Midterm 2 Flashcards
what occurs in the latch state of vascular smooth muscle contraction (caused by tonic stimulation)?
- sustained stimulation maintains modest increases in Ca2+ required for sustained tension
- Ca2+ leads to low levels of MLCK activation (cross-bridges already formed)
- MLCP dephosphorylates a portion of myosin molecules
- dephosphorylated myosin has a low rate of detachment from actin
- slow cross-bridge detachment maintains tension with lower ATP use
why is development of force is VSM slow?
- it doesn’t need to be fast
- requires a slow, sustained contraction
- VSM must sustain vasoconstriction for min-hours
what are the characteristics of the force-velocity relationship of VSM?
- slow velocity of shortening
- high force generation
- a large range of length due to “side polar” myosin thick filaments (different isoform)
how does smooth muscle shortening velocity increase?
increases with fraction of MLC that is phosphorylated
- increased calcium binds more calmodulin (Ca-CaM)
- activates more MLCK, more MLC phosphorylated
- leads to increased shortening velocity and maximum force (velocity and force dictated by MLCK activity)
how are store-operated channels (SOCs) involved in Ca2+ regulation?
ex) Orai in plasma membrane of VSM
- connects to STIM (SR Ca2+ sensor on SR)
- STIM detects low levels of Ca2+ in SR, allowing Orai to allow Ca2+ from extracellular space to directly enter SR
how are receptor-operated channels (ROCs) involved in Ca2+ regulation?
- second-messenger activated (ex. GPCR - Gq)
- often non-selective cation channels; can work in 2 ways:
- can open directly and allow Ca2+ influx
- can open allowing cation influx, depolarizing the membrane and open Cav1.2 channels
what is Istretch and how does it contribute to Ca2+ regulation?
- Istretch is stretch-activated; enters through K+ channels or non-selective ion channel
- can directly allow Ca2+ influx or depolarize the membrane and open Cav1.2 channels
how is Ca2+ released from the SR?
- through RYR3 channels activated by Ca2+ binding (CICR - not a big factor in VSM)
- through IP3R channels activated by IP3 binding (greater factor)
which SERCA isoform is present in VSM?
SERCA2b (SERCA2a in cardiac muscle)
- much slower
in the Ca2+ vs time graph during VSM contraction, what mechanisms are responsible for the transient Ca2+ peak and the sustained Ca2+ plateau?
transient Ca2+ peak:
- SR Ca2+ release
sustained Ca2+ plateau:
- Ca2+ entry via ROCs, SOCs, and Cav1.2
in the Ca2+ vs time graph during VSM contraction, what mechanisms are responsible for the clearance of cytosolic Ca2+? what are their properties?
- NCX (3Na in, 1Ca out): causes final fall; low affinity, high capacity (no ATP required)
- PMCA (1Ca out for every ATP): causes initial fall; high affinity, low capacity
- SERCA: causes initial fall; high affinity, low capacity
low capacity because they require ATP
where does the IP3 that is required to activate IP3Rs come from?
ex) SNS activation
- NE binds a1-adrenergic receptors, activating Gq
- Gq activates PLC which converts PIP2 (in the membrane) to inositol triphosphate (IP3) and diacylglycerol (DAG)
- IP3 activates IP3R on SR, increasing SR Ca2+ release
how does DAG contribute to VSM regulation?
- activates PKC which inhibits MLCP
- inhibited MLCP increased Ca2+ sensitivity of VSM contraction
- increases cross-bridge formation and force of contraction -> vasoconstriction
in summary, what are the transporters involved in Ca2+ regulation in the sarcolemma?
Ca2+ entry:
- Cav1.2
- ROCs
- SOCs
- stretch-activated cation channel
extracellular efflux:
- NCX
- PMCA
in summary, what are the transporters involved in Ca2+ regulation in the sarcoplasmic reticulum?
- SR Ca2+ release channels: RYR3 and IP3
- SR Ca2+ uptake by SERCA and PLB
what are the dominating mechanisms in each type of muscle for excitation-contraction coupling?
- skeletal: voltage-dependent Ca2+ release (VDCR)
- cardiac: calcium induced calcium release (CICR)
- smooth: IP3-induced calcium release (IP3ICR)
what is VDCR?
- physical coupling of Ca channel and RYR
- depolarization required for RYR Ca2+ release but Ca2+ entry not necessary
what is CICR?
- Ca2+ entry through Cav1.2 is an absolute requirement
- Cav1.2 is in close proximity with RYR
- triggers RYR Ca2+ release from SR
what is IP3ICR?
- Cav1.2 and RYR not in close opposition (little CICR)
- binding of IP3 to SR IP3 receptors triggers Ca2+ release (RYR causing some CICR)
- role for Ca2+ entry pathways across sarcolemma
what are the different types of VSM regulation?
1) frequency dependent (eg. GI tract)
- summation
- AP upstroke initiated by Cav1.2
2) slowly depolarizing waves (eg. uterus)
- oscillating membrane potential
3) tonic depolarization induced waves, no APs (eg. multi-unit SMCs)
4) pharmacomechanical coupling
- force generation w/o depolarization
- most common and diverse stimulation of VSM
what ways are there to depolarize the membrane?
- pacemaker channels (gut)
- inhibition of Na/K-ATPase (slower depolarization)
- changes in K+ channel
- non-selective cation channels
what mediators and second messengers are involved in pharmacomechanical coupling?
- mediators: drugs, hormones, NTs, local environmental changes
- second messengers altering Ca2+: IP3, cGMP, cAMP
how is VSM neurally regulated?
at the varicosity of a sympathetic axon synapsing onto a VSM cell, neural force generation occurs from fastest to slowest by the following mechanisms:
1) ATP (binds to non-selective cation channel (P2x receptor) causing Ca2+ and Na+ influx)
2) norepinephrine (binds to a1-adrenergic receptor, Gq activation, PLC, IP3, IP3R, SR Ca2+ release)
3) neuropeptide Y (binds Y1 receptor, increases intracellular Ca2+)
what factors are involved in endothelial regulation of VSM contraction?
- endothelium-derived relaxation factor (EDRF)
- now known to be nitric oxide (NO)
- endothelin (ET)
- endothelium-derived hyperpolarizing factor (EDHF)
how are EDRF/NO levels increased in VSM endothelium?
ex) in response to ACh binding m3-muscarinic receptor on endothelium-> activates Gq and increases intracellular Ca2+
- increased Ca2+ activates endothelial NO synthase (eNOS) which converts L-arginine to NO
exogenous factors: ex. glycerol trinitrate (GTN) administered as a pill/spray
- enters endothelial cells and is a direct donor of NO
what does EDRF/NO do after it has passively diffused from the endothelium to the VSM cells?
- activates guanylyl cyclase (GC) -> GC converts GTP to cGMP -> elevated cGMP activates protein kinase G (PKG)
- PKG does 2 things:
1) phosphorylates phospholamban (PLB), removing the brake from SERCA, allowing faster Ca2+ uptake into the SR
2) phosphorylates MLCK, inhibiting it (inhibits contraction)
net effect: NO = faster relaxation = vasodilation
what is phosphodiesterase E5 (PDE5)? how does Viagra affect this?
- PDE5 breaks down cGMP to GMP to return to homeostatic conditions
- sildenafil (Viagra) inhibits PDE5, keeping cGMP levels high and promoting vasodilation -> treatment for erectile dysfunction
how does endothelin work in high pressure vessels (ex. arteries)? what is the net effect?
- endothelium releases endothelin -> endothelin binds to ETa receptors on VSM cells
- ETa activates Gq pathway (PLC, PIP2 -> IP3)
- Ca2+ is released from SR through IP3R
- net effect: vasoconstriction
how does endothelin work in low pressure vessels? what is the net effect?
- endothelium released endothelin -> endothelin binds to ETb receptors on endothelial cells
- stimulates eNOS and NO pathway
- net effect: vasodilation
how does endothelium-derived hyperpolarizing factor (EDHF) work?
(less understood)
- EDHF released from endothelial cells activates K+ channels, causing increased K+ efflux -> hyperpolarizes membrane and making Em far away from threshold so Cav1.2 won’t open
- no Ca2+ influx = no VSM contraction = vasodilation
what other tissues are involved in regulation of VSM contraction?
- Mast cells
- kidneys
- pituitary and hypothalamus
- surrounding tissue
how do Mast cells regulate VSM contraction?
- produce histamine
- histamine binds to H1 receptor on endothelium
- activates NOS -> vasodilation
how do the kidneys regulate VSM contraction?
- produce renin
- renin converts angiotensinogen to angiotensin I
- angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE)
- angiotensin II binds AT1 receptors on VSM cells
- activates Gq, PLC, IP3, Ca2+ release pathway
- angiotensin II = very potent vasoconstrictor (can cause cardiac hypertrophy by raising BP)
how do the pituitary and hypothalamus regulate VSM contraction?
- produces antidiuretic hormone (ADH)
- ADH prevents water loss at the kidney
- ADH = vasoconstriction
how does surrounding tissue regulated VSM contraction?
- produces metabolites (usually means we need more blood)
- adenosine, increased K+, increased CO2, decreased O2, decreased pH
- usually cause vasodilation
what does Q equal? how does it change?
Q = MAP/R
- changes in Q are due to changes in R (which is due to changes in r)
what receptors are present in cardiac muscle vs VSM? what are their effects?
cardiac = B1 (Gs pathway) (NE > E)
- increase HR
- increase contractility
skeletal muscle and coronary arteries = B2 (E > NE)
- vasodilation (epinephrine)
- increase blood supply during exercise
VSM = a1 (PLC pathway) (NE > E)
- profound vasoconstriction
- increase BP
what is the function of capillaries? how does their anatomy facilitate this?
- primary exchange for gases, nutrients, water, waste
- only one cell layer thick (only tunica intima layer)
where is capillary density the greatest?
in tissues with high O2 consumption
- high density: cardiac and skeletal muscle, glands, brain
- low density: cartilage, subcutaneous
are capillaries open all the time? how are they regulated?
no
- only 20% open in skeletal muscle at rest
- regulated by small arteries, arterioles, metarterioles (route to bypass capillaries)
- precapillary sphincters open/close in response to local conditions (not innervated by NS)
what are the types of capillaries?
from least to most leaky:
- continuous
- fenestrated
- sinusoidal (discontinuous)
what are the properties of continuous capillaries?
- most common
- junctions 10-15 nm wide
- blood brain barrier has tight junctions (restricts exchange to only specific elements)
what are the properties of fenestrated capillaries?
fenestrations = membrane-lined holes through cells
- 20-100 nm wide
- can be closed by diaphragm
- intestine, glomerulus, exocrine glands, etc.
what are the properties of sinusoidal (discontinuous) capillaries?
- large gaps between cells
- 100-1000 um
- facilitate exchange
- present where large materials involved in exchange (liver, spleen, bone marrow, etc.)
what are the mechanisms of transcapillary exchange?
- diffusion (gases, small solutes)
- filtration
- bi-directional vesicular transport
how does bi-directional vesicular transport work?
1 of 2 ways:
a) transcytosis of macromolecules
b) transendothelial channels (stack of fused endocytotic vesicles across cell)
- allows macromolecules to move straight through one side to the other
what is Fick’s Law of Diffusion?
J = ([solute]out - [solute]in) x P x A
- J = flux = quantity moved per unit time
- P = permeability coefficient
- A = capillary surface area
how does each type of molecule (gases, small solutes, polar molecules, large solutes) diffuse across the membrane?
- gases: direct (freely) diffusion across endothelial membrane (large P)
- small molecules: diffuse through small pores and clefts (ex. junctions)
- polar molecules: have decreased permeability (poor lipid solubility)
- large molecules: no diffusion above 60 kDa (albumin = 69 kDa)
what 2 forces govern filtration at the capillary (ie Starling forces)?
- hydrostatic pressure (~32 mmHg): blood pressure (falls as it travels through capillary from arterial to venous end)
- oncotic or plasmoid osmotic pressure (~25 mmHg): blood proteins (albumin, globulin, fibrinogen); remains constant b/c proteins in blood remain constant
what is the net filtration pressure?
0.3 mmHg
- 2-3 L/day
what forces dominate at the arteriolar end? the venular end?
- arteriolar end: hydrostatic > oncotic (allows filtration)
- venular end: hydrostatic < onctotic (allows absorption)
what factors can cause disturbances of net filtration balance but decreasing plasma protein concentration?
all increase leakiness of capillaries:
- pregnancy (increases blood volume; same amount of proteins but more blood)
- capillary injury
- severe burns
- inflammation (ex. due to infection, injury)
what happens when plasma protein concentration is decreased?
decreased oncotic pressure -> increased filtration -> increased interstitial fluid -> lymphatic tissue OR edema
when does edema (pooling of fluid in interstitial space) occur?
when lymphatic tissue capacity is exceeded:
- motionless (lymph not circulating)
- lymph glands removed
- lymph blocked by tumors
how does dehydration affect plasma protein concentration?
increases plasma protein concentration
how does standing affect net filtration balance?
increases venous pressure (blood pools in legs) -> increases filtration -> increases interstitial fluid -> lymphatic tissue OR edema
how does hypertension affect net filtration balance?
increases hydrostatic pressure -> increases filtration -> increases interstitial fluid -> lymphatic tissue OR edema
where does the lymph drain into from below the neck? from the left head and neck?
- below the neck: thoracic duct -> drains into left subclavian vein at junction with the left internal jugular
- left head and neck: thoracic duct
- right head and neck: right subclavian vein at junction with right internal jugular
what are properties of lymphatic capillaries?
- closed ends
- valve-like inter-endothelial junctions (gaps) -> open when interstitial pressure increases
- fine filaments that anchor lymph capillaries to surrounding tissue
what occurs during the expansion phase of lymphatic flow?
- interstitial P > lymphatic P
- interendothelial “valves” allow interstitial fluid to enter initial lymphatic
what occurs during the compression phase of lymphatic flow?
- movement of tissue (ex. skeletal muscle pump)
- lymphatic P > interstitial P -> causes interendothelial valves to close
- increased interstitial P opens the secondary lymph valves, forcing the lymph downstream
how is lymphatic flow regulated?
1) interstitial pressure: increased net efflux from capillaries -> increased interstitial P -> increased lymphatic flow
2) compression forces: skeletal muscle contraction propels lymph towards central areas
3) myogenic tone: stretch causes smooth muscle contraction and lymphatic constriction -> moves lymph towards central areas
what are some pathological conditions associated with the lymphatic system?
- removal of lymph nodes (ex. breast cancer) can cause lymphedema of hand, arm, back, breast, trunk
- elephantiasis: extensive swelling of lower half of body due to obstruction of lymph flow by parasitic round worms
what are properties of veins?
- 3 layers:
- tunica intima (with endothelial cells)
- tunica media (with VSM cells)
- tunica adventitia (with connective tissue and
nerves)
- highly compliant, very distensible
- 70% of blood in venous circulation at rest
- have valves for unidirectional flow
what are the properties of arteries?
high compliant and distensible
- important for their role in receiving high pressure blood flow
- allows arteries to reduce pulsatility and act as pressure reservoirs
(low volume capacity but can withstand large intramural pressure differences)
how does compliance of veins vary with blood pressure?
- compliance is very high at low blood pressures
- high capacitance: large change in V with small change in P
- capacitance allows veins to act as volume reservoirs
- compliance decreases at high blood pressures
(large volume capacity)
what is passive capacitance? what is active capacitance?
- passive: passive changes in venous volume (ex. flow changes)
- active: active changes in venous volume (ex. sympathetic vasoconstriction)
how does sympathetic stimulation (ex. hemorrhage) increase cardiac output?
constriction of arteriole VSM -> decreased flow into vascular bed -> decreased venous flow -> passive recoil of veins -> decreased venous volume -> increased venous return -> increased cardiac output
what kind of capacitance occurs in peripheral veins?
ex) in canines, direct sympathetic stimulation to peripheral circulation
- limb inflow decreases during sympathetic stimulation, decreasing limb outflow
- if limb inflow is held constant, limb outflow and capacitance are constant during sympathetic stimulation
capacitance changes in peripheral veins are passive (no vasoconstriction, veins are reacting to what is flowing through them)
what kind of capacitance occurs in splanchnic circulation?
ex) in canines, direct sympathetic stimulation to abdominal circulation
- when inflow rate held constant, sympathetic stimulation increases outflow
splanchnic circulation shows active capacitance
- ~200 mL
- increase CO by 20%
- 90% occurs in liver
- resting upright sympathetic drive is sufficient to induce near maximal active capacitance
what are varicose veins? what are some symptoms?
due to destruction of valves causing backflow of blood
- heavy/aching legs
- ankle swelling
- skin discolouration (build up of metabolites)
what are some complications and treatments of varicose veins?
complication:
- predisposition to syncope (blood pooling in legs, less reaching the brain)
- intolerance to standing
- eczema
- thrombophlebitis
treatment:
- compression socks
- elevation of legs
- anti-coagulant drugs
- vein removal
what determines venous return?
VR = Q = changeP/R
changeP = Pmeansystemicfilling - Prightatrial (driving force of VR)
R = resistance expressed for entire vasculature
- total peripheral resistance (TPR) (~20 mmHg/L/min)
what is the mean systemic filling pressure?
- theoretical pressure if the circulation is experimentally stopped and arterial and venous pressures equilibrate (~7 mmHg)
- represents the driving force of filling of the right atrium
how is MAP calculated?
MAP = diastolicP + 1/3pulsepressure
(pulse pressure = diastolic - systolic)
- Q = MAP/R
~93 mmHg
what is the critical closing pressure on the vascular function curve?
when transmural pressure is negative and the veins collapse
- top left portion of curve that is a horizontal line
what happens when RAP equals mean systemic filling pressure?
no CO or VR
what are the values of VR and RAP at resting?
- VR = 5 L/min
- RAP = 2 mmHg
- the lower the RAP, the greater the driving force for VR
what does the slope of the vascular function curve represent?
1/R (=Q/P)
- shallow slope = increased resistance (decreased Q for a given P)
- steep slope = decreased resistance (increased Q for a given P)
how do vasodilation and vasoconstriction affect the VFC?
- vasodilation: increased slope (decreased resistance), greater VR for a given RAP
- vasoconstriction: decreased slope (increased resistance), lower VR for a given RAP
how does blood volume affect the VFC?
shift the curve without affecting the slope (increase PMSF)
- ex) hemorrhage shifts curve left
- ex) blood transfusion shifts curve right
what happens to CO when RAP is increased? how is this disequilibrium between VR and CO restored?
- increased RAP increases CO but decreases VR
equilibrium restored: - increased CO will cause increases in VR by:
- increased venous pressure
- sucks blood out of RA, decreasing RAP
- after the brief increase in CO due to increased RAP, the decreased VR will decrease CO
want to maintain the steady-state point where CO=VR
how can the steady-state point be shifted?
shifting the vascular function curve, ex. with transfusion:
- new steady state with higher CO, higher VR, higher RAP
shifting the cardiac function curve, ex. with positive inotrope:
- new steady state with higher CO, higher VR, lower RAP
what happens to the VFC and CFC with sympathetic stimulation?
both get shifted
- new steady state with much higher CO, much higher VR, and similar RAP
what is heart failure? what is it often due to? what happens as a result of it? how can recovery occur?
heart failure: compromised cardiac pumping capacity often due to myocardial infarction
- infarction = complete cessation of blood flow and tissue death
- ischemia = reduced blood flow and O2 supply < demand
tissue/cell death can be due to:
- necrosis (unregulated cell death)
- apoptosis (highly ordered cell death)
- recovery means improving the function of the remaining cells
what are the stages of compensated heart failure?
- from normal to acutely damaged: cell death decreases CO
- from acutely damaged to damaged with SNS stimulation (acute compensation): CO decrease activates baroreceptors and SNS activity, increasing contractility
- SNS causes vasoconstriction which increases MSFP
and decreases slope of VFC (increased R) - mins-hrs
- SNS causes vasoconstriction which increases MSFP
- from damaged w/ SNS stim. to partially recovered: renal fluid retention increases blood volume and MSFP, stunned myocardium recovers
- hrs-days
what occurs in decompensated heart failure?
cannot maintain CO
- renal fluid retention causes over-stretch of the myocardium and pulmonary edema due to too much fluid retention
what are treatments of decompensated heart failure?
cardiac glycosides; eg. Digitalis
- increase contractility
diuretics; eg. furosemide
- increase renal excretion
- lowers blood volume
what is the autoregulatory range of a vessel?
limited change in flow due to properties of the vessel (ex. myogenic tone; increased Q = increased stretch)
- prevents high flow at high Ps
ex vessels) brain, kidney, skin, coronary
- vascular beds change their radius in response to changes in pressure
what factors contribute to autoregulation of blood flow? what do they do?
- myogenic: increased flow -> increased stretch -> reflex constriction
- metabolic: decreased flow -> metabolites build up (decreases PO2) -> local vasodilation
- ANS control (baroreflex): SNS stimulation -> vasoconstriction; PNS stimulation -> vasodilation (not big role)
what type of autoregulation dominates at rest in skeletal muscle?
sympathetic tone
- NA binding to a1 (and a2 to amplify signal) adrenoreceptors causes vasoconstriction
- adrenaline levels low so little B2 adrenergic stimulation
what type of autoregulation dominates during exercise in skeletal muscle?
metabolic effects
- vasodilator metabolites (especially adenosine) cause vasodilation
- dilation predominates despite increased sympathetic tone
- adrenaline levels rise causing B2 adrenergic stimulation and dilation
what is active hyperemia?
metabolite-induced vasodilation and therefore increased blood flow
- few seconds to initiate
what is reactive hyperemia?
increased flow in response to ischemia (ie the beginning of exercise is similar to ischemia b/c amount of blood flow is not sustaining needs)
- K+ release hyperpolarizes VSM, causing vasodilation
what blood flow changes occur during exercise?
- metabolic dilation predominates in muscle and heart (blood diverted to those areas)
- thermoregulatory dilation occurs in skin vasculature
- adrenergic constriction restricts flow to non-essential organs (kidneys, abdominal, etc.)
- skeletal muscle pumps enhance VR
how does blood flow in apical skin (nose, lips, ears, hands, feet)?
contains arteriole to venule shunts (arteriovenous anastamoses - bypass capillaries and dissipate heat)
- low resistance pathway: allows a high flow of blood, sympathetic regulation, insensitive to metabolic vasodilators
what happens to apical skin when core temp is increased?
decreased sympathetic output leads to less vasoconstriction and more flow through anastamoses + heat dissipation
how does blood flow in non-apical skin?
neural autoregulation predominates over metabolic
- sympathetic cholinergic innervation of sweat glands
- in response to heat, increased sweating occurs due to sympathetic cholinergic vasodilator activity and sweat glands release bradykinin + other local mediators
- causes vasodilation and increased heat dissipation
what are some characteristics of cerebral blood flow?
- 10-15% of CO yet only 2% of body weight
- intolerant of ischemia (dependent on oxidative metabolism of glucose; interruption for a few seconds can cause syncope)
- autoregulation is pressure and metabolic predominate (not neural)
- BBB
what are properties of the blood-brain barrier?
- continuous tight-junctions and limited transcytosis
- few select breaches (ex. posterior pituitary)
- highly lipid soluble molecules can pass (CO2, alcohol, caffeine, nicotine)
- permits water through endothelial water channels
what arteries supply cerebral blood flow? what is the function of the Circle of Willis?
- internal carotid and vertebral arteries
- COW maintains effective flow even if flow in one artery is reduced
why are some people prone to syncope?
- cerebral autoregulation is less effective (more pronounced reduction in flow as cerebral pressure falls upon standing)
- cerebral circulation abnormally sensitive to CO2
- baroreflex BP control is impaired (decreased systemic pressures with standing further reduce cerebral pressure)
how does increased cerebral CO2 sensitivity cause syncope? how does MCA velocity differ in syncope patients?
- more pronounced pathway: standing causes increased ventilation and decreased CO2, causing vasoconstriction and decreased blood flow
- MCA velocity is reduced at a much faster rate in response to drops in CO2 in syncope patients
how is O2 delivery increased in coronary circulation?
by increasing blood flow (not O2 in blood)
- b/c near maximal O2 extraction at rest, must increase O2 consumption by increasing blood flow
- myocardial O2 consumption has a linear dependence on coronary blood flow (more O2 reaches myocytes with more blood flow)
where does coronary circulation originate? what are the paths of blood? where does coronary circulation drain into? at what part of the cardiac cycle is the most blood entering coronary circulation?
- originates from just behind the aortic valve
- aorta gives rise to left and right coronary arteries
- right coronary artery supplies RV, AVN and SAN
- left coronary arteries splits into left anterior descending (supplies LV, Bundle of His and conduction tissue) and circumflex arteries
- drains into coronary sinus and then RA
- most blood is entering during diastole (LCA blood flow peaks right after systole, after aortic valve closure)
how is coronary blood flow mechanically regulated?
myocardial contraction increases resistance in coronary arteries causing decreased flow during systole (most flow occurs in diastole)
- endocardium is most vulnerable to ischemia/infarct b/c most distal part of arteries
how does coronary blood flow receive neural regulation?
- high intrinsic vasomotor tone: resting sympathetic vasoconstriction (NA binding a1-adrenergic, activating Gq, PLC, pathway)
- vasodilator reserve that can be activated by epi binding B2-adrenergic receptors
what are examples of metabolic dilators in coronary circulation?
- decreased O2
- increased CO2
- increased adenosine
- decreased pH
- increased K+
- decreased ATP
- increased NO (GTN and nitroprusside used to treat angina)
how does coronary blood flow receive myogenic regulation?
intrinsic mechanism: stretch due to increased blood flow causes vasodilation to reduce pressure and vice versa
when does the fetal heart start beating? what does placenta fulfil the role of? what are the 4 circulatory shunts?
- fetal heart starts beating at 4 weeks
- placenta fulfils role of lungs, GI tract, liver (waste removal), and kidneys (waste removal, electrolyte balance)
- 4 shunts: placenta, ductus venosus, foramen ovale, ductus arteriosus
how does placenta contribute to fetal circulation?
mixes maternal and fetal blood
- receives 50% of CCO via umbilical arteries
- exchange occurs across the placental membrane
- fetal hemoglobin (FHb) has high O2 affinity
how does the ductus venosus contribute to fetal circulation?
connects umbilical vein bringing blood from the placenta to the IVC
- bypasses liver
how does the foramen ovale contribute to fetal circulation?
connects RA to LA
- fetal ventricles pump in parallel
how does the ductus arteriosus contribute to fetal circulation?
connects pulmonary artery to the aorta
- flow to pulmonary vessels is low due to hypoxic vasoconstriction
what cardiopulmonary adjustments occur at birth?
1) infant takes first breath (requires huge inspiratory pressure)
2) umbilical arteries vasoconstrict
3) ductus venosus closes (< 3 hrs)
4) increased pressure in LA (and decrease RAP) causes foramen ovale to close (takes few days or months-yrs)
5) direction of flow in ductus arteriosus changes (immediately)
what happens when the infant takes its first breath?
- occurs due to (temporary) hypoxia and hypercapnia and decreased temp
- pulmonary vascular resistance decreases (increases O2 and alveolar expansion)
- increases flow of blood to the lungs and PaO2
how do the umbilical arteries vasoconstrict and what happens after?
- stretch during delivery triggers reflex vasoconstriction
- sudden increases in PaO2 also causes vasoconstriction
- umbilical veins drain into newborn supporting its blood volume
- closes placental circulation -> increased systemic resistance drives blood back to the heart
why does the ductus venosus close?
due to cessation of flow through umbilical vein
- constriction of VSM
why does the direction of flow in ductus arteriosus change?
- decreased pressure in pulmonary artery and increased aortic pressure
- high O2 in arterial blood constricts ductus arteriosus
- prostaglandin (vasodilator) levels fall causing vasoconstriction
- closes 1-2 days after birth
what is a patent foramen ovale? what are its consequences?
foramen ovale doesn’t close completely, occurs in 20% of population
- coughing, sneezing, straining can cause mixing and briefly decrease O2 concentration
- permits clots that are usually removed in lungs (but bypass lungs) to enter systemic circulation, increasing stroke risk
- if severe, can cause increased pressures in right heart (shortness of breath, arrythmias)
what is a patent ductus arteriosus? what are its consequences? how can it be treated?
ductus arteriosus doesn’t close; most common in premature babies (high levels of prostaglandin), girls, hypoxia (low O2 = vasodilation)
- can cause increased pressure in pulmonary circulation (taking aortic blood)
- can be treated with indomethacin (blocks prostaglandin synthesis)
what are arterial baroreceptors?
- spray nerve endings (terminal arbourization/branching)
- unmyelinated
- arteries are highly distensible/compliant; stretch causes depolarization which is detected by afferent fibres
what are the 3 types of baroreceptors?
1) carotid sinus (at bifurcation)
- innervated by carotid sinus and glossopharyngeal nerves
2) aortic arch baroreceptors
- innervated by vagus nerve
3) coronary artery baroreceptors (at branch point of LAD and circumflex arteries)
- coronary pressure is increased -> coronary baroreflex mediates vasodilation -> decreases MAP
what activates baroreceptor afferents and where do they project?
when BP goes up, distention of arteries are sensed by baroreceptors, increasing afferent firing rate
- project to the medulla, specifically the nucleus tractus solitarius (NTS)
how is parasympathetic (vagal) output increased through baroreflex?
afferents synapse onto interneurons in the NTS which synapse onto preganglionic parasympathetic efferents in the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus nerve (DMVN) - excitatory synapses
- increase postganglionic ACh firing
how is sympathetic output decreased through baroreflex?
afferents synapse onto interneurons in the NTS which synapse onto the vasomotor area (inhibitory synapses) in the rostro- and caudal-ventrolateral medulla
- inhibits preganglionic sympathetic efferents
where do baroreceptor efferents arise from?
- parasympathetic (vagal): medulla
- sympathetic (heart): T1-T4; regulates heart rate, rhythm, and force
- sympathetic (blood vessels): T1-L2; regulates BP
- splanchnic vasculature: T1-T5
how does spinal cord injury affect baroreceptor efferents?
deficits in sympathetic innervation
- impaired ability to control BP, regulate HR, etc.
how does afferent firing occur in carotid sinus baroreceptors?
- regulated both by changes in MAP and the rate of change of MAP (ex. will fire when MAP is changing
- firing rate is higher in early systole
- more responsive to pulsatile pressure than constant pressure
how do hypertension and syncope alter baroreflex sensitivity?
- hypertension: altered set point (shifts to the right; set point at higher pressure)
- syncope: normal set point but reduced baroreflex sensitivity
what is the time course of MAP control mechanisms?
- baroreflex is activated first but a short term solution, decreasing activity after ~2 hrs
- renal mechanisms play a role in long-term solutions
what is the renin-angiotensin-aldosterone system (RAAS) pathway?
decreased MAP triggers renin release from juxtaglomerular apparatus -> renin converts angiotensinogen to angiotensin I -> in endothelial cells of lung capillaries, ACE converts ang I to ang II
- ang II causes vasoconstriction, increasing BP
- ang II causes aldosterone release from adrenal cortex, increasing Na+ reabsorption and increasing plasma + blood volume, increasing BP
how is renin secretion regulated?
1) decreased pressure at the afferent arteriole
- detected by granular cells -> secrete renin
2) decreased systemic BP
- increases sympathetic activity -> renin release
3) decreased [NaCl] or filtrate flow at the macula densa
- detected by macula densa cells -> renin release
what is the juxtaglomerular apparatus?
part of distal tubule that comes into close proximity with Bowman’s capsule
- contains macula densa cells (detect Na+)
- contain granular cells (secrete renin)
what is pressure diuresis? how does it influence MAP?
large loss of fluid in response to increased BP
- increased MAP increases GFR -> increases filtrate volume -> increases excretion -> decreases plasma volume -> decreases VR -> decreases CO -> decreases MAP
how is ADH secretion regulated?
1) increased plasma osmolarity detected by hypothalamus
- posterior pituitary releases ADH
- more water conserved
- increases BP and osmotic correction
2) decreased blood pressure detected due to baroreceptor input to paraventricular neurons in hypothalamus
- posterior pituitary releases ADH
- increases plasma volume
- increases MAP
ADH can also directly vasoconstrict blood vessels
what is the effect of ADH on vascular tone at high concentrations?
ADH binds renal V1a receptors, activating Gq pathway (vasoconstriction)
what is the effect of ADH on vascular tone at low concentrations?
ADH binds renal V1a receptors, activating phospholipase D (PLD) -> activates PKC -> inhibits MLCP -> vasoconstriction
- also blocks Kv channels causing less K+ extrusion (relative depolarization brings membrane closer to threshold, opening Cav1.2 more frequenctly -> vasoconstriction)
how does ADH act on the nephron?
ADH increases the expression of aquaporin water channels in the collecting duct, increasing water absorption
alcohol inhibits ADH
what triggers atrial natriuetic peptide (ANP)?
when MAP is increased, VR is increased
- stretches atrial wall, stimulates atrial stretch receptors -> ANP secretion
how does ANP influence MAP?
- decreases aldosterone, increases GFR -> increases natriuresis (Na+ excretion) and decreases Na+ reabsorption -> increases Na+ excretion, decreases plasma volume, decreases VR and CO, decreases MAP
- ANP directly dilates resistance and capacitance vessels, decreasing MAP
how does standing contribute to hypotension?
gravity has hydrostatic effects -> causes venous pooling and capillary filtration of plasma (due to increased hydrostatic pressure) -> decreased effective circulatory volume (lower volume of blood doing something) -> decreased VR and CO -> decreased cerebral blood flow
what is orthostatic tolerance? how is it tested?
how long it will take for you to pass out
- using a tilt table with lower body negative P
what occurs during presyncope?
- loss of vision
- loss of hearing
- sweating
- nausea
- muscle weakness
what is vasovagal syncope?
- withdrawal of SNS
- increased PNS (vagal)
- vasodilation (decreased TPR and CO) and decreased HR
- increase in HR precedes major decrease in HR
- most common cause of fainting
- triggered by emotional distress (sight of blood, etc.) or postural (prolonged standing)
what is orthostatic hypotension?
drop in BP upon standing up
- impaired baroreflex response to standing due to autonomic failure (ex. Parkinson’s disease)
what are some other causes of hypotension?
- supine hypotension: spinal cord injury, pregnancy (high blood volume going to fetus)
- shock (ex. hemorrhage)
- post-exercise hypotension (venous pooling)
what are some lifestyle adjustments for treating orthostatic hypotension and syncope?
- tilt training: improving baroreflex (not very effective)
- salt (increases plasma volume and BP)
- exercise training (increases plasma volume and baroreflex sensitivity)
- water drinking
what are some other treatments for orthostatic hypotension and syncope?
- salt loading (water retention, plasma volume expansion)
- head-up sleeping (increased plasma volume; decreased atrial filling -> decreased ANP -> sodium retention)
- fludrocortisone (synthetic corticosteroid: mimics aldosterone -> promotes renal Na+ absorption -> increases plasma volume)
- midodrine (short acting a1 agonist, vasoconstriction)
- pacemakers (very effective for syncope due to arrhythmia, not due to hypotension)
why aren’t pacemakers useful for syncope due to hypotension?
prevent the fall in HR that occurs with faint but not the fall in blood pressure -> does not prevent faint
what is a normal BP? what is the threshold for hypertension?
- normal = 120/80
- anything over 130/80 is high BP
- the risk of CVD doubles with increments of 20/10 mmHg
why is hypertension problematic?
- can lead to hypertrophy (reduces pumping force and SV)
- can promote atherosclerosis
- can lead to increased risk of stroke
- its silent - you don’t know you have it
what is the etiology of hypertension?
- 10% = renal hypertension (problem with renal artery - blocked blood flow, reducing P) -> renin is released even though P is only low in renal circulation, not systemic)
- 90% = idiopathic (unknown origin)
common = increased TPR
what are pharmacological treatments of hypertension?
- diuretics
- ACE inhibitors
- angiotension II receptor blockers (ex. losartan; reduce action of angiotensin II)
- Ca2+ channel antagonists
- B-blockers (decrease CO and MAP, not suitable for asthmatics - can cause airways to contract)
how do diuretics treat hypertension? what’s an example?
ex) furosemide
- limit Na+ reabsorption (inhibits Na-K-2Cl symporter)
- decrease plasma volume
- decrease MAP
how do ACE inhibitors treat hypertension? what’s an example?
ex) captopril; reduce angiotensin II
- decreased vasoconstriction
- decrease aldosterone secretion (decreased Na+ reabsorption, decreased plasma volume, decreased MAP)
- decreased cardiac hypertrophy
how do Ca2+ channel antagonists treat hypertension? what’s an example?
ex) nifedipine
- block Cav1.2
- greater effect on VSM vs cardiac
- decreased Ca2+ current = vasodilation and reduced contractility
what are some lifestyle treatments for hypertension?
diet:
- DASH diet
- reduce Na+ intake, caffeine intake, fat intake
lifestyle:
- increased activity levels
- smoking cessation
- healthy body weight
- decrease alcohol intake and stress
what are the early cardiovascular adjustments to exercise?
cerebral cortex (planning or anticipating exercise) activates cardiovascular control centres in the medulla -> increases sympathetic output -> increased CO and vasoconstriction (to divert blood from non-essential organs)
what are the delayed cardiovascular adjustments to exercise?
1) skeletal muscle dependent effects increase CO
- mechanical (muscle pump)
- chemical (metabolites)
2) increased medullary sympathetic output
- adrenaline released from adrenal medulla activates B2-adrenergic receptors in vasculature supplying skeletal muscle -> enhances vasodilation
3) increased core temp
- detected by thermoreceptors in hypothalamus -> inhibition of dermal vasoconstriction and increased blood flow to the skin
how does O2 consumption change with exercise? what limits O2 consumption?
- increases with increased power - 10-20 fold increase during exercise (varies with age, fitness, genetics)
limits: - uptake of O2 by the lungs
- delivery of O2 by blood flow
- extraction of O2 from the blood
what is Fick’s principle? how is it changed during exercise?
VO2 = (a-vO2)(Q)
- 4x increase in a-vO2 difference
1) capillary recruitment increases exchange surface
2) increased unloading of O2 from Hb due to increased PCO2, decreased pH, and increased tissue temp
- 4x increase in CO
- 3x increase in HR and 2x increase in SV
how does training increase VO2max?
training-induced changes in blood flow and O2 extraction:
- decreased resting heart rate (possible decreased HCN channel expression)
- little effect on max HR; increased HR reserve (lower resting, same max therefore increased range of HR)
- minor increase in O2 extraction: increased capillarization of muscle, increased diffusion gradient due to increased mitochondrial content
increased VO2max is mainly due to increased SV, thus increased CO
how does training increase SV?
increased contractile force = increased ejection fraction
- due to increased hypertrophy (contractility) and increased plasma volume -> increases VR and EDV
- training = decreased resting HR -> more time in diastole -> increased time for filling and VR (during max exercise this effect is lost; contractility becomes more important)
what kind of hypertrophy is caused by exercise?
physiological hypertrophy
- increased heart mass
- normal or improved function
- reversible (halting training takes you back to normal)
- no fibrosis, normal organization of cellular structures
what kind of hypertrophy is caused by CVD?
pathological hypertrophy
- increased heart mass
- reduced function
- irreversible
- upregulation of fetal genes (MHC, SERCA)
- increased fibrosis (collagen) = stiffness
- cardiac dysfunction and increased mortality
- often working against a higher afterload
what is eccentric hypertrophy?
increased cell length
- ventricular dilation and increased wall thickness
- seen with volume overload (endurance exercise, faulty valve)
what is concentric hypertrophy?
increased cell width
- increased wall thickness, no dilation
- seen with pressure overload (resistance training, hypertension)
what signalling pathway is involved in pathological hypertrophy?
- excessive AngII, endothelin, NA activation of Gq (activates hypertrophic gene expression)
- Gq knockout mice don’t develop hypertrophy
what signalling pathway is involved in physiological hypertrophy?
- insulin-like growth factor 1 (IGF1) activation of PI3-K
- PI3-k regulates cell growth and survival
- in transgenic mice: overexpression of IGF1/PI3-K causes hypertrophy with normal cardiac function; underexpression of IGF1/PI3-K causes less hypertrophy
what is arteriosclerosis? what is atherosclerosis?
- arteriosclerosis: hardening of the arteries due to arterial wall thickening and loss of elasticity
- atherosclerosis: hardening due to intimal lesions (plaques)
- soft, yellow, cholesterol-rich core
- white, fibrous cap
- protrude into vessel lumens
where is plaque most likely to form?
from large to small arteries
- coronary and carotid arteries
- particularly at bifurcation points
- aorta
what are the cardiovascular effects of atherosclerosis?
1) plaques decrease the effective vessel radius
2) plaque rupture
3) increased risk of embolism
- myocardial infarction
- stroke
how does atherosclerosis decrease the effective vessel radius?
ex) in coronary arteries
- atheromas (plaques) impede local reflex vasodilation
- vasodilator reserve is reduced
- tolerance to exercise is reduced
- can cause angina or MI
how is plaque rupture dangerous?
exposes collagen and other thrombogenic substances
- local thrombus (clot)
- partial or complete vessel occlusion
how does atherosclerosis increase risk of embolism (obstruction of a vessel)?
- debris gets lodged downstream
- thromboembolism -> thrombus or debris from ruptured plaque (embolus) occludes a downstream vessel
what are classical risk factors for atherosclerosis?
- hypercholesterolemia (excess cholesterol in bloodstream)
- dyslipidemia (incorrect lipid balance)
- altered ratio of low density lipoprotein (LPL) and high density protein (HDL)
- obesity
- diabetes mellitus (uncontrolled)
- smoking
- sedentary lifestyle
- hypertension
- gender (M>F) -> post-menopausal decreases estrogen, increasing risk
- hyperlipidemia
what is the function of LDL? HDL? what ratio is a risk factor for atherosclerosis?
- LDL: transports cholesterol from liver to tissues
- HDL: transports cholesterol from tissues to liver
- high LDL or low HDL is associated with atherosclerosis
how do we know that lipids are involved in atherosclerosis?
- epidemiological studies
- genetic disorders (Tangier disease, familial hypercholesterolemia)
- transgenic mice
- pharmacological intervention - lipid lowering drugs
what is Tangier disease?
congenital mutation in ABC protein
- ABC enables cholesterol to exit tissue and bind ApoA1 of HDL
- genetic defect causes decrease of HDL cholesterol in blood and increased risk of CVD
what is familial hypercholesterolemia?
mutation in tissue LDL receptor (cholesterol bind LDL allowing it to leave bloodstream and be taken up into tissues)
- increased LDL cholesterol in blood and CVD risk
how do transgenic mice tell us that lipids are involved in atherosclerosis?
overexpression of ApoB (lipoprotein associated with LDL)
- increased development of atherosclerosis and CHD
- increased risk of CVD
what lipid lowering drugs tell us that lipids are involved in atherosclerosis?
statins: reduce cholesterol synthesis by blocking HMG-coA reductase in liver
- decreased CVD risk (preventative treatment)
alirocumab: inhibitor of PCSK9
- PCSK9 degrades the LDL receptor in liver, therefore decreased PCSK9 increases LDL receptors in liver and decreases blood LDL
what are diagnostic indicators of atherosclerosis?
- C-reactive protein
- bacteria/viruses
- hyperhomocysteinemia
- lipoprotein A
- blood iron concentration
- platelet aggregation
- erectile dysfunction
- peridontal disease
how is C-reactive protein a diagnostic indicator of atherosclerosis?
- released from the liver in response to cytokines (ex. IL-6 from active macrophages)
- indicator of inflammation or infection
how are bacteria/viruses a diagnostic indicator of atherosclerosis?
chronic inflammation, leukocyte and lipid accumulation
- bacteria and viruses found in plaques
how is hyperhomocysteinemia a diagnostic indicator of atherosclerosis?
increased blood homocysteine concentration associated with CHD (increased oxidative stress)
- folic acid reduces homocysteines (uncertain therapeutic effect)
how is blood iron concentration a diagnostic indicator of atherosclerosis?
- contributes to lipid peridoxation
- pre-menopausal women are protected
- some advise to reduce red meat intake
how is erectile dysfunction a diagnostic indicator of atherosclerosis?
- may be a warning sign of impaired vascular health
- high C-reactive protein promotes endothelial function
how are lipoprotein A, platelet aggregation, and peridontal disease diagnostic indicators of atherosclerosis?
- lipoprotein A: genetic variant of LDL associated with increased coronary and cerebrovascular disease
- platelet aggregation: increased susceptibility to aggregation = increased risk
- peridontal disease: 20% higher risk of CHD due to inflammatory risk
what is the oxidized LDL hypothesis of atherosclerosis?
- endothelial damage and accumulation of oxidized LDL in the tunica intima and the vessel lumen
- in lumen: oxidized LDL causes expression of macrophage chemoattractant protein (MCP-1) which triggers the movement of monocytes and T-cells from vessel lumen to tunica intima
- in intima: oxidized LDL changes endothelial cell lining to express vascular cell adhesion molecules (VCAMs) -> causes monocytes and T-cells to adhere to endothelium by interacting with VCAM
- monocytes diffuse from the lumen to the intima and differentiate into macrophages and express scavenger receptors, which help them ingest LDL by binding LDL -> causes accumulation
- after consuming LDL and becoming filled with fatty droplets, macrophages become foam cells
- foam cells and T-cells create fatty streak (early form of plaque)
- foam cells release growth factors, inflammatory factors, and cytokines to regulate the properties of the vessel wall
what is the process of plaque progression and rupture in atherosclerosis?
VSM cells migrate into intima (proliferate) and switch to secretory phenotype -> secretion of ECM proteins produces a tough fibrous cap -> cap weakened by inflammatory substances secreted by foam cells -> plaque ruptures -> foam cells may display a factor that promotes blood clotting; contact with collagen in the plaque triggers platelet aggregation -> thrombus blocks vessel (can cause ischemia, MI, etc.
what are some associations between risk factors and cellular events in atherosclerosis?
1) hypertension
- causes turbulent blood flow
- non-laminar shear stress increases endothelial adhesion
- triggers pro-atherosclerotic signalling pathways
2) diabetes
- high blood glucose causes increased glycosylation and oxidation of LDL
- associated with hypercholesterolemia
3) inflammation/infection
- components of infection can increase cytokine levels
- increase protease activity (break down ECM) -> increases likelihood of plaque rupture
what are lifestyle treatments for atherosclerosis?
1) diet (decrease LDL:HDL ratio)
- decrease intake of saturated fats (ex. animal fats)
- increase omega-3 fats (ex. flax seeds)
- decrease caloric intake
2) stop smoking: chemicals can change endothelium and increase lipid oxidation
3) exercise: decreases body weight and LDL
4) the French paradox: red wine, garlic, and tomatoes contain anti-oxidants
what are pharmacological treatments for atherosclerosis?
1) statins: decrease LDL, inhibit HMG-coA reductase, reduces CHD
2) folic acid: reduces homocysteine levels (effectiveness not proven)
3) aspirin: decreases coagulation, reducing risk of clots
4) antihypertensives: B blockers of ACE inhibiters reduce BP
5) vitamin B3: decreases LDL and increases HDL levels
what occurs during an angioplasty?
- catheter with balloon
- plaque ruptured and reduced
- stent holds artery open
- thromboembolