GMS 6474- Cardiology

sarcomeres

Basic structural & functional unit of skeletal muscle because it is the smallest portion of skeletal muscle capable of contracting.

driving pressure

- change in P = P1- P2 - pressure difference - responsible for blood flow

Metabolic requirements of smooth msk contractions

- low: ATP is needed but metabolic requirements of smooth mks is much less than cardiac or skeletal msk -unlike skeletal & cardiac msk, the mechanical activity of smooth msk is not constantly modulated by load or length so metabolic demad is relatively constant

SR

- membrane containing structure that regulates Ca2+ - primary signaling mechanism

Thin filament activation

- secondary mechanism - tonic inhibition of actin-myosin binding by caldesmon & calponin is relieved by Ca activated CaM activity. Both are bound to actin & myosin & inhib ATPase activity in the absence of Ca-CaM --> enhances binding of mysoin heavy chains to thin filaments

Action Potential

- squid axon: very fast depolarization & short refractory period - frog skeletal msk: slower depolarization & short refractory period - guinea pig atrium: slow, long refractive period

Dihydropyridine Receptors (DHPR)

- voltage sensor - senses the moving AP that propagates from outside of msk cell to the deepest areas

What begins before ventricular contraction or systole?

QRS complex (phase 4-5)

What structures are optimized to prevent fatigue?

capillary density, mitochondrial content to ATPase

Sarcomeres & Cytoskeleton

composed of z disk (alpha-actinin, desmin)

MAP

diastolic pressure + 1/3 (systolic -diastolic)

Tropomodulin and CapZ

located at the end of the thin filament, toward the center of the sarcomere, and may participate in setting the length of the thin filament - alpha-actinin & capZ protein serve to anchor the thin filament to the Z line

DMD (Duchenne Muscular Dystrophy)

problem set

Smooth Muscle Organization

- E- isolation of cells allows finer motor control - gap jx permit coordinated contraction - Multi-unit: ea. smooth msk cell receives its own synaptic input --> usually do not from AP - Unitary --> only a few of smooth msk cells receive direct input & are connected by gap jx (propagates an AP, visceral smooth msk)

A bands, I bands and H zones in contraction?

- I bands shorten during contraction - H zones disappear - A band remains the same size in contraction - sarcomere has shortened b/c myosin heads from thick filaments are pulled from actin (thin filaments) & move towards the center

Cardiac ion channels for K+

- K currents outwards - makes cell more negative inside when they flow (repolarization) - 4 types of K channels 1. inward rectifier 2. transient outward K+ current 3. 2 x delay rectifier K currents - IKr & IKs

Change in Pressure of systemic circulatory system:

- P1: aorta (120/80 mmHg) - P2: right atrium (-4 to 4 mmHg)

Change in Pressure of pulmonary circulatory system:

- P1: pulmonary artery (25/8 mmHg) - P2: left atrium (7 mmHg)

sarcoplamsic reticulum (SR) & transverse tubules (t-tubules)

- SR: vesicles contain Ca2+ - t-tubules: communication system from outside muscle cells - both make up a complex tht activates regulation & triggering of contraction

Motor Unit

- a single motor end plate per msk fiber - single motor neuron may innervate many msk fibers

Force that the contraction must overcome

- afterload - opposing force or arterial pressure - experiments on isotonic contractions focuses on the after-load, factors that the ventricle sense only after the contraction has begun -- decreased cardiac output -- after isometric (shortening) phase

Structure of thick filament

- composed of myosin - regulatory light chains for skeletal and cardiac msk - heads of myosin: responsible for ATPase - tail region of heavy chains: forms alpha helix dbl strand with tail & neck - Heads will bend in opposite directions at opposite ends of the filament (bend towards each other)

Cardiac Muscles (myocytes)

- contractile of myocardial cells, which produce the fast response action potential

