRS complex?)
3) increases contractility of heart muscle
Parasympathetic innervation of heart overview:: 1) cell bodies in medula; get to heart via vagus.
2) release ACh that binds to NICOTINIC receptors on postganglionic vagal efferents.
3) postganglionic efferents innervate:
a) Sa and AV nodes
b) atrial muscle
c) NOT VENTRICULAR MUSCLE11
4) they release ACh again, this time it binds to MUSCARINIC receptors
What does Ach binding to Muscarinic receptors in the heart cause?: 1) decreased HR via action on SA node cells
2) decreased conduction velocity thru AV node
3) decreased contractility of atrial cells (REMEMBER: no parasympathetic innervation of the ventricles)
Is there a NMJ between cardiac nerves and cardiac muscle?: NO. NE (symp-->b1 adrenergic) and ACh (para-->muscarinic) diffuse from nerve endings to myocte.
Are skeletal muscle cells electrically interconnected?: No.

But cardiac myocytes ARE. Intercalated discs between cells hace gap junction pores on longitudinal parts; allows cells to function as a syncytium.
Excitation-contraction in cardiac v. skeletal myocyte: 1) basically same as skeletal muscle BUT
2) free cytosolic Ca levels induced by AP can be GRADED, so CTY can be GRADED
Excitation-contraction coupling steps in cardiac myocyte: 1) AP sweeps down T tubule
2) AP on scell surface opens L-Type VOCC (voltage-operated calcium channels).
3) influx of Ca during plateau phase of AP
4) AP on T tubule causes release of some of the Ca store in the SR
5) So extracellular and SR Ca cause rise in intracellular Ca and cause contraction
Do skeletal myocytes have VOCC? why does this matter?: No. Drugs that block VOCC decrease CTY without affected skeletal muscles.
Repolarization of cardiac myocyte during diastole: 1) repol phase of AP closes both L-type VOCC and SR Ca chanels
2) ATP-dep Ca pumps in SR and sarcolemma, as well as the Na/Ca exchanger, pumps free Ca out of the cytoplasm and lowers intracellular Ca.
How does Ca level effect cardiac CTY?: More intracellular Ca, the more cross bridges that can pull per unit time
Ways to increase intracellular Ca (and thus CTY) in a CM.: 1) increase extracellular Ca (no effect on SkM)
2) increase in SR Ca levels.
3) increase number or duration of VOCC that open
4) decrease activity of Ca extruders
What else can bind to sympathetic beta1 adrenergic receptors eliciting response in heart?: Not just norepinephrine from postganglionic sympathetic efferents.

ALSO circulating EPI (epinephrine) that comes from adrenal medulla
What are the detailed effects of NE or EPI binding to B1-adrenergic receptors?: 1) cAMP goes up in cell, activating a cascade that causes:
2) increased VOCC activity
3) less inibition of SR pump (increased storage of Ca in SR)

this causes:
1) more Ca influx during depol from outside
2) more Ca stored in SR, so more SR release
3) quicker lowering of intracellular Ca after repol.

NET: Catecholamines increase the FORCE and RATE of both contraction and relaxation
What are the catecholamines?: Norepinephrine (from postganglionic sympathetics)

Epinephrine (from adrenal medulla)

