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# UTSW physio block 1

### UTSW school of medicine 2009 physiology class

Fick's First Law of Diffusion J= -D*A*delta(c)/delta(x) . D = diffusion coefficient, A = area of membrane, c = concentration difference, x = thickness of membrane
effects of molecule size on diffusion proportional to hydrated diameter. An 8-fold larger molecule has 2-fold greater diffusion rates. For mol. weights up to 1000, size doesn't really matter.
diffusion time diffusion time (msec) = distance^2 * 1/2. To go 1 micron takes 1.2 msec. To go 10 microns takes 50 msec. To go 100 microns takes 5 sec. To go 1 mm takes 10 min.
Gas Constant R change of energy in 1 mole of gas per change of temperature of 1 Kelvin. R = 2 calories/K*mole = 8.3 joules/K*mole
isoosmotic solution ~290 mosmol/L
osmotic pressure (P) P=R*T*delta(osmol/L) . Units of energy/volume = pressure/area.
concentration energy Energy/mole = R*T*ln(C1/C2). C = concentration on 1 or the other (2) side of the membrane.
[Na+]i vs. o 6-12 mM in, 140 mM out (1:15 ratio)
[K+]i vs. o 155 mM in, 4 mM out (35:1 ratio)
[Cl-]i vs. o 4-25 mM in, 120 mM out (1:10 ratio)
[HCO3-]i vs. o 10-20 mM in, 24 mM out
[Ca++]i vs. o (free) 0.1-10 microM in (free) vs. 1.2 mM out (1:10K ratio). pCa in = 5 to 7, pCa out = 2.9.
[Ca++]i vs. o (total) 3 mM in, 10-300 microM out. More total calcium inside the cell but more free calcium outside the cell.
converting mL/L to moles/L for gases divide by 22400 (1 mole gas takes up 22.4 L)
components of air 600 Torr N2 (79%), 160 Torr O2 (20%), 27 Torr CO2 (1%)
flux across a membrane J=Kp*A*delta(C) . J = flux, A = membrane area, delta(C) = concentration difference
high membrane permeable substances O2, CO2, NO, NH3, caffeine, ethanol, barbituates, acetate
crenation the spiky appearance of red blood cells when placed in a hypertonic solution
spherocytosis hemolytic anemia in which the ability of RBC's to withstand hypotonic solution stress is reduced
Gibbs-Donnan Equilibrium bulk negatively charged proteins attract a cation shell which is then surrounded by a water shell. Kprotein/Kbulk = Clbulk/Clprotein. In plasma, proteins behave as if they have double the predicted mosmol/L.
Oncotic Pressure osmotic pressure exerted by proteins in plasma
Concentration of protein in plasma 0.8 mM (oncotic pressure = 22 mmHg instead of the predicted 13.5 mmHg)
Hemolysis of RBCs by Nystatin Nystatin makes RBC's permeable to all small ions. K+ enters, attracted to - charged proteins. Cl- enters to maintain electroneutrality. Water follows high osmolarity -> hemolysis.
histamine and oncotic pressure histamine causes capillary endothelial cells to separate, permitting protein to enter the interstitium -> swelling
gap junctions/connexins mol. weight up to 800 can pass
porins mitochondrial/bacterial. let most small molecules through the outer membrane (not present in the inner membrane)
alternating access model binding site on one side of the transporter open first, then on the other side, alternating in availability. Occurs also in the absence of substrate.
uniporters driven by concentration gradients, work faster when substrate is present
antiporters/exchangers binding sites reorient ONLY when substrates are bound, NOT when binding sites are empty. Can generate huge concentration gradients. transporter is closed on both ends in the intermediate state.
P-type Ion Pumps ATP phosphate binds to intracellular pump. E1 = cytoplasmic binding site open, E2 = extracellular open (ion affinity for intracellular species v. low).
Order of events in Na/K pumps 3 Na+ ions bind intracellularly, ATP hydrolyzed, Na+ occluded, deoccluded extracellularly, released. 2 K+ bind, dephosphorylation, occlusion, K+ binding site deoccluded intracellularly, ATP binds, K+ released. (10 msec)
V-type Ion Pumps related to ATP synthase (mitochondria) w/reverse function. 13 subunits, V0 domain in the membrane, V1 domain in the cytoplasm, located in lysosomes/endosomes/secretory vesicles, acidify lumen w/H+, use ATP but gamma Pi is not covalently attached to pump.
plasma membrane-located V-type pumps intercalated cells of kidney (pump protons into urine, allowing HCO3- resorption), osteoclasts, macrophages, neutrophils, sperm (acidified acrosome helps penetrate egg), some tumor cells
ABC-Transporters (ATP-binding cassette transporter genes) 2 ATP binding domains & 2 TM domains. eg. CFTR, MDR (multi-drug resistance, expressed in tumors). Export toxins/lipids/sterols/ions/small mol's/drugs/proteins outside cell or into organelles. critical for cholesterol/phospholipid transport.
Bacterial ABC Transporters pump sugars, vitamins, metal ions into the cell
Order of events for ABC transporters ATP binds each cassette, conformational change = cavity opens, ligands bound to binding domain travel through the cavity. = POWER STROKE
transported by Uniporters glucose, urea, some aa's, fatty acids
transported by Symporters Na-K-Cl, K-Cl, Na-glucose, Na-aa's, Na-NT's, H-lactate
transported by Antiporters Na/H, Na/Ca, Cl/HCO3
examples of P-type pumps Na-K, Sarcoplasmic reticulum Ca pump, Plasmalemmal Ca pump, H pumps in yeast/fungi/plants
examples of ABC Cassette Pumps MDR, cholesterol & lipid pumps. (50 kinds in humans)
examples of F & V pumps ATP Synthase (F pump), Vesicular H Pump (V pump)
electrical potential (Volts) = energy(Joules)/charge(Coulombs) = charge(Coulombs)/capacitance(Farads) . V = J/C = C/F
rate of change of membrane potential change in Em over time = dEm/dt = -Im/Cm . rate is directly related to current and inversely related to membrane capacitance
Nernst Potential # ions diffusing in one direction = # diffusing in opposite direction. E = RT/FZ * ln(C-out/C-in) = 60 mV/Z * log(C-out/C-in)
specific capacitance capacitance of membrane per unit area. = 1 microF/cm^2 in all cells
diffusion potential the electrical potential difference that attracts anions and cations together
How much energy is released when an ion moves down its electrical gradient across a cell membrane? Energy/mol = z*F*Em . z = valence, F = Faraday constant, Em = membrane potential of the cell.