Physical Structure of Smooth MSK

- dense bodies are similar to z- disk in skeletal msk - 5-10 actin: myosin filament - sidepolar cross bridges - shorten by 80% instead of 30% in skeletal msk -- allows smooth msk to clam down & contract the most possible (can cause vasoconstriction) - have rudimentary invaginations of the plasma membrane called caveoli where Ca++ is stored, contacting with the SR

cardiac ion channels for Na+

- fast voltage gated Na channels - opens at -70mV - activates rapidly (opening m gate) & then inactivates rapidly (closes h gates) - Na+ enters down its conc. gradient inwards - this depolarizes the cell (inside is more positive)

2 Basic types of msk fibers are distinguished on the basis of their speed of contraction.

- fast vs slow twitch. The difference in speed of contraction is attributed to the expression of different myosin isoforms that differ in myosin ATPase activity. In addition to the difference in myosin ATPase activity, fast and slow twitch msk also differ in metabolic activity, fiber diameter, motor unit size, sensitivity to tetany, & recruitment pattern.

Molecular Organization of Thin filaments

- g actin: area where myosin head binds - f actin: active site where they dimerize together - actin filament: active site exposded on the outside - tropomyosin: hides active site - troponin: TropI & tropC: Ca2+ binds to tropC & changes tropomyosin away from active site - thin filament: turns off & on the cell - Ca2+ is a signaling molecule

Myosin-linked regulation of smooth muscle contraction

- have thick and thin & tropomyosin - lack troponin 1. Ca binds to comodulin 2. activates myosin light chains kinase & phosphorylates regulatory light chains 3. changes orientation of mysoin heads & to heads reach around to tropomyosin & binds to active sites 4. undergoes crossbridge cycle

Ryanodine receptor (RyR)

- inside of msk - Ca2+ release channel that when activated, released Ca2+ that is stored inside SR - goes against concentration gradient & requires ATPase

Calsequestin

- low affinity Ca2+ binding protein that is present in the lumen of the terminal cistrne - allows calcium to be stored in high concentrations

cross striations

- made up of sarcomeres - contractions driven by pacemaker cells - allows blood to pump - allows valves to open - determines flow & pressure of blood

Spatial Summation (recruitment of motor units)

- motor units behave in all or none manner - more force is produced by activating more units - @ low intensity ST fibers (type I) are recruited (tend to be small) - FT fibers (type II) are recruited as intensity increases, IIa first (tend to be large)

smallest structure to outer structure

- muscle cell --> msk fiber contains myofilaments - sarcolemma --> msk membrane surrounds msk cell - endomysium --> connective tissue surrounds msk fiber - perimysium --> connective tissues surrounds muscle bundles - epimysium --> connective tissues surrounds entire musk

T-tubule

- narrow tubes that are continuous with the sarcolemma and extend into the sarcoplasm - allow propagation of AP to the deepest set of sarcomeres & myofilaments - allows AP to reach triad

2 types of smooth msk contractions

- phasic (twitch like contractions) - tonic

PCA curve

- sigmoidal curve - determines Ca2+ sensitivity & sensitivity of contractile mechanisms - the contractile forces of skeletal msk increases in Ca -- dependent manner as a result of binding of Ca to tropC & subsequent movement of tropomyosin away from myosin binding sites on the underlying actin m/c & allows cross bridges to form

Actin-linked regulation of msk contraction: cardiac msk

- single AP does not result in maximal force since SR has limited capacity of Ca++ - "reserve capacity" --> more Ca++ level & force - more Ca, then more force production

Cardiac msk vs skeletal msk

- smaller in diameter and length - sarcomeres (z-lines), t-tubules & SR are not developed as skeletal msk - similar sliding filaments actin myosin & length/tension relationship - intercalated disks separates fibers but myofibers still act asyncitium: mechanically connected by desosomes & electrically connected by gap junctions. - greater # of mitochondria to meet increased demand for ATP - modulated by ANS - contraction triggerred by electrical signals originating in the pacemaker region of the heart (the SA node) - larger t-tubules forming a dyad (conducts AP to DHP voltage sensor)