[bind to B1-AR)
What Ca source does SM myocte depend on? Extracellular, SR, both, neither: Extracellular, even moreso than CM
Describe the SR of SM cell: 1) instead of ryanodine receptor/Ca channel:
2) It has IP3 receptor
3) when IP3 binds, it opens and releases Ca
Which has more grading of contraction: CM or SM?: SM
How is SM membrane potential determined: 1) majur determinannt is rise in internal Ca
2) THEY HAVE NO INDUCIBLE NA CHANNELS
3) binding of hormones and nuerotransmitters alters conductance of other ions
4) this alters Em, which alters conductance of L-type VOCCs.
5) changes in stretch also cause change in VOCC activity (myogenic tone)
Types of SMC excitory and inhibitory stimuli: 1) Neural. Symp (NE) and Parasymo (Ach). The transmitters diffuse to receptors on syncitially-coupled SMCs
2) Hormonal.
3) Stret ch. SM stretch causes depol, which causes opening of VOCC and thus contraction.
4) Metabolic changes in chem composition of extracellular fluid--metabolites can affect vascular tone.
5) Paracrine/autacrine factors
Describe the mechanism of contraction and relaxation in SMC: 1) different from striated: it is based on myosin phosphorylation
2) cross bridge cycling rate determined by amt of myosin phosphorylation
What does NE from postganglionic symp nerves do in vascular smooth muscles?: Binds to ALPA-ADRENERGIC (compare beta1 in the heart) receptors. Causes CONSTRICTION.
How do neurotrasnmitter and hormonal vasoconstrictors work?: 1) signal binds to receptor.
2) Receptor generates intracellular IP3
3) IP3 stimulates SR to release Ca
4) Ca influx from outside via VOCC isthe 2d major source of contractile Ca.
How does neurotransmitter and hormonal vasodilation work?: 1) adenosine (metabolite) activates adenylate cyclase, which makes cAMP
2) circulating epinephrine (catecholamine) binds B2-adrenergic receptors, which leads to cAMP formation
3) NO difuses across membranes, activates production of cGMP
4) cAMP and cGMP induce vasodilation
Name what ions/channels each muscle cell type depends on for depolarization intiiation:: 1) Skeletak: VO Na achannels
2) Cardiac: VO Na and VO Ca channels
3) Receptor operated K channels (no voltage operation, esp no VO Na channels!)
What confers myogenic tone? What cell type does this?: SMC

Stretch-induced contraction confers myogenic tone
what do chatecholamines do in SMC?: 1) NE: binds to alpha-AR to cause contraction
2) EPI: binds to B2-ARs to cause relaxation
What do parasympathetic neurotransmitters (ACh) do in SMC?: they bind to muscarinic receptors and cause constriction in gI tract an airways
What are the differecnes of cAMP elevation effecetsin CM v. SM?: In CM, cAMP rises and causes more contraction.

Ins CM, cAMP rises and causes less contraction.
What goes on during phase 4: IRK channels hold rmp near Ek.
What happens at phase 0: 1) depolarization past threshhold opens VO Na channels. MP shoots toward Ena.
2) as MP depolarizes, IRK channels inactivate
What happens at phase 1: 1) Na channels inactivate
2) MP moves away from ENa
3) VO Ito K channels activate.
4) MP is forced back toward Ek
5) VO Ca channels begin to activate
6) net effect is that MP settels around 0 (between Ex and ECa.
What happens during Phase 2: 1) voltage dependant Ca channels (L-type VOCC) are activated. This helps keep membrane depolarized.
2) Substantial Ca influx here, which triggers more Ca release from SR
3) note: Ca channels are slow to activate and inactivate
4) Ito and DRK channels keep membrane potential from going too high: Ito inactivate during 2, DK activate here.
What happens in phase 3: Repolarization caused by inactivation of Ca channels and activation of enough DR K channels.

MP returns toward Ek
What makes refiring impossible during the ARP?: Na channels are inactivated due to depol
Ca channels are either activated, or inactivated due to depol (their inactivation is a slower process)
What allows the relative refractory period in cardiac muscle?: Once enough *CA* channels recover from inactivation, then you can have enough available to trigger an AP.

Most fast Na channels are still inactivated, though.

So the AP you get is a SLOW, Ca type depol.
Do Na channels play any role in pacemaker cell depol?: NO. the membrane potential in pacemaker cells NEVER becomes negative enough to remove the Na channel inactivation.

Thus, NA channels are CHRONICALLY INACTIVATED in cardiac cells
Why is the MDP for SA nodal cells not low enough to allow for Na channel recovery from inactivation?: THere are fewer IRK channels that are open during phase 4
wWhat causes gradual depol in pacemaker SA node cells?: 1) Few IRK channels makes MDP less negative to begin with

2) DRK channels begin to close at end of phase 3

3) If channels become voltage activated upon DEPOLARIZATION: these let in Na.