electrochemical potential difference delta mu = chemical energy (R*T*ln([in]/[out])) + electrical energy (=x*F*Em)
energy released by ion channels released as heat (~50% of excess energy). ATP hydrolysis creates too much energy + ion movement down gradient generates heat. ion channels generate 5-30% of total heat in the body.
membrane current = 1st derivative of membrane potential
whole-cell current Ik = Gk* (Em - Ek) . for potassium. G = impedance = inverse of resistance. driving force exists when Em-Ek does not = 0.
cytotoxic Na+ levels 15 mM (pathological b/c sodium transporters do not function effectively)
Cl- regulation in neurons vs. somatic cells somatic cells [Cl]in <35mM, neurons [Cl]in = 5mM. Neurons have NT-activated Cl channels that hyperpolarize, so must keep [Cl]i lower. Neurons have K-Cl coporters to do so.
cytoplasmic pH regulation 1. sodium/proton exchanger activated allosterically @ proton binding sites (< pH 6.8), 2. anion exchanger exports bicarbonate for imported Cl -> lowers pH when above pH 7
volume regulation: shrink a swollen cell activate Cl channels -> K follows -> water follows, or K-Cl coporters
volume regulation: swell a shrunken cell 1. activate Na-K-2Cl coporter -> water follows in, 2. activate Na/H exchangers -> H+ leaves cell -> more HCO3- made -> pH rises -> anion exchangers activated -> NaCl enters cell -> water follows
# water molecules/ions entering a cell 187 water molecules follow each ion
extracellular free Ca++ regulation by kidneys, = 1.3 mM
intracellular Ca++ regulation 1. ATP-driven Ca++ pump, 2. Na/Ca exchanger (small increases in cytoplasmic Na increase intracellular Ca immensely)
CFTR chloride channel, 12 TMD's, 2 NBD's, cytoplasmic regulatory R domain. ABC-like structure. mutation in NBD prevents proper folding & export from Golgi. Only P'ated channels can open (P'ated by cAMP-dpdt kinase)
tight junctions water, cations can pass (usually. sometimes only anions can pass)
Sweat generation Na/K pump on basolateral side generates driving force. Na-K-2Cl coporter brings in Cl. K leaves (basal) via channel & Na pumped out (basal). Cl leaves @ apical side channels. Na enters lumen from interstitia (via tight jxn's). water follows (aquaporins).
Sweat salt resorption K enters @ basolateral Na/K pump, K cycles out via channels. Cell negatively charged = Na enters @ apical side, migrates to basal side = negative charge @ lumen side -> Cl enters cell & migrates to basal side. (CFTR important in both membranes)
CFTR & diarrhea bacterial toxins cause diarrhea by activating adenylate cyclase -> cAMP ->phosphorylation of apical CFTR -> activation & Cl export = Na follows = water follows -> diarrhea
pancreas & CFTR Na/K pump basolateral, K leaves through channel, carbonic anhydrase converts CO2 & H2O to HCO3- & H+, H+ -> lumen via Na/H exchanger, bicarbonate exchanged for Cl. CFTR in apical membrane sends Cl back to lumen (- potential), Na follows via tight jxn's.
airways & CFTR CFTR functions as Cl channel + some other fxn (e.g. regulates Na channels
glucose absorption in GI tract Na/K pump in basal membrane, K cycles back through K channels, Na coported w/glucose thorugh apical membrane, glucose exits @ basal membrane via channels.
channel gating vs. permeation gating = what opens channel (Em, extracellular/cytoplasmic ligands, metabolites), permeation = which ions can pass (physical properties of channel + driving force). All modulation of channels by cell signaling alters open probability [gating])
conductance change of current per change in Em (Siemens = reciprocal of Ohms)
Nernst vs. Reversal potential Nernst = physiological fact for a specific ion. Reversal = measured potential @ which net current = 0 (flow in == out). Nernst = Reversal ONLY if channel perfectly selective for a particular ion (K channels closest).
reversal potential of nonselective cation channels -20 mV
patch clamp 0.2- 1.0 micron diameter pipette, 1 channel isolated, currents of 0.1 to several pA (6 million charges/sec)
reversal potentials (each channel) K -90, Na +60, Cl -80 to -30 (varies with [Cl]in), Ca +90, nonspecific cation -20
channel selectivity K & Cl completely selective, Na channels have 10% K, v-gated Ca channels have some K
structure of K inward rectifiers 2 TM subunit, homotetramer, P-loop from extracellular to mid-membrane forms pore. poor conductance @ depolarized potentials, but don't close. K-ATP/K-ACh/IRK/ROMK
structure of v-gated K channels 6 TM domains (2 are similar to inward rectifiers -> form pore, other 4 = for voltage sensor), S4 domain = voltage sensor -> physically moves in response to change in voltage
structure of v-gated Na & Ca channels monomer, 4 repeats similar to 4 K subunits,
ENAC channel structure ="Epithelial Na Channels", heterotetramer, each subunit has 2 TM domains w/large extracellular domain
Cl channel structure "CLC family" (does NOT include CFTR), monomer, 2 sets of 6 homologous TM domains, each 6-subunit domain forms an independently-active pore (in between = regulatory domain)
ionotropic channels 4-5 subunits, heterooligomers, bind multiple NT molecules to open (e.g. glu & ACh or GABA), desensitize, excitatory channels are nonspecific cation, inhibitory are Cl channels
selectivity filter in ionotropic channel ions shed associated water, carbonyl groups of protein bind ions lightly,
requirements for voltage-gating 1. selectivity filter (extracellular side), 2. open & close, 3. modulation by sensor, 4. localized to particular cell regions (do not diffuse in membrane)
KATP channels control secretion of insulin from beta cells. low glucose->low ATP ->KATP channels open->decreases Ca AP frequency = prevents Ca activation of insulin release.
electrical time constant Tau time to get to 66% of steady state. Tau = C/G (capacitance/conductance)
major factors limiting speed of electrical responses of long cell processes compared with a wire 1. far larger numbers of ions must cross in cell vs. wire, 2. cytoplasm is far less conductive, 3. membrane conductance is much higher than the cytoplasm conductance
space/length constant distance @ which charge decreases by 66% along a dendrite (higher value when the membrane resistance is higher = fewer K channels open, OR when the cytoplasmic resistance is lower = wider diameter). = sqrt(Rm/Ra)
r(m) vs. r(a) r(m) = axon membrane resistance (ohm*cm), r(a) = longitudinal resistance of axon cytoplasm (ohm/cm)
Total membrane resistance Rm Rm = r(m) * length/Area = Ohms
ROMK channel K+ inward rectifier, activated by low ATP, controls insulin release in kidney. "Renal Outer Medullary Potassium channel"
K(ACh) channel inward rectifier, activated by ACh, control heart rate & neuronal activity
TRP channels transient receptor potential channels. nonselective cation channels permeable to enough Ca to permit Ca signaling
Time of Action Potential neuron = up to 120 m/sec (2 m/sec when unmyelinated), skeletal muscles = 2-10 msec or longer for slower contraction, cardiac = 250 msec long.
channel kinetics Na channels: instantaneous open/deactivate, inactivation (esp. if held at +20mV for a long time). K channels: 1-4 msec open/deactivate, no inactivation.
refractory period Na channels inactivated + K channels still open. Limits rate of firing.
Accommodation Na channels inactivate at an Em just slightly depolarized, so that it is more difficult to fire
Pacemaker neurons nonspecific cation channels responsible for after-hyperpolarization & repetitive firing. More channels = increased firing frequency.
Generator potential nonspecific cation channels in sensory neurons open -> few action potentials. usually followed by accommodation.
KATP channel structure inward rectifier. homotetramer + 4 CFTR-like (ABC Cassette) SUR (sulfonylurea) subunits. NBS's on K channel & SUR's. ADP activates/ATP deactivates.
high length constant = few channels can change membrane potential over long distances + conduction velocity is high
motor unit single alpha motor neuron + all muscle fibers it innervates (alpha motor neurons innervate 20-100 fibers)
terminal motor nerve branches unmyelinated, Na & K channels for AP, V-gated Ca channels for ACh release
Botulinum Toxin injestion of toxin-> transport to axon terminals, endocytosed, protease eliminates ACh exocytosis machinery. in CNS, blocks inhibitory NT's -> muscle rigidity. death from suffocation.
Motorneuron Synaptic Cleft 50 nm wide, 50-300 vesicles fuse, 10,000 ACh molecules released (more than sufficient for receptor stimulation b/c of AChEsterase), fast diffusion. endplate basement membrane has collagen & anchoring laminins. end plate potential (EPP) due to Na.
AChR general anchored to dystrophin @ top of secondary synaptic fold. Muscle nuclei near endplate make more AChR mRNA due to neuronal cytokine. short half-life (esp. when cross-linked by Ab's). 2 ACh bind 2 alpha subunits to open. nonselective cation, but mostly Na.
AChR structure homopentamer, 4 TM domains, large peripheral pores (3 nm) narrowing @ center to 0.6 nm diameter (double the narrowest part of Na or K channel)
Myasthenia gravis pathophysiology Ab's to AChR inhibit neuromuscular transmission. weakness 1st in eyes, then oropharynx. active stage = years of severe effects, inactive state = fluctuations in symptoms, 15-20 years = fixed muscle atrophy.
Myasthenia gravis treatment AChE inhibitors = difficult to titer, & side effects due to smooth muscle & glands. Immunosuppressants work after 4-8 months, must continue on drugs forever. plasma exchange helps immediately, but lasts short-term. Good before surgery & intermittently.
Duchenne Muscular Dystrophy Xp21, recessive, Dystrophin (usually binds actin & sarcolemma glycoproteins that bind laminin -> prevents membrane rupture during contraction). progressive loss of skeletal muscle fibers.
myofibril organelle attaches to cell membrane, thick (myosin & titin) & thin (actin & nebulin) filaments
T-tubules in striated muscle "transverse tubules", contain L-type Ca channels, arranged in triad @ junction of A & I bands (t-tubule + 2 terminal cisternae),
striated muscle contraction nAChR (ionotropic) -> depolarization -> dihydropyridine receptor (L-type Ca) opens, mechanically linked to ryanodine receptor in SR that releases Ca. Ca binds troponin -> contraction. Ca resequestered by ATPase (terminates contraction).
Structure of Dihydropyridine Receptor (N-type Ca Channel) homotetramer (each w/6 TM domains & 1 P-loop). in striated muscle acts as voltage sensor. in heart & smooth muscle acts as C channel.
Striated Muscle Contraction Physio 1 troponin (binds Ca) per tropomyosin (blocks actin) in thin filaments, ATPase activity precedes muscle force, [Ca] goes from 0.1 to 10 micromolar, troponin reveals actin binding site for myosin.
Troponin Structure (3 subunits) TnC subunit binds Ca, pulls TnI subunit from actin site -> tropomyosin moves into groove, revealing myosin binding site
Myosin ATPase activity ATP binds -> myosin releases actin, ATP hydrolyzed -> myosin head cocks, myosin binds actin, Pi released -> power stroke, ADP released. (myosin dissociation of ADP & Pi much faster in presence of actin)
malignant hyperthermia succinylcholine + volatile anaesthetics, prolong ryanodine R opening, mutation -> muscle rigidity, hypermetabolism, high O2 usage & CO2 production (hypercarbia), hyperthermia, rhabdomyolysis. trtmt= dantrolene (blocks RyanodineR)
types of muscle contractions isometric = fixed muscle length (force proportional to myosin binding to actin), concentric = muscle shortening, eccentric = muscle lengthening, isotonic = tension remains same even though muscle length changes
stretch-induced muscle damage eccentric contraction = stretch TRP channel lets in Ca -> calpain activated -> SR damage, increases P-lipase activity-> cell leaks creatine kinase, mitochondria uptake Ca -> increased ROS's & peroxides, decreased Ca sensitivity, decreased force & tetanus
ATP recycling in muscle contraction creatine phosphate phosphorylates ADP. CrP comes from glucose and fatty acids (generates lactic acid). O2 consumption remains high during recovery to restore cell homeostasis. fatigue = Pi & lactic acid buildup
energy for muscle contraction: high to low PCr (only in striated muscle), ATP, Anaerobic Glycolysis, Carbohydrate Oxidation, Fat Oxidation
types of muscle fibers FG (fast glycolytic/Type IIb) = white, SO (slow oxidative/Type I) = red (myoglobin), FOG (fast oxidative glycolytic/ Type IIa) = lots of mitochnodria & lots of glycogen. all use some oxidation/glycolysis.
characteristics of SO motor units high resistance to fatigue, efficient ATP production, modest tension, slow velocity of contraction. Very small. Antigravity/postural muscles.
characteristics of FG motor units rapid & powerful contractions for short periods of time. Lots of myosin. Rapidly contracting, superficial muscles.
muscle force development SO, FOG, then FG fibers recruited, small distal muscles increase firing rate for large force, large proximal muscles recruit additional motor units
McArdle's Syndrome pain, stiffness, & weakness after brief intense activity. accumulated glycogen in muscle. myophosphorylase deficiency. 2nd wind due to fatty acid & hepatic glucose mobilization. rhabdomyolysis -> myoglobinuria. avoid anaerobic exercise, ingest sucrose.
glycogen supercompensation low carb diet, vigorous exercise, high carbs. only in muscles that were trained. on low carb diet, glycogen decreases then rebounds to double [].
resting muscle ATP binds quickly, but is very slowly hydrolyzed
cardiac muscle striated, but not attached to bone. Cannot be overstretched because of fibrous fascia support
maximum muscle force equivalent to the gravitational pull of the weight. faster velocity of contraction for smaller oppositional weights. single isometric twitch force (less than tetanic force).
maximal velocity of contraction dependent on different forms of myosin. stretch during muscle contraction generates extra force. when it happens quickly, myosin heads caught attached -> extra force for a short period of time
striated muscle banding A band = M line + H band + thick filaments, I band = Z disc + thin filaments
muscle fatigue low pCr, glycogen, glucose. high lactate, H. Inflammation & serum creatine kinase high for 5-6 days. satellite cells differentiate into myoblasts & myotubes to replace damaged fibers.
denervation nerve terminals degenerate, nuclei centralize in muscle fiber, loss of sarcoplasm leading to necrosis w/ adipocyte invasion & scar tissue formation. Group atrophy when no healthy axons.
renervation axonal growth cone connects with previous endplates. initially inactive synapse becomes functional with fxnl differentiation of muscle fiber. collateral sprouting in neurodegen disease.
muscle wasting large muscles waste faster. selective loss in muscles w/abundance of one fiber type. Wasting greatest for leg antigravity muscles, least for hand muscles. Decreased myofibrillar protein & glycolytic/oxidative enzymes.
strength training neural adaptation accounts for immediate muscle hypertrophy (mostly fast-twitch) & muscle enlargement occurs over the longterm. FOG fibers increase specificially in intense body building.
endurance training more and larger mitochondria, more capillaries, high glycogen & glycolytic enzymes, little/no hypertrophy.
energy for ATP regeneration in different exercise regimes CrP for low duration & impact. Glycolysis for moderate duration & impact. O2 for high duration & impact.
eccentric contraction muscle damage sarcolemmal, contracile protein, cytoskeletal, & extracellular matrix damage. Excessive Ca activating protease, calpain & P-lipase. Fatty acid free radicals. Neutrophil, macrophage.
aging & muscles FG motor units shrink & SO fibers grow larger. motor neurons degrade + limited sprouting = fewer motor units.
structural protein skeletal muscle disease Duchenne/Becker (Dystrophin), Limb Girdle (Sarcoglycans), or Severe Congenital (Merosin) muscular dystrophies
excitation-contraction coupling skeletal muscle disease Myasthenia Gravis (AChR), Malignant Hyperthermia (Ryanodine R)
Metabolic skeletal muscle disease McArdle's (Phosphorylase), Tarui's (PFK), Carnitine Palmitoyltransferase deficiency
subdivisions of the enteric autonomic system myenteric = food motility. Submucosal plexus = secretions. Both are motor & sensory.
celiac ganglion inhibits gastric, duodenal & gallbladder digestion, stimulates liver glucose release
aorticorenal ganglion stimulates suprarenal gland epinephrine release
superior mesenteric ganglion vasoconstrits intestinal & rectal vessels
inferior mesenteric ganglion vasoconstriction in intestines, ejaculation, constricts urinary sphincter (pelvic plexus), stimulates orgasm
superior cervical ganglion dilates puil, elevates eyelid, stimulates salivation
paravertebral thoracolumbar ganglia accelerate heartrate, relax airways, piloerection, sweaty palms
beta 1 receptor mediation HEART: SA node & ventricles (increase heart rate & contractility), adipocytes (lipolysis). Epi & NorEpi activate.
beta 2 receptor mediation skeletal muscle (vasodilation), bronchi (dilation), GI (decreased motility), detruser (relaxation), skeletal muscle & liver (glycogenolysis), adipocytes (glycogenolysis)
alpha adrenergic receptor mediation skeletal muscle (vasoconstriction), iris radial muscle (contraction), skin & mucosa (vasoconstriction), lung/tummy/intestine (decreased secretions), ejaculation, hair cell piloerection, sweaty palms, liver glycogenolysis
muscarinic channel subtypes coupled to Gq M1,3,5. activate PLC -> PIP2 cleaved to form IP3 -> Ca release. DAG also formed -> PKC activation.
muscarinic channel subtypes coupled to Gi M2, M4. inhibit adenylyl cyclase
nAChR structure 4 TM domains, heteropentamer: 2 alpha, beta, delta, gamma. ACh binds alpha subunit
mAChR structure 7 TM domains. ACh binds = G protein associates -> G-alpha hydrolyzes ATP -> G protein leaves receptor -> G-alpha separates from beta/gamma ->G-alpha(q) activates PLC or G-alpha(i) inhibits adenylyl cyclase
alpha & beta adrenergic receptor G-protein coupling alpha 1/3/5 adrenergic receptor = Gq coupled (activates PLC). beta 1 & 2 receptors = Gs coupled (activated adenylyl cyclase).