Tonic contractions

- sustained contractions over time tht occur in sphincters & blood vessels. there are no AP: contraction is modulated by external stimuli tht modulate membrane potential & calcium availability - produced by prolonged stimulation, Ca++ & phosphorylation levels typically fall from an initial peak. Force is maintained during tonic contractions @ reduced [Ca] with lower cross bridge cycling rates manifested by lowering shortening velocities & ATP consumption (LATCH state)

Phasic (twitch like contractions)

-single stimuli or brief bursts of stimuli, associated with AP, slow waves associated with periodic depolarization and generation of AP - associated with Ca++ mobilization, followed by cross bridge phosphorylation & cycling to produce brief phasic, twitch like contraction

Slow-Response: Pacemaker Action Potential (no phase 1-2)

0- Depolarization - opening of slow L type Ca channels - influx of Ca 3- Repolarization - opening of K channels - efflux of K 4. Pacemaker potential (slow depolarization) - closure of K channels - opening of funny (IF) channels (opening of depolarizing charges) - opening of 2 Ca channels, transient (t) type & eventually opening of slow (L type)

Fast-Response: Ventricular/Atrial Muscle Action Potential

0: Depolarization -opening of voltage dependent fast Na channels -influx Na 1. Early Repolarization - opening of voltage dependent K channels, Na channels inactivate - efflux K 2. Plateau Phase - opening of voltage dependent slow L type Ca channels balance w/ slow delayed rectifier K channels - influx of Ca, efflux of K 3. Rapid Repolarization - K currents supersede Ca currents - efflux K 4. Resting membrane potential: - inward rectifier K channels open (efflux) to maintain resting membrane potential

excitation-contraction coupling phases

1. AP propagation 2. Ca2+ release 3. Exposure of actin active site

Cross Bridge Cycle

1. Binding of myosin to actin, ADP + Pi remains bound to myosin 2. Power stroke - myosin head swivels, causing displacement of actin filament, ADP + Pi released from myosin 3. Rigor - myosin head firmly attached to thin filaments 4. Disassociation- ATP binds to myosin, actin & myosin dissociate (cross bridges detach) 5. Activation- energy from the hydrolysis of ATP used to activate the myosin head, ADP + Pi remain bound to myosin

excitation-contraction coupling in smooth msk

1. Ca entry thru voltage gated Ca channels 2. Ca release from SR (via CICR or IP3) 3. Ca entry thru stored operated Ca

Excitation-Contraction Coupling

1. Resting: active sites are covered by tropomyosin 2. AP in the sarcolemma carried to the interior of the cell thru t-tubules 3. AP reaches triad & activates voltage sensitive DHPR in the t-tubule which opens the RyR calcium release channel in the SR. 4. Calcium binds to TnC subunit of troponin, causing exposure of actin active site 5. Activated myosin head binds to active site pulling the actin over the myosin and contracting the sarcomere

Reflects an intrinsic regulatory process referred to as the Frank-Starling Law of the Heart. It is attributable to:

1. an increase in the maximal force of contraction 2. an increase in the sensitivity of contraction to Ca++ - look at graph - short: right ward shift since less sensitivity to Ca++ - as cardiomyocytes are stretched, their sensitivity to Ca++ increases.

Requirements for effective operation for the heart to be functioning.

1. contractions of individual cardiac msk cells must occur @ regular intervals & be synchronized (not arrhythmic) 2. valves must be fully open (not stenotic) 3. valves must not leak (not insufficient or regurgitant) 4. muscle contractions must be forceful (not failing) 5. ventricles must fill adequately during diastole.

