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Flashcards in cell structure and function long Deck (23):

PO 1.44 mechanism of excitation contraction coupling

1. Ca++ enters cell in depolarization through Ltype channels and triggers release of Ca++ by terminal cisternae

2. Ca++ binds TN-C causing change in Troponin-tropomyosin complex – it moves away from myosin binding site on actin

3.Myosin head binds to actin
• This causes ATP hydrolysis and energy for the cross bridge movement and reduces sarcomere length

4.Ca++ sequestered by sarcoplasmic reticulum by  sarco-endoplasmic reticulum calcium ATPase (SERCA) pump

5. Ca++ removed from TN-C, myosin unbinds (needs ATP), sarcomere resumes original relaxed length 


PO 1.44

physiology of cardiac muscle - basic

o striated

o differences to skeletal
• single nucleated, diameter 25microm and length 100microm
• skeletal run length of muscle and no cell to cell conduction, contract when activated by motor neurons

o connect through intercalated disks, gap junctions are low resistance pathways that conduct ionic currents so contracts as a unit

o each myocyte has myofibrils made of myofilaments

o sarcomeres are the contractile units in the myocyte 


PO 1.44 physiology of cardiac muscle: sarcomere

o sarcomeres are the contractile units in the myocyte image 17 also

• between 2 z lines

• myosin makes up thick filaments
300 moleules per filament, 2 heads per molecule, site of myosin adenosine triphosphatase (myosin ATPase) which hydrolysis ATP needed for cross bridge formation between thick and thin

• actin makes up thin filaments
 6 thin around each thick
 thin also made of tropomyosin – 1 rod for 7 actins, and troponin ( 3 subunits)
TN-T – attaches tropomyosin
 TN-C -  Ca++ binding site
 TN-I – binds actin

• titin connects myosin to Z line

NOTE: TN-I and TN-T released into circulation when myocytes die – trop rise


PO 1.44 physiology of cardiac muscle: myocyte

o Sarcolemma is the membrane of the myocyte, it has deep invaginations called t tubules through which ions exchange through Ca channels.

• Sarcoplasmic reticulum is adjacent to T tubules, the terminal cisternae are the end pouches that touch T tubules

• Terminal cisternae have ryanodine sensitive calcium release channels in their ‘feet’ which picks up Ca and releases more


PO 1.43 Factors that may influence cardiac electrical activity:iontropy modulation


see following cards for how each phase actually works

- calcium entry into cell through L-type calcium channels
- calcium release by the sarcoplasmic reticulum
- calcium binding to TN-C
- myosin phosphorylation (can be increased by cAMP which then increases iontropy)
- SERCA activity
- Calcium efflux across the sarcolemma (Na+Ca++ exchange pump) and ATP dependant Ca++ pump


PO 1.43 factors influencing cardiac electrical activity: ionotrops


How is Ca+ entry through L-type calcium channels regulated/how does norephedrine and ephedrine work as a positive inotrope

- norepinephrine from sympathetic nerves of epinephrine from adrenal glands binds to B1 adrenoceptors on the sarcolemma
- which is coupled to Gs-protein
- which activates adenylyl cycylase
- which hydrolyzes ATP to cAMP
- cAMP acts as second messenger to activate protein kinase A (PK-A)
- which phosphorylyses L type Ca++ channels (and sites on SR to increase Ca++ release)
- this increases the permeability to calcium
- increases SR release of Ca++ and iontropy


PO1.43 factors influencing cardiac activity: negative iontropes


how does acetylcholine and adenosine act as negative iontropes (opposite of nor/ephed)

- acetylcholine from parasympathetic nerves in the heart binds to Muscarinic receptors (M1)
- coupled to Gi-protien (as are adenosine receptors)
- inhibits adenylyl cyclase
- decreases intracellular cAMP
- less phosphorylation of L type Ca++ channels
- decreased permeability to Ca++
- less SR release of Ca++ and iontropy


PO1.43 factors influencing cardiac activity: SR release of Ca++


how can you increase SR release of Ca++ 

- PK-A released as a result of noreph/eph also acts on SR to increase Ca++ release
- Norepinephrine binds alpha1 adrenoceptors, antiotensin II binds AT1 and endothelin-1 binds Eta
o These all activate phospholipase-C to form inositol triphosphate IP3 from phosphatidylinositol 4,5-biphosphate (PIP2)
o This stimulates SR Ca++ release


PO1.43 factors influencing cardiac activity:force of actin and myosin

how can you increase the force generated when actin and myosin bind

- increase the affinity of TN-C for Ca++by:
o increase intracellular Ca++
o increased preload (increased sarcomere length)
o acidosis decreases the affinity


PO1.43 factors influencing cardiac activity: SERCA activity

how can SERCA activity modulate ionotropy

- if activity increased get more Ca++ released next time so increased ionotropy
- activity increased by increased intracellular Ca++ and by PK-A phosphorylation of phospholamban (which usually inhibits SERCA)


PO1.43 factors influencing cardiac activity:digitalis

- inhibit Na+/K+ ATPase pump
- so increased intracellular Na+
- so increased intracellular Ca++ because Na+/Ca++ must work
- so increased ionotropy


PO 1.43 factors that may influence cardiac activity: lusitrophy


how is lusitrophy regulated

- how fast intracellular Ca++ can be reduced (so trop-tropo complex resumes resting) affected by:

o ischemia as more permeable to Ca++
o inhibition of of Na+/Ca++ pump

o impaired SERCA pump (increased lusitropy and ionotropy if increased activity from B adrenoceptor stimulation see ionotropes)

o Pk-A phosphorylation of troponin-I increases Ca++ dissociation from troponin-C, increasing lusitrophy (B adrenoceptor stimulation see ionotropes)

o NOTE: some ionotropes increase Ca+ binding to TN-C so reduced lusitropy


PO 1.46 factors affecting myocardial O2 supply and demand (add to from chap 8)

- need energy in form of ATP to maintain ionic pumps
- high metabolic rate as continuous contraction/relaxation, dramatic increase in demand if HR increases
- limited anaerobic capacity to meet ATP requirement- without O2 can only contract for 1 minute

- if increased HR there are biochemical signals to dilate coronary blood vessels to meet increased O2 demands (chap 8)
- so has lots of mitochondria
- uses
o 60% fatty acids – or can use amino acids and ketones in place 

o 40% carbohydrates – can use exclusively post high carb intake. Or can use lactate in place of glucose when exercising


layers of vasculature

- intima – innermost, single layer of endothelial cells
o separated from media by connective tissue in large vessels then basal lamina
o smallest vessels only have this and basal lamina

- media – smooth muscle cells in collagen, elastin and glycoproteins. Ratio of these determines the mechanical properties
o sm cells circumfrential and helically
o contraction reduces diameter
o lots of elastin (aorta) means canpassively expand and contract
o small arteries mostly smooth muscle to regulate organ blood flow
o separated from advntitia b external elastic lamina

- adventitia – made of collegen, fibroblasts, vessels (vasa vasorum), lymphatics and autonomic nerves (sympathetic adrenergic primarily)


vascular smooth muscle facts

Vascular smooth muscle
- 5-10microm diameter
- 50-200microm long
- caveolae (invaginations in cell membrane) increase the SA
- poorly developed SR
- actin and myosin not in distinct repeating units
o actin filaments anchored by dense bodies (like Zlines) to sarcolemma
o each myosin surrounded by several actin
- electrically connected by gap junctions

- contraction slow and sustained (cardic rapid and short ~300 milisec)
- normally sits partially contracted – resting tone, depends on:
o sympathetic adrenergic nerves
o circulating hormones – epinephrine, angiotensin II
o substances released by endothelium
o vasoactive substances released by tissue around the vessel


triggers of vascular smooth muscle cell contraction

o electric depolarization
• voltage dependant L-type Ca+ channels and SR release
• increased intracellular K
• receptor coupled opening of Ca++ channels

o chemical stimuli
• norephinephrine, ephinephrine, angiotensin II, vasopressin, endothelin-1, thromboxane
• bind to receptor to increase intracellular Ca++

o mechanical
• passive stretch – myogenic response
• from stretch induced activation of ionic channels


how Ca+ causes contraction of smooth muscle cells


o Ca++ binds to calmodulin, this complex activates myosin light chain kinase (MLCK), an enzyme that phosphorylates myosin light chains (MLC) on myosin heads in presence of ATP, causing cross bridge and contraction 

o Ca+ reenters SR by ATP dependent Ca pump similar to SERCA, also removed by Na/Ca exchanger and Ca pump


 Intercellular Ca+ modulation in smooth muscles

o IP3 via Gq activation of PL-C (image 19)
•  Like myocytes, In addition to NE, AII and ET-1, acetylchoine via M3

o cAMP via Gs-protein activation of AC
• opposite of cardiac, cAMP causes relaxation as it inhibits MLCK so no actin myosin interaction
• drugs include epinephrine,adenosine, prostacyclin (PGI2)
• B2 adrenoceptor activation causes relaxation

o increased cGMP causes relaxation
• happens when Ach, bradyknin and substance P bind to endothelial receptors, L-arginine converts to NO which activates cuanylyl cyclase which increases cGMP
• cGMP also inhibits Ca+ entry and activates K+ causing hyperpolarization and decreased IP3


endothelial facts function and dysfunction


- flat, single nucleus

lines the whole CVS, contacts with blood
- .2 -2.0 micro m thick, 1020micro m across
- joined by intercellular junctions
o tight in arteris and skeletal muscle capillaries
o gaps between capillaries of spleen and bone marrow so blood can easily flow in and out

Fucntion (3 main things)

o autoregulates blood flow
• synthezise vasoactive subsances to regulate local arteriolar smooth muscle tone to match regional blood supply to metabolic demand of tissue
• nitric oxide NO - relax
• prostaglandin PG2 - relax
• endothelins - contract

o coagulation and fibrinolysis
• PGI2 and NO and their antiplatelet effects as below
• heparin sulfate – enhances antithrombin III activity
• tissue plasminogen activator (tPA) – stimulated by local thrombin production
• glycocalyx – prevents platelet activation
• thrombomodulin – surface receptor for thrombin, the complex of which activates protein C
• Surface ADPase activity – prevents platelet aggregation

o Angiogenesis
• releases Growth factors such as vascular endothelial growth factor (VEGF)

o barrier for exchange of fluid, electrolytes, macromolecules and cells to extravascular space
o Modulate leukocyte adhesion and transendothelial migration - Through NO and expression of surface adhesion molecules



• haemodynamics – vascular constriction
• Cardiovascular – positive inotrope and chronotropic effects
• Respiratory bronchoconstrciton
• Renal – decreased renal flow and GFR
• Endocrine – increased ANP, renin, aldosterone and catecholamine release
• Metabolic – increases gluconeogenesis


o In atherosclerosis, HT, diabetes, hypercholesteroleamia
o Decreased NO and PGI2 so vasoconstriction, thrombosis, inflammation
o If damaged at capillaries get leakage and oedema


NO production and function

NO production

o L-arginin and O2 converted to NO by enzyme NO synthase (NOS)

  • Arginine +O2+NADPH by NOS3

o Released basally
o Enhanced by:

  • Acetylcholine (but if endothelium damaged Ach causes contraction through IP3 pathway), bradykinin, H1 receptors, VIP, substance P, histamine
  • shearing force on endothelial surface from increased blood flow – flow dependant vasodilation
  • metabolic activity of tissue (↓O2, ↑CO2, H+, T, lactic acid, pyruvate, ADP, AMP, adenosine, Pi ↓ATP)
  • increased intracellular Ca++ , increased K+
  •  cytokines like TNF and interleukins released by leukocytes in infection

- NO function
o Diffuse out of endothelial cells, activates guanylyl cyclase to make cGMP which:

  • relax smooth muscle (↓ Ca++ calmodulin activation, decreased MLKC activity, activates myosin phosphatase to reduce concentration of phosphorylated myosin)
  • inhibit platelet aggregation
  • inhibit inflammation


prostacyclin production and function

o Made from arachidonic acid metabolism by prostacyclin synthase via COX pathway Cox-1

o Primarily Inhbits platelet aggregation

  • Its in balance with thromboxane A2 (TXA-2) released from platelets (which causes localized plt aggregation and clot formation) so it stops clot extension and allows blood flow to continue around clot

o Aspirn

  • Inhibits COX irreversibly, so inhibits production PGI2 and TXA-2, but unlike platelets endothelium produces more COX, balance tipped to anticoagulation

Triggered by pulsatile flow, shear stress

Causes smooth muscle relaxation
• Via activation of adenylyl cyclase → ↑cAMP → ↓MLKC activity → vasodilatation


endothelin-1 production  and function

Endothelins (ET1,2,3)
o Vasoconstrictor – binds to smooth muscle, mobilizes calcium through IP3 (see image 22) contraction. Enhanced production causes hypertension

  • ET-1Most potent of all vasoconstrictors (100 x NA)
  • Made when ‘big-endothelin 1’ is cleaved by endothelin converting enzyme
  • Acts locally and systemically

o Synthesis stimulated by angiotensin II, vasopressin, thrombin, cytokines, shearing forces, insulin, hypoxia, endothelial damage, catecholamines
o Works via activating Gq proteins through Eta receptor
o Inhibited by NO, PGI2 and ANP

21 amino acid peptides, 3 types:
ET1 = endothelium, brain, kidney
ET3 = adrenals


other vasoactive substances released by endothelium

Tissue factor (TF) - Loss of endothelium → exposure of tissue matrix TF
Heparin sulphate - Expressed on surface - Effect: ↑AT3 activity
-Binds and inactivates thrombin 
-Activates protein C / protein S → inactivate factors V and VII / inactivates
plasminogen activating factor. Results in ↑tPA and ↑fibrinogen