cell structure and function long Flashcards
PO 1.44 mechanism of excitation contraction coupling
- Ca++ enters cell in depolarization through Ltype channels and triggers release of Ca++ by terminal cisternae
- 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
- Ca++ sequestered by sarcoplasmic reticulum by sarco-endoplasmic reticulum calcium ATPase (SERCA) pump
- 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)
Demand
- 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
Supply
- 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
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
Facts
- 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)
Also:
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
Effects:
- 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
Dysfunction:
o In atherosclerosis, HT, diabetes, hypercholesteroleamia
o Decreased NO and PGI2 so vasoconstriction, thrombosis, inflammation
o If damaged at capillaries get leakage and oedema