4) when M hits a threshhold, Ca channels start to open (slow). MP rises toware ECa.
Correction on how If works: It is not a Na channel--it is a non-ion-specific channel. So when open, it lets Na in and K out. But this works to make MP an average between ENa and Ek. So this is still a depolarization.
What is the rmp (roughly) of SA and AV node cells?: Around -55 mV
Name a physiological reason why conduction is slow in the AV node?: 1) fewer gap junctions between the cells
Can AV node cells spontaneously depol on their own? Can they normally reaach threshhold on their own?: 1) yes, but more slowly than SA
2) no
Describe the ARP in nodal cells: 1) starts at beginning of phase 0
2) lasts till middle of phase e (like other myocytes)
3) determined by the inactivation of Ca channels and the activation of DRK channels (increase DRK channels --> decrease ARP...Increase inactivation time of Ca channels, increase ARP)
Describe the RRP in nodal cells: 1) begins in midddle of phase 3: when enough Ca channels have recovered from inactivation to fire a 2d AP
2) lasts to beginning of slow depol in phase 4: when all the Ca channels from recovered from inactivation
How does Ca channel blocker affect nodal ARP and RRP?: ARP: decreases ca channel activity. AP is shorter, as is then ARP.

RRP: INCREASES the RRP, since it is taking even longer for Ca channels to lose their inactivation
What is the overall response of CAT binding to B1-AR?: Increased HR
Increased CTY
What are the mechanisms of Symp-induced positive chronotrophy?: 1) increased Ca channel activity: lowers threshhold and increases depol rate
2) Increased If activity
3) Also DRK is stimulated, so repolarization occurs more quickly, counteracting the increased Ca channel activity that would otherwise prolong the plateau period
Mechanism of CAT-induced positive inotropy: 1) increased Ca channel activity. More Ca rushes in to myocytes during plateau. This triggers more release of Ca from SR. this causes increase of CTY.

2) Also increase of resequestrationof CA into the SR, allowing for more quick relaxation
Is there parasympathetic innervationof the ventricles? So what?: NO: so PNS can only affect HR (via the SA and AV node innervation), but not CTY
How does PNS induced negative chronotropy work?: 1) inhibition of Ca channel activity lowers the rate of phase 4 depol and raises threshhold.
2) If channnels are inhibited
3) GIRK channels stimulated (this makes MDP more negative)
What do GIRK channels do?: They hyperpolarise nodal cells; are stimulated by parasympathetic ACh binding to muscarinic receptors
what is the PR segment?: Baseline segment BETWEEN p wave and QRS
What is the PR INTERVAL?: The time from BEGINNING of P wave until beginning of QRS
What is the ST segment?: Baseline segment between end of S and beginnig of T.

Represents time when most of ventricle is depolarized.
What is the QT interval?: Time from beginning of QRS to END of T wave.

Measures the length of the AP.
what is length of an abnormally long PR interval?: .20 sec
What is normal QRS duration?: .1 sec
HR determining sequeence to remmeber:: 1 lg division between beats (.2 sec)=300bpm
2 divisions between=150
3 divisions between=100
4=75
What is a possible bad cause of sinus tachycardia?: CHF
Describe Premature atrial contractions: 1) ectopic pacemaker in atria
2) P wave may or may not be normal
3) PR may or may not be reduced
4) overall rhythym irregular
5) QRS of ALL beats is NORMAL
6) may be caused by stress, caffiene
Describe PVCs: 1) beat originates in the ventricle
2) no P wave (no atrial contraction associated with the beat)
3) Weird and long QRS, since ventric contraction does not start via AV node-->bundle of His-->etc.
What can establish a reentry loop?: Unidirectional block
Why must their be a region of slow conduction near the unidirection block for reentry loop to occur?: The retrograde current that hops the unidirectional block must then slow down in order to not continue the retrograde path before the cells ahead have recovered from their refractory period
What is a PSVT or PAT: Paroxysmal supraventricular (atrial) tachycardia