pupillary dilation vis-a-vis autonomic control strong light stimulates mAChR -> circular iris muscle contracts -> pupil constriction. weak lights stimulates NE release for alpha1 receptors -> radial muscle contracts -> pupil dilation. No reciprocal inhibition.
alpha & beta adrenergic receptor response to Epi vs. NorEpi Alpha = slightly more sensitive to Epi. Beta1 = equal sensitivity to both. Beta2 = >>> sensitivity to Epi.
skeletal muscle response to sympathetic stimulation beta2 receptors respond to v. low levels of Epi -> vasodilation. Higher levels of Epi + NorEpi activate alpha receptors -> vasoconstriction. Alpha Dominant!
average cardiac stats (70 kg woman) 5 L/minute cardiac output. 5 L blood volume. 60 bpm heart rate. 80 ml stroke volume. exercise -> 200 bpm HR & CO 20 L/min. (for man, increase amounts by 10%)
cardiac output equation CO = SV x HR [remember: work = force x distance = volume x pressure]
blood voume percentages 85% systemic/10% pulumonary. 80% low pressure/15% high pressure. 65% systemic venous/20% systemic arterial. 5% in heart, 10% in lungs at all times.
relationship b/tw pressure, velocity & cross sectional area slowest velocities @ highest cross sectional areas (summed). Highest pressures at lowest cross sectional area (not summed).
Windkessel heart analogy systole SV -> some forward flow of blood, but much energy stored in elastic large arteries. Systolic elastic recoil of large arteries maintains capillary flow.
aging and CV function arteries & the heart become stiff -> increased speed of arterial pressure waves -> decreased contribution of elastic recoil in diastole
LaPlace's Law Wall Stress = [Pressure*Radius/2*WallThickness] (w = wall thickness). Note that wall stress is the same in the left vs. right ventricle even though left ventricle generates 4x the pressure -- it also has 4x the wall thickness.
Why is ventricular contraction better described as auxotonic instead of isotonic? isotonic = contraction against a constant load. But the backpressure from the aorta increases load during ventricular contraction. auxotonic describes contraction against a spring, which is a better metaphor.
limitations of peak isovolumetric pressures must be higher than pressure needed to open the aortic valve
Cardiac Work equation CW = CO x MAP
Cardiac Energy Consumption Equation CEC = CW + Other Energy Expenditures = ~ Cardiac Oxygen Consumption
Cardiac Efficiency Equation CE = CW/CEC = ~25-35%
main determinants of cardiac oxygen consumption heart contractility, heart rate, wall stress
dog heart-lung prep ventricular volume is controlled, vessels to heart are cannulated
isolated perfused heart vessels cannulated. measure/control venous & arterial pressure
isolated superfused muscle thin strips of papillary/cardiac muscle mounted in an oxygenated bath. contraction frequency controlled by electrical stimulation is muscle undergoes nonspontaneous contraction.
cardiac myocyte "cell-attached" patch clamp digest extracellular matrix of heart w/preoteases. control cytoplasm via pipette. study ion channels & transporters.
gap junction uncoupling occurs when hemichannels not fused, acidic cytoplasm, or overly high [Ca]
refractory period of cardiomyocytes plateau of action potential (absolute refractory period) + relative refractory period (huge shock can cause partial action potentials). RyR inactivates every cycle 1-2 sec (not V-gated ion channels).
modulating the magnitude of cardiomyocyte contraction small delta [Ca] has large effect on contractility. Dihydropiridines block Ca influx -> decreased contractility. Ouabain increases Ca transients -> increased contractility. No effect on skeletal muscle @ dose (decreased sensitivity).
Ca regulation in ventricular cardiomyocytes gap junctions -> K+ influx & depolarization. V-gated Na Channels open. L-type Ca Channels open. Ryanodine R opens in response to high [Ca] -> contraction. repolarization by Na/Ca exchanger.
contribution of V-gated Ca channels to Ca needed for contraction 10-25% (also = % Ca extruded by Na/Ca exchanger)
cardiac Na/Ca exchanger 3 Na for 1 Ca. Brings Ca in at beginning of AP (driven by membrane polarization). Brings Ca out during AP (driven by concentration difference). cytoplasmic Na competes w/Ca, so small increases of cytoplasmic [Na] cause large decrease in [Ca] expulsion.
mechanism of heart glycosides ouabain/strophantidin = steroids inhibit small % of Na/K pumps -> decreased Na gradient slows Na/Ca exchanger -> Ca builds up in cytoplasm to 12 mM. [Na] > 15 mM can = Contracture (failure to relax) & myocyte death. e.g. foxglove.
cardiac ischemia & ion gradients lactic acid builds up inside cardiomyocytes -> Na/H pump activated. Na builds up in cells = can now only move Ca into cell. 'Overload' -> Contracture.
mitochondrial Ca sensitivity in cardiomyocytes 10% of cytoplasmic Ca is taken up by mitochondria (Ca uniporter) & released between heart beats (Ca/Na exchanger). Mt Ca stimulates oxidative phosphorylation.
L-type vs. N-type Ca Channels N-type in skeletal muscle. L-type (open a Long time) in cardiac & smooth muscle.
Mechanism of dihydropyridines inhibit L-type Ca channels specifically. e.g. Nifedipine. concentrations needed to affect heart (negative inotropic effect) = 10x higher than concentrations needed to relax arterial smooth muscle.
inotropic/chronotropic/dromotropic/contractility ino = alters strength of muscle contraction, chrono = alters heart rate, dromo = alters conduction rate. contractility = ability of heart to contract independent of pre/afterload.
Mechanism of ryanodine insecticide from bark of exotic trees. skeletal muscle goes into contracture, but not cardiomyocytes (Na/Ca exchanger works harder to extrude Ca from SR). negative inotropic agent.
stiffness of cardiomyocytes rises steeply past stretched lengths of 2.2 microns/sarcomere. Titan protein linked to Z-bands run entire length of sarcomere between filaments.