3 Ways to Initiate Smooth Msk Contraction

1. innervated by ANS & makes multiple contacts (variscosities) causes Junctional potentials -> slow L type Ca++ channel allows Ca to enter smooth msk cell 2. can initiate spontaneous e- activity (pacemaker current --> slow waves --> depolarization of membrane) 3. can contract w/o an AP --> NT --> GProtein --> IP3 --> SR Ca++ release --> contraction

ionotropic agents affect contractility

1. positive --> inotropic agents: increase Ca, either by opening Ca channels, inhibiting Na-Ca exchange, changing Ca stores or inhibiting the Ca pump : epi, cardiac glycosides, high EC Ca, low EC Na, increased HR 2. negative --> inotropic agents: decrease Ca: Ca channel blockers, low EC Ca con, high EC Na conc

3 potential actions during msk contractions

1. shortening: isotonic - shortening against fixed load, speed, dependent on MATPase actigvity & load (sarcomeres brought to center & msk shortened) 2. isometric: no change in length, m-heads are cycling & generating tension 3. lengthening: myosin heads try to pull thin filaments on top of thick filaments, can cause msk damage, posing force is greater

______ released by motor neurons that bind to post-synaptic junction. This results in an increase in ___________ permeability, shifting the membrane potential from ______ to _____ mV. Results in end plate potential.

AcH Na+ and K+ -80 to -15mV

Stimulation of B-adrenergic receptors in the heart increases the force of contraction

E- stimulation of myocardium results in a transient rise in IC Ca++ & force Isoporterenol (B-adrenergic R agonist) increases the amplitude of the IC Ca++ transiet and hence the amt of force generated (graph)

thin filaments are made up of

actin, troponin, tropomyosin (nebulin, tropomodulin, alpha-actinin, capZ protein)

Sustainable ATP production comes from ___________ ATP sources (mitochondria).

aerobic

Pulse pressure is influenced by conditions that alter what?

arterial compliance and/or stroke volume

LATCH state

contractile state of some smooth muscles; force can be maintained for prolonged periods w/ very little energy use; cross-bridge cycling slows to the point when phosphorylated cross-bridges become dephosphorylated while still attached to actin

pharamacomechanical coupling

contraction of smooth msk in response to an agent that does not produce a change in membrane potential & reflects the ability of the agent to increase the level of the IC 2nd messenger InsP. Other agents (cGMP or cAMP) result in a decrease in tension, also w/o a change in membrane potential

cardiac muscle

cross striations & functional syncytial contractions driven by pacemaker cells

skeletal muscle

cross striations and voluntary

Sarcolemma

dystrophin & dystrophin associated proteins - look at figure

Initial sarcomere length & EDV Pre load

force that must be overcome before the ejects blood from the ventricle during systole. - isometric phase --> filled with blood

End Plate Potential

initiation: by Ach rising phase: simultaneous increase in Na & K falling phase: passive decline in permeabilities due to acetylcholinesterase action potential change: does not exceed -10 mV additional: no regenerative action and no refractory period pharmacology: blocked by curare, not influenced by tetrodotoxin

Action Potential

initiation: by depolarization rising phase: selective increase Na+ permeability falling phase: selective increase in K+ permeability potential change: reverses polarity additional: regenerative ascent followed by refractory period pharmacology: blocked by tetrodotoxin, not influenced by curare

smooth muscles (visceral)

lacks cross striations & functional syncytial in interstitial tissues (causes vasodilation & contractions)

thick filaments are made up of

myosin & titin (myomesin & c protein)

SA and AV nodes

pacemakers of the heart- stimulate the heart to pump blood - conduction of myocardial cells which produce to slow response action

Msk fibers will train by respond based on their activation history --> ATP synthesis by anaerobic sources. What are these sources?

phosphocreatine --> creatine + PO3 glycogen --> lactic acid glucose, FA, AA + O2 --> CO2 + H20 + urea

Aging (atherosclerosis)

results in decreases in the maximal capabilities of cardiovascular responses that are distinct from any disease processes.