1) caused by reentry circuit around AV node
2) often no P wave
3) QRS Might be irregular
4) atrial rate becomes 150-200, maybe even 300 (fibrilation)
5)) this usually causes partial block at AV node when atrial raete is that hi
What is atrial flutter?: 1) due to reentry circuits in the atria
2) high frequency baselien oscillations instead of P wave
3) slo conduction and refractory periods in AV node usually cause partial ventricular block
What is atrial fibrillation: 1) caused by chaotic atrial excitation
2) no P wave
3) fine oscillation on baselin
4) vent rate depends on AV block
How is AV block graded: Based on length of PR interval

1) 1st degree: prolonged but uniform PR interval
2) 2d degree: AV conduction worse. may lead to missed V beat
3) 3rd degree. Complete block. V rythym independend to atrial rythym. Low frequency QRS, independent of P waves
Equation for blood flow thru a circuit: Q = pressure drop [del P] / R
What is MAP roughly equal to?: MAP = CO * SVR
What is CO equal to?: CO = HR * SV
Normal pressure at aorta level: 100
Normal arterial pressure at head level: 95
Normal arterial pressure at lower trunk level: 95 (?!)
Normal pressure on venous side just after cap beds: 10
Normal pressure in vena cavae: 1-3
normal pressure in pulmonary artery: 15
Normal pressure in pulmonary vein: 5
normal CO: 5 L/min
MAP equation, again: MAP = CO * SVR
What is SVR mainly determined by?: arteriolar diameter
what causes S4?: aditional spurt of blood into ventricle due to atrial contraction after P wave
what causes S1: closure of mitral then tricuspid valvs at beginning of systole
What is the ejection fraction? what are normal figures?: EF = SV/EDF.

Normally around 60%
What is the cardiac index?: CI = CO/body surface area1
What causes S2: closure of aortic valve, the pulmonary
What causes S3: Rapid passive ventricular filling that begins following isovolumetric ventricular relaxation
Why does LV contraction occur before right?: Because depol gets to LV bevfore it gets to RV via the purkinji system
Why can gou et S2 aplitting?: Since LV starts contracting before RV, it ends ocntracting first too. If this is accentuated by a right His bundle block, then you get S1 splitting (M valve closes, T valve closes) AND s2 splitting (aortic valve closes, pulmonic valve closes)
Which begins first: LV or RV ejection?: RV ejection: because presure is so much less on the venous side. Even though RV contraction starts later, it ejects first.
Which ejection ends first: RV , or LV: LV. It is pumping against higher pressure. So it starts contracting first, starts ejecting second, but stops ejecting first.
What kind of defect causes S2 splitting?: Ventral septal defect. Aortic valve closes eaerlier bc it is losing pressure to RV. Pulmonic valve closes later because it is getting more blood from the L side.
LV S/D pressure: 120/4
LA pressure: 5
RV s/d pressure: 25/2
RA pressure: 3
MAP s/d: 120/80
pulmonic artery pressure, s/d: 25/9
A wave of arterial p: rise in CVP due to contraction of R atrium (no valve).

triscuspid narrowing increases a wave
C wave: Atrial pressure rises slightly at beginning of isovolumetric ventricular contracction. Tricuspid insufficiency or VSD increases c wave
what is v wave: during v ejection, blood fills atria while AV valves are closed. this distends atrial walls (and thorasic veins) and causes gradual rise in atrial pressure. This drops quickly as sooon as AV valves open.

Tricuspid insufficiecny also increases this wave, since more bloood is entering the atria (due to V contraction)
what can cause s3 gallop?: Dilated ventricle. makes passive filling more noisy.
What can cause an S4 gallop?: L ventricular hypertrophy--stiffens walls and makes spurt more audible
what 3 factors determine SV (and thus affect CO and thus hep deterine MAP): 1) PL
2) AL
3) CTY
What are the 3 most common determinants of preload?: 1) CVP. This afffects atrial pressure
2) other stuff that we dont have to kno
What are the determinants of CVP (which determines atrial filling which determines preload): 1) venous smooth muscle tone. More tone in veins (via increased symp activity) increased preload.
2) blood volume. BC increase increases CVP, which increases preload, which increases SV--and vice versa.
3) Body position. Standing up pools blood in leg veins-->decreases CVP-->decreases PL-->decreases SV
What are the determinants of afterload?: 1) Major: arterial diastolic pressure (mainly due to SVR). Increas in pressure increases afterload.