Frank-Starling Mechanism with greater preload, the left ventricle end-systolic volume is the same, and peak pressures are somewhat increased.
mechanism of cardiac stretch-contractility relationship stretched cardiomyocyte filaments become more compressed with respect to each other = easier crossbridge formation & Ca binding to Troponin C.
Anrepp Effect Preload OR Afterload increase -> stretch receptors activate (takes 20-60 sec to activate) -> Na & Ca enter cardiomyocytes -> 10-20% increase in Ca transient.
large delayed beat conduction to ventricles occasionally fails. next beat = stronger due to: reserve SR Ca released due to RyR reactivation (extra beat caused by ectopic source of AP)
frequency inotropy when several rapid heart beats occur in sequence, subsequent contractions strongly enhanced b/c Ca entering cytoplasm now 'overload's the SR.
Treppe / Bowditch Staircase myocardial contraction strength increases when frequency of stimulation increases. Due to cytoplasmic Na buildup causing decreased Ca extrusion -> Ca buildup in cell
effects of Increased Preload on pressure-volume curve heart contracts more strongly (Frank-Starling). Same End-Systolic Volume. Slightly higher pressures required for mitral valve closing = shift of isovolumetric ejection phase to the right).
effects of Increased Afterload on pressure-volume curve shift of systolic ejection phase upward (more pressure required before aortic valve opens). Less blood is ejected.
effects of Contractility Increase on pressure-volume curve. = 'vigor' of blood ejection (max. systolic pressure). decreased ESV for positive inotropes, increased ESV for negative inotropes.
rate of change of membrane potential directly related to the total membrane current
pacemaker atrial myocytes -65 mV resting potential, slow AP upstroke. SA node faster than AV. no v-gated Na or leak K channels. V-gated Ca Channels, delayed V-gated K channels, If channels.
working atrial myocytes fast AP upstroke, duration (from upstroke to 80% repolarization) = 100 msec.
cardiomyocyte repolarization cardiomyocytes located on outer wall of heart repolarize faster than cells located on inner wall of heat.
ventricular action potentials 200 msec = 2x 'working' atrial myocytes. v-gated Na channels = fast, inactivate @ plateau, reset @ repolarization. 'delayed' v-gated K channels = slow to open (>100 msec) & close. inward rectifier K stabilize V(rest) (open @ - potentials, close during AP)
Purkinje fiber AP repolarizes quickly to 0 mV, plateaus at 0, then repolarizes to -85 mV.
Phases of the cardiac AP 0. depolarization, 1. brief repolarization, 2. plateau, 3. repolarization, 4. inter-AP interval
AP velocities in different heart cells nodes = 0.05 m/sec, cardiomyocytes = 0.3 m/sec, inter-nodal tracts = 1 m/sec, His-Purkinje cell = 3-5 m/sec
ECG magnitude usually of 1 mV or less. P = atrial depolarization. Q = upper ventricular septum, R = ventricles, S = base of left ventricle, ST segment = uniform depolarization, T = ventricular repolarization. atrial repolarization hidden by QRS.
why are both P and Q wave positive deviations when one is de- and the other re-polarization? The direction of the depolarization is opposite to that of the repolarization.
PR interval and QT interval PR should be < 200 msec or else conduction problem b/tw atria & ventricles. QT = time b/tw ventricle AP & end of ventricular repolarization.
Triangle of Einthoven Lead I (0 degrees) left->right arm. Lead 2 left leg -> right arm. Lead 3 left leg -> left arm. P & T largest in Leads 1 & 2.
augmented limb leads unipolar recording w/single positive lead compared against the sum of the other electrodes (-). Gives greater deflections. aVR, aVL, aVF (a for augmented, right/left/foot)
Precordial leads for EKG V1 right side of sternum, V2 on sternum, V6 axillary line
cardiac cell metabolic stress Ca/Na exchanger activated -> slight inward current -> Ca overload -> Ca-dpdt Ca release. Occurs as 'after-depolarization' (after AP) & can lead to another AP.
Phase I repolarization Ventricular Myocytes & Purkinje cells (due to fast inactivating v-gated K channels)
K-Inward Rectifier (cardiac) in all cardiac cells except the nodes. when blocked by barium, all cardiomyocytes become pacemakers (i.e. all cells have If Ch.)
K-ATP channels most abundant. open during ischemia (low ATP) -> raises K-Nernst & Vrest -> prolonged depolarization -> 'injury current' across heart (when localized region of ischemia). ST elevation.
ACh-activated K channels ONLY IN ATRIA cardiomyocytes. Activated by ACh (vagus nerve). Parasympathetic modulation of heart rate.
pacemaker definitions true = normally generates heart beat. latent = pacemaker capability, located outside SA node (e.g. in AV & Purkinje). ectopic = spontaneous AP generation by other cell (usually due to Na/Ca exchanger)
cardiac AP depolarization (V-gated Na) propagates to t-tubules (near Z-lines). V-gated Ca Ch's + Na/Ca exchanger activated. RyR open & release Ca. Ca sequeseterd in SR & by Na/Ca exchanger & a little by Ca pumps.
phospholambin inhibits SR Ca pumps only when it is phosphorylated by cAMP-dpdt protein kinase.
autonomic control of heart rate vagal ACh innervation primarily to atria. sympathetic innervation (NorEpi) = all over heart.
sympathetic (NorEpi) molecular FX NorEpi @ beta1R: Gs ->adenylyl cyclase makes cAMP-> activates PKA-> 1. P-Ca Ch. increased prob. open. 2. P-lamban -> SR loaded w/extra Ca + faster recovery. 3. P-delayed K Ch's increased prob. open (faster repolarization). requires high ATP.
sympathetic physiological FX increased heart rate, contractility, conduction rate (in pacemakers). Higher plateau potential & longer AP's. decreased recovery time.
cardiac alpha receptors involved in cardiomyocyte growth in the long-term
ouabain physiology less energetically expensive than catecholamines + slows heart rate due to vagal reflex in response to increased cardiac output.