Intercalated disks

separates fibers, but small myofibers act as a syncitium: mechanically connected by desmosome and electrically by gap junctions (connexons)

Henneman Size Principle of Motor Unit Recruitment

starting w/ smallest motor units, progressively larger units are recruited w/ increasing strength of msk contraction. The result is an orderly addition of sequentially larger & stronger motor units resulting in a smooth increase in msk strength. the recruitment sequence is thought to begin w/ type I motor units, to progress to type II units that first include type IIa, & to a end with type IIb units, which are active only @ relatively high force output

What occurs before ventricular relaxation or diastole?

t-wave (phase 6-7)

A triad is made up of

terminal tubule, SR, DHPR, RyR

NMJ or motor end plate

the chemical synapse between the presynaptic membrane of motor neurons and extensively folded post-synaptic membrane of skeletal muscle cells

equilibrium potential

the membrane potential at which chemical and electrical forces are balanced for a single ion.

Pathway of blood through the heart

vena cava-> R atria -> tricuspid valve ->R Ventricle -> pulmonary artery -> lungs -> pulmonary vein -> L atria -> mistrial valve ->L ventricles -> aorta --> arteries to body

CICR is necessary for which type of msk contraction and where is it found?

CICR is necessary for cardiac msk contraction and is found in ringer's solution (ECF Ca++) CICR is not necessary for skeletal --> no external Ca++

Which wave occurs before atrial contraction?

P wave (phase 3)

short term high levels of ATP synthesis are provided by anaerobic metabolism of substrate stores what ?

PCr and glycogen

Terminating Contraction

Primary mechanism sequestering by SERCA -- responsible for to requester Ca2+ back to SR -brings back 2Ca2+ for every 1 ATP hydrolyzed - distributed throughout longitudinal tubules & terminal cisternae - helps modulate Ca2+ out of myoplasm

Systemic & Pulmonary Pressures

Mean pulmonary: 14 (25/8) Mean systemic: 100 (120/80) RV: 25/0 LV: 120/0 RA: 2 LA: 5

Electrical events always occur before the ______?

Mechanical events

General Hemodynamics

The heart is a dual pump. It serves two circulations which are linked in a series. 1. Systemic circulation 2. Pulmonary circulation Each circulation receives and ejects the same volume of blood per minute. each circulation has a parallel arrangement. • Enables independently regulated blood flow to each organ Parameters: Individual Blood Vessel Diameter, Mean Blood Flow Velocity Total Cross-Sectional Area, Blood Volume Distribution, Total Peripheral Resistance (TPR), Mean Blood Pressure Total Peripheral Resistance (TPR): The arterioles represent the site of the greatest change in resistance in the systemic circulatory system. Almost all resistance in the circulatory system lies in the arterioles as they are a major site of sympathetic control of resistance. Mean blood pressure: The average (mean) blood pressure decreases from arteries to capillaries to veins. Since blood flows from areas of high pressure toward areas of low pressure, this allows blood to flow continuously down a pressure gradient from the Aorta to the Vena Cava. Total cross-sectional area of each vessel type increases from arteries to capillaries because of vascular branching. Blood volume distribution: Most of the blood is in the systemic circulation at rest (~80%), but of this volume only ~14% is in the high pressure arterials. In the systemic circulation the low pressure veins contain the majority of the blood (~60%) and serve as a reservoir that can be utilized during times of low blood volume or pressure. Only ~5% of blood is contained in the capillaries at rest.

Properties of fast & slow msk fibers

Type I: Slow twitch - fatigue resistent - color: red - metabolism: oxidative - mitochondria: high - glycogen low Type IIa: Fast - fatigue resistent - red - metabolism: oxidative - mitochondria: higher - glycogen abundant Type IIb: Fast - fatiguable - color: white: low myoglobin - metabolism: glycolytic - fewer mitochondria - high glycogen

The stationary end-plate potential triggers

a moving AP along the fiber