2) Aortic compliance: less compliance increases AL

3) aortic valve resistance: if stenosed, it increases afterload
what will increase in CTY do to the ESVP point on the volume/pressure curve?: It moves it up left. For a given preload, this decreases ESV and increases SV.
What are the main cellcular determinants of CTY?: 1) Ca ckinetics. CATs bind B1-AR and incrase Ca influx, SR Ca crelease, adn removal during repol. This all increases rate of contraction, peak force, and rate of relaxation. ACh has opposite effecte mediated by Muscarinic receptors in the atria. But this don't rully affect CTY.

2) Myosin ATPase activity: responsible for a/m crossbridge cycling. Can be increased by training, decreased by disease.

3) ATP level. Ischemia-->low ATP-->low CTY

4) Number of cross bridges. Loss of sarcomeres (infarc/necrosis) decreases CTY
What point best indicates CTY?: Point of aortic valve closure in P/V curve.
Name 2 indicies of CTY other than P/V point of aortic valve closure: 1) Peak dP/DT
2) peak LVSP
Poiseuille's law - 1: Resistance is proportional to

length * viscosity / pi * r^4

So increase radius, decrease resistance a lot. EXPONENTIAL INFLUENCE.
Poisseuille's law 2: flow is proprtional to:

pi*r^4 * pressure drop / viscosity.

So increase radius, increase flow exponentially.
La Place relationship: T=tension of wall
P=pressure inside vessel
h=wall thickness.

T=P*r/h
hypertrophy and laplace: In hypertrophy, after an increase of P and then R as wall distends, h then increases, to help bring T back to normal
what are the major determinants of the arterial pressure waveform?: 1) systolic pressure (mainly via SV).
2) Diastolic pressure: mainly determined by SVR (increase in SVR increases systolic AND diastolic pressure, but it is a proportionately larger increaser of systolic.
how do you define compliance?: Change in volume of vessel per change in pressure
compliance and sympathoexcitation: The decrease in compliance caused by the contraction of venous VSM during sumpathoexcitation is a critical aid to speed venous return to the heart
Major determinants of CVP: (and thus major determinants of preload)

1) constriction of venules/smalll veins (by NE, EPI, AII, and vasopressin (AVP). CPL decreases, mobilizes blood from the stretchy venous reservoirs to go back to the heart.

2) decreased large vein compliance

3) total blood voume (BV up-->CVP up)

4) Gravity: standing up decreases CVP (and decreases PL, thus decreasing CO).

5) decreasae in CO (raises CVP due to back up of blood)
Little example regarding sympathoexcitation during exercise: 1) this causes increase in CTY.
2) but the increase in CTY initially causes a decrease in the "back up" of blood behind the L heart.
3) this causes a brief drop in CVP
4) but the other effects of sympathoexcitatio--vascular constriction, CTY drop--force more blood out of venous side and back into heart, compensating for this momentary drop in CVP
Intrinsic regulatory mechanisms of blood flow in resistance vessels: 1) autoregulation of flow
2) myogenic regulation of Vascular SM
3) Metablooic regulation of vascular SM
3 kinds of intrinsic regulatory mechanisms of blood flow in vascular beds: 1) Autoregulation of blood flow: seeks to keep flow constant when metabolism is constnat, in the face of fluctuating arterial pressure.

2) Myogenic regulation: Property of smooth muscle in arterioles to contract when stretched by a pressure increase and vice versa. (Venous SM doesn't do this).

3) Metabolic regulation: depends on local release of diffusible vasodilator molecules by parenchymal cells in proportion to ther metabolic rate and availability of oxtygen.
When is metabolic regulation of vascular bed flow important?: 1) IF TISSUE METABOLIC RATE IS CONSTANT: normally production of vasodilators will equal diffusion of vasodilators into cap (washout). This keeps the ISF [VD] constant. But if flow in cap increases, more VD washed away. This increases diffusion gradient, and more ISF VD diffues out of ISF. ISF [VD] drops, cap constricts.

Similarly: when flow goes down, and less O2 is delivered, then the reduced O2 levels favor dilation.

2) WITH CHANGES IN METABOLIC RATE:
if met rate goes up, VD metabolites in ISF go up. this causes dilation of resistance vessels, increase of flow. In addition, there is more O2 demand in the tissues, and ISF O2 drops. This all works to increase O2 availability and delivery.
Hola, señor: ¡Hola!
does venous SM exhiit myogenic or metabolic regulation?: no
Note: My card on three intrinsic regulartors was wrong... see C-65 to 68
Thromboxane: Vasodilator released byt platelts
what does NO do?: released by endothelial cells
tonic releas provides local dilator
inhibits platelet aggregation
antiatherogenic
inhibits SMC prooliferation
Sympathetic control of arteriolar radius: Symp postganglionics release NE

NE binda ALPHA-Adrenergic receptors on SM

causes constriction

This is the major type of innervation of cap beds
hormonal control of vessel radius (and compliance, which should be added to previous card): Adrenal medulla releases EPI. Relesase is increased by sympathoexcitation.

In heart, EPI binds to B1-AR.

at high systemic levels, EPI also binda A-AR, and constriction is produced almost everywhere.
Effects of emergency EPI: HR up
CTY up
CVP up
CPL down
Preload up
SC, CO, and SVR up

This all increases MAP in shock
Angiotensin: Potent Peptide vasoconstrictor from kidney

Released during sympathoexcitation, hemmorhae, dyhhydration, low salt, etc.

Increases SVR, decreases venous CPL to support MAP
Vasopressin: Potent peptide constrictor from the posterior pituitary

Released during sympathoexcitation, decreased CVP, hemorrhage, dehydration.

Same action as angiotensin (increased SVR, decreased venous CPL)
what are the 2 opposing mechanisms in microcirculation?: 1) exxtrinsic (neural/hormonal) mechanisms (neural hormonal): attempt to maintain systemic MAP, at the expense of flow to cap beds
2) local (intrinsic) mechanisms: attempt to match perfusion to metabolic activity. They care not for MAP, but for appropriate flow and tissue O2.
Equation for rate of flow of particle across capillary: dq/dt = Permeabililty * available survace area (how many caps open) * concentration gradient / diffusion path length
Starling ultrafiltration equation: CFR=flow of water (and dissolved substances) across cap wall): cap fil. rate
Kf: capp filt coeff: SA * permeability
Pc: cap blood hydrostatic P
COPp: plasma colloid osmotic pressure

CFR = Kf (Pc - COPp)
(and remember: Kf depends on permeability and SA)
COP v. Pc: COP is constatnt at 25
Pc decreases over length of cap
Why is COP constant?: It is created by large proteins that normally cant cross cap wall. So it is always there and favoring keepiing water in the caps.
filtration v. absorption amounts in cap: Filtration slightly exceeds absorption. Excess goes into lymphatic capillary
when does edema occur?: when:
1) excess cap filtration exceed lymph uptake ability
2) excess plasma proteins escape into interstitium (and water follows)
3) lymphatics become occluded
What are the determinants of CFR?: 1) COP. normally constatnt
2) Kf. Varies with # open caps (SA) and permeability (inflammatory response)
3) MAJOR FACTOR: Cap hydrostatic pressure.
What is the main determinant of Pc?: Arteriolar constriction and dilation.
What is VO2: Volume of O2 extracted from RBCs by muscle per minit. Heart has the highest VO2.
Extraction of O2 from coronary arteries: Maximal. All cap beds perfused. Cant realy increase it. Flowalways high.
describe 1:1:1: In heart, 1:1:1 relationship always occurs between CO, VO2, and coronary flow, or else you get ischemia. If CO goes up, VO2 must go up equally. If VO2 goes up, flow must go up. This causes FUNCTIONAL HYPEREMIA.
What factors determine work heart does (and thus O2 demand and thus VO2 in coronary arteries and thus coronary flow)?: 1) preload. Increased r of chamber means more tension in wall which means more work to compress. Preload increases SV, but at O2 expense.

2) afterload. Increase afterload and you increase amt of work the heart has to do--plus you are decreasing SV! High MAP is thus bad if your heart is weak.

3) CTY. But this requires O2 as well. So you want PARTIAL B-AR blockade: you want to decrease CTY and heart rate to decrease O2 demand. but you can't go too far, or you lose too much MAP and lose perfusion in the heart.

4) HR. also O2 dependent.
Phasic coronary blood flow: Flow to L ventricle during systole is 1/5 of that during diastole, since vessels are squeezed, R goes up, flow goes down.
Control of coronary vascular resistance and BF: 1) intrinsic metabolic: the MAJOR mechanism. ensures proper coupling/flow autoregulation. Increased work-->increased metabolism-->increased metabolites-->increased dilation-->increased flow

2) Extrinsic neural. Weak. There are few alpha-adrenergic receptors, so sympathoexcitatory constriction due to noradrenergic release is small and overwhelmed by metabolite autoregulation.
why is cerebral edema a big problem: 1) fixed volume: bony case
2) no lymphatics to drain excess filtrate
why do you get light headed when you hyperventilate/: Brain has good metabolite autoregulation. When you hyperventilate, co2 drops in blood and thus in tissue. Brain associates this with high O2, and it loses metabolite vasodilation.

PO2 has little effect on CBF! C-85
Series arrangemetn of heart and lung: 1) LV failure causes backup behind LV
2) This increases pressure in pulmonary circuit
3) this causes interstitial edema in lung, diminishing gas exchange
4) it also increases pumonary vessel resistance (squeezing on vescicles), which increases AL or R ventricle
5) this can lead to RV failure.
6) increased pulmonary resistance also decreases filling of LV-->decreases PL-->decreases SV and CO.

So it is all connected.
Why is perfusion pressure low in lung even though flow is the same?: Q=delP/R. Del P is low, but R is really low too.
Is net Starling force filtration favorable to filtration: Unlike most tissues, no--because mean cap pressure is mostly below oncotic pressure. This helps prevent edema.

There is also a lot of lymphatics in lung to prevent edema.
does lung arterial cir show myogenic behavior?: No. So when you stand up, and there is more flow at the base due to gravity, there is no autoregulatory myogenic tone to constrict vessels, increase R, and reduce flow.

This increased flow means there may be excess filtration and edema in the base.

All this means that when standing, there is more tissue O2 at apex because it is underperfused and less O2 is carried off. Opposite occurs in the base.
is pullmonary flow regulation more passive or autoregulatory?: More passive. No myogenic or metabolic regulation of flow. This helps the vessels to keep the ability to passively distend and accomodate 5-fold increases in cardiac output and flow without increasing pressure too much and causeing edema.
What happens when there is regional lung hypoxia?: O2 drops and CONSTRICTION occurs--this is opposite from nonpulmonary beds. This deverts blood flow away from underventilated areas
Neural and hormonal control in pulmonary vessels: 1) sparse SNS noradrenergic constrictor innervation.
2) Minimal SNS response: it would be bad to constrict vessels in lung when sympathoexcited!
3) but there is some degree of decreased compliance, to make sure that increased pressure with increased LV CTY does not overdistend the vessels and cause accumulation of blood in the lungs.
where are b1 cat receptors?: Mainly in mucle: EPI binding favors vasodilation here.

Compare EPI and NE binding to A adrenergic receptors in smooth muscle: this causes constriction
which receptors mediate effects of SNS on heart muscle?: b1-AR

b2-AR in smooth muscle (causes constriction)

A-AR in skeletal muscle, causes vasodilation
what does atropine do?: inhibits affects of ACh from PNS binding to muscarinic receptors.
What does vagal stimulation cause?: 1) decrease in HR
2) decrease in conduction velocity in the AV node
3) decrease in atrial contractility that minimally decreases preload and SV
Arteriol baroreceptors:: Nerve endings located within the adventitia in the CAROTID SINUS and AORTIC ARCH. Stretching generates nerve impulses. Afferent fibers travel away with either glossopharyngeal or vagal nerve.
Stimulation of baroreceptors via inceased MAP causes:: decreased SNS stimulation
Increased PNS/vagal stimulation

All of these efefects decrese CO and or SVR, and we all know that MAP = CO * SVR.
Neuro-humoral arterial baroreflex components: 1) adrenal catecholamines (already discussed: NE on adrenal stimulates EPI release)

MAP decrease can cause:
1) increased renal secretion of renin
2) increased renal secretion of angiotensin II
3) increased pituitary release of vasopressin

These changes are slower
Cardio-pulmonary Low Pressure Baroreflex: aka Henry-Gauer Reflex
Similar to arterial baroflex

But this senses distension of THORACIC VEINS and involves mainly adjestments to vascular blood VOLUME.
Characteristics of cardiopumonary low pressure baroreflex response: Upon decrease in CVP:

QUICK:
1) increase in vascular sympathetic tone (NE)
2) decrease in cardiac parasympathic activity

SLOW (but stronger):
1) ADH (aka vasopressin) released from pituitary
2) Renin released from kidney (so angiotensin goes up)
3) increased retention/resorbtion of water and Na in kiney--> BV up
4) increased angiotensin II stimulates adrenal release of aldosterone, that also promotes na/hoh retention.
5) Vasopressin/ADH also promotes water retention
What does chemoreflex activation by hypoxemia, acidemia, or ssypercapnia cause?: Increase in sympathetic drive to heart and BV.

Thi decreases venous compliance and increases MAP. This increases blood flow to facilitate O2 delivery to the tissues.

But these effects may be counterbalanced in muscle if there is severe PO2 decrease and PH decrease
Chemoreflex and baroreflex?: Hypoxemia and Hypertension: baroreflex predominates, and Smp drive devreses.

But if you have hypoxemia and hypotension, say, then they augment themselves.
Cerebral ischemic reflex: 1) triggered by big loss of blood volume, drop of MAP
1.5) first baroreflex kicks in sympathetic response
2) cerebral perfusion continues to drop as the baroreflex is insufficient
3) intense sympathetic response kicks in
4) HR goes way up, SVR goes way up, CTY goes way up. Breathing at first fast (due to CO2 buildup in brain) but then it slows

HALLMARKS: High HR, but normalish MAP
Cushings reflex: 1) caused by intracranial hemmorhage that increases intracranial pressure and decreases perfusion (not a MAP decrease)
2) again, triggers an intense sympathetic response.
3) this increases MAP effectively, but brain perfusion still impaird.
4) [there eventually is vagal stimulation of heart rate]

Hallmarks: Hypertension and bradycardia, slow and deep breathing.
What is circulatory shock?: Indufficient blood flow troughout the body such that tissue damage occurs bc of insufficient delivery of o2 an dnutrients to tissues including brain.
Causes of circulatory shock: 1) inadequate CO
2) inadequate SVR
3) septic shock: shock without initially decreased CO
Map and hemorrhagic shock: MAP can be normal early on in shock!
Tolerable blood losses: less than 10%: almost no effect on CO or MAP

Over 25%: decreases CO, decrease MAP because reflex capacity is exceeded.
Factors in progressive shock: 1) cardiac depression due to inadequate coronary blood flow and from microembolic clots
2) loss of vacular tone due to hypoxia
3) increaed Kf;
4) endotoxin: decreasd flo to intestines, hypoxia, destruction of mucus, enhansed absorbtion of endotoxin
5) Generalized cellular deterioration.

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Number of cards 217