ACh molecular FX (innervation to ventricles is very slight) ACh binds mAChR's -> beta/gamma G-protein subunit binds & activates GIRK channel in atria -> hyperpolarized Vrest = decreased heartrate. Atrial contraction strength decreases (shorter AP's).
FX of metabolic state on cardiac contraction 1. low pH -> lower contractile protein sensitivity to Ca, 2. high K currents (leak), 3. downregulated Ca Ch's, 4. low pH + low ATP -> adenosine released extracellularly -> activates GIRK Ch's on other cells & dilates coronary arteries
effects of cAMP in cardiac nodal cells increases Ca open prob., increases If open prob., more Ca enters cells => Na/Ca exchanger generates inward current. ACh can reverse all FX by blocking adenylyl cyclase (even when administered to ventricles).
effects of ACh in 'working atrium' GIRK Ch. activation -> hyperpolarized Vrest -> shorter AP's & less Ca influx (Ca Ch's close immediately upon repolarization).
Carbachol mimics ACh, not broken down by AChEsterases
ventricular phases of heart contraction 1: filling 2ndary to atrial contraction (ventricle 75% full of blood from previous phases of diastole), 2: isovolumic conctraction, 3: rapid ejection, 4: slow ejection, 5: isovolumic relaxation, 6: rapid filling, 7: slow filling
stroke work done by the left atrium & ventricle in P-V curve, work done by atrium = under LV filling line. Work done by ventricle = inside loop!
stroke power =stroke work/ejection time
pressure gradient across a cardiac valve (stenosis) pressure gradient = 4v^2
methods for measuring heart chamber volume 1. 2D echocardiography, 2. contrast ventriculography, 3. conductance catheter (impedance inversely proportional to volume), 4. multi-gated image acquisition (radioactive tracer in circulation), 5. MRI
measuring CO (Fick's principle) CO = O2 uptake @ lungs/(arterial O2-Venous O2).
indicator-dilution method of determining CO volume of liquid in beaker = amount dye added/([dye]* (t2-t1)). t2 = time disappearance from tube, t1 = time appearance in tube.
measuring stroke volume 1. Electromagnetic Flowmeter, 2. Doppler Method, 3. WD Echo, 4. multi-gated image acquisition (radioactive tracer in circulation)
causes of pathological increases in CO Beriberi (thiamin deficiency), AV shunt, Hyperthyroidism, Anemia, Anciety, Pregnancy (from highest to lowest)
CO related to oxygen consumption directly related. delta-CO:delta-O2-consumption = 5:1
CO related to end-diastolic volume & venous return directly related to EDV, inversely related to venous return
vascular function curve: delta mean systemic pressure higher mean systemic pressure (from more blood volume/less venous compliance) shifts curve to the left (lower shifts to the right). CHANGES ONLY VENOUS RETURN CURVE.
vascular fxn curve: delta arteriolar resistance decreased TPR (total peripheral resistance) -> clockwise rotation of venous return curve about msfp point (mean systemic filling pressure). counterclockwise rotation of CO curve around 0 point. CHANGES BOTH CURVES, NOT RIGHT ATRIAL P @ equilibrium point.
digitalis FX on vascular fxn curve positive inotropic effect. rotation of CO curve counterclockwise. No FX on venous return curve.
msfp point mean systemic filling pressure point. @ X intercept of venous return curve.
splitting of the 1st heart sound due to either (1) mitral & triscupid sounds, or (2) when left ventrical isovolumic contraction markedly prolonged (when strength:load ratio decreased due to left heart failure).
splitting of the 2nd heart sound closing of each semilunar valve. physiological splitting = during inspiration. more blood enters right atrium & goes to lungs, but less blood leaves lungs = right ventricle takes more time, left ventricle lates less time.
FIXED splitting of the 2nd heart sound due to atrial or ventricular septal defect ejecting blood from left to right
PARADOXICAL or REVERSED splitting of the 2nd heart sound due to (1) left bundle branch block (right ventricle activated first), (2) depressed left ventricle w/ prolonged isovolumic contraction & ejection
3d heart sound when ventricular pressure drops precipitously below atrial pressure. sound = sudden rush of blood & low frequency vibration due to relaxed ventricular walls
diastolic murmur caused by (1) stenotic AV valves (constant), (2) aortic/pulmonary insufficiency (decrescendo). bt/w S2 & S1
systolic murmur caused by (1) stenotic semilunar valve (diamond-shaped, begins w/onset of ejection, doesn't overlap w/heart sounds), or (2) AV insufficiency = regurgitation (constant/pansystolic=holosystolic)
Grades of heart murmur 1. v. faint, 2. faint, 3. moderately loud, 4. very loud, 5. extremely loud w/ only edge of stethoscope on chest, 6. extremely loud w/ stethoscope off chest
Continuous murmurs always present, may shift in intensity. caused by patent ductus arteriosus
ECG procedural 1 mV usually = 10 mm tall, speed = 1 mm/0.04 sec
EKG signs of heart block 1st degree: long PR interval. 2nd degree: long (type I) or normal (type 2) PR interval plus occasional lack of R. 3d degree: P not at all in sync w/R
EKG signs of bundle branch blocks Right bundle: wide QRS w/exaggerated Q-R. Left bundle: wide QRS w/elevated QR.
EKG signs of Delta Wave (Wolff-Parkinson-White Syndrome) Shortened PR interval
EKG signs of atrial/ventricular fibrillation atrial = Irregular R-R interval. Ventricular = scribble appearance (fibrillation) & tachycardia (exaggerated sine wave)
Classes of arrhythmias 1. Abnormal impulse Propagation (reentry/block) OR Generation (node/, 2. Narrow OR Wide complex (= originates above/below Bundle of His), 3. Regular OR Irregular
3 examples of abnormal impulse generation arrhythmias (can lead to triggered activity) (1) premature ventricular contractions, (2) premature atrial contractions, (3) multifocal atrial tachycardia, (4) Delayed or Early after-depolarizations
3 examples of irregular EKG arrhythmias atrial fibrillation, multifocal atrial tachycardia, premature atrial contractions
rate of spontaneous depolarization of pacemakers in the heart SA 60-80 bpm, AV 40 bpm, ventricular muscle 30 bpm
Conditions for reentry (1) barrier to normal conduction establishes a new circuit, (2) Unidirectional Block (different refractory period) must be present somewhere in the circuit, (3) slow enough conduction speeds to permit recurring impulse to enact contraction again.
Drug therapy goals for reentry trtmt (1) slow conduction (removes unidirectional block), (2) prolong refractory period (prolongs AP)
ischemia vs. infarction ischemia = insufficiency of oxygen & cells damaged (ST depression). Infarction = lack of oxygen & cells die (ST elevation).
types of heart failure (4 stages based on risk/structural disease/symptoms) (1) SYSTOLIC DYSFUNCTION (e.g. abnormally weak contraction), (2) DIASTOLIC DYSFUNCTION (e.g. "stiff ventricle")
PCWP vs. LVEDP Pulmonary Capillary Wedge Pressure catheter in pulmonary vein (in diastole == pressure in LA & LV). Left Ventricular End Diastolic Pressure = pressure measured directly from the left ventricle @ end-diastole.
estimating Afterload aortic pressure or systemic vascular resistance (SVR)
measuring contractility change in pressure / time
factors causing low CO (1) low preload, (2) high afterload, (3) impaired contractility, (4) low HR
FX of renin-antiotensin-aldosterone Na retention + peripheral vasoconstriction. High Na increases blood volume hence preload (can lead to congestivity). Vasoconstriction increases afterload (adds to ventricular wall stress & cardiac O2 consumption). Increased HR requires more O2.
causes of pulmonary oedema LVEDP (filling pressure) past 25 mmHg exceeds pulmonary capillary oncotic presure
Left Ventricular Hypertrophy temporarily relieves Left ventricular wall stress but increases risk of heart failure & ventricular arrhythmia
signs of right heart failure elevated jugular venous pulsations, edema, ascites (= peritoneal oedema), hepatomegaly
signs of left-sided heart failure rales (clicking/rattling/crackling of lungs), orthopnea (shortness of breath while lying prone), paroxysmal noctural dyspnea (shortness of breath), dyspnea on exertion
low CO leads to... fatigue, exercise intolerance, azotemia (high urea due to low clearance), altered mental status
phasic smooth muscles coupled w/gap junctions = single-unit groups. e.g. GI tract/uterus/ureter/bladder. spontaneous myogenic contraction, AP's, gap jxn's, slow phasic contraction.
tonic smooth muscles uncoupled, multi-unit groups -- neural regulation key to coordination. arrector pili/ciliary muscle/iris/vas deferens/large arteries. neurogenic graded depolarizations w/no gap jxn's. Slow sustained contractions.
smooth muscle sarcolemma Na/K pump, Ca/H ATPase pump, V-gated Ca, V-gated K, extracellular Ca activates contraction. NO T-tubules/V-gated Na channels. IP3 release SR Ca = contraction. cAMP = relaxation.
smooth muscle SR lower Ca capacity than heart/skeletal muscle, located close to sarcolemma.
smooth muscle organization higher actin/tropomyosin: myosin ratio than other muscle. no organized sarcomeres. actin linked to cytoplasmic dense bodies (analogous to Z bands).
types of smooth muscle x electrochemical mechanism (1) Ca action potential (slow), (2) pacemaker depolarizations & Ca AP's, (3) graded changes in membrane potentials in response to NT's/hormones [due to e.g. PKC inhibition of K Ch's causing depoloarization]
smooth muscle change in [Ca]i with no change in Em IP3 binds receptor in SR & then rapidly degraded -> SR Ca release
types of smooth-muscle AP's spike, plateau, slow waves
slow wave smooth muscle AP mechanism Ca-dpdt K channels close when low Ca -> depolarization -> V-gated Ca Ch's open -> 1 or several Ca AP's -> Ca-dpdt K Ch's open
smooth muscle actomyosin contractions ATPase activity & contraction stimulated by: Ca/Calmodulin binding to myosin light chain kinase, which then autophosphorylates -> change in conformation -> myosin head can bind actin. terminated by light chain phosphatase (MLCP).
mAChR 1,3,5 activation on smooth muscle INCREASED MLCK ACTIVATION. Gq -> PKC P'ates CPI-17 which inhibits PP1c "catalytic" subunit of MLCP. Gq also -> Rho Kinase activation -> RhoK P'ates & inhibits "myosin protein targeting" subunit (MYPT1) of MLCP.
NO & smooth muscle NOS makes NO (calmodulin-dpdt). NO diffuses to smooth muscle & activates guanylyl cyclase -> cGMP. cGMP activates kinases whose activity decreases cytoplasmic [Ca] in contracting smooth muscle -> decreased MLCK activity & myosin light chain is de P'ated
sustained NorEpi during tonic smooth muscle contraction alpha adrenergic R activation -> decreased [Ca] & decreased myosin P'ation. [ADP] increases, which inhibits myosin crossbridge cycling to conserve ATP. FORCE IS MAINTAINED.
smooth muscle relaxation mechanism beta adrenergic receptor stimulation -> Gs activates cAMP production -> PKA activation ->->->decreased [Ca} & dilation.
mechanisms for erection nonaroused = penis arteries & arterioles constricted. erection = NO & ACh (parasymp.) -> dilation. more blood = spongy tissue fills and occludes exit veins. PDE5 degrades cGMP to GMP. sympathetics ->arteriolar constriction.
NorEpi effects on penis vascular smooth muscle (phasic) alpha adrenergic R's -> Gq activated. IP3-> Ca release. Ca/Calmodulin activates MLCK -> myosin light chain P'ation. (tonic) Ca-sensitizing pathway: Gq activates RhoA -> Rho Kinase activation -> P'ation of regulatory subunit of myosin light chain.
Inhibitors of PDE5 sildenafil, vardenafil, tadalafil (promote smooth muscle relaxation e.g. erection when proper stimulation is present)
Locations of opposing Adrenergic sympathetic & Muscarinic ACh FX SA node, bronchial muscle & gland, GI motility & secretions, urinary detrusor muscle
Why are cardiac AP's longer than neuronal AP's? fewer K Channels in heart + slower opening stoichiometry
Created by: rbxbrown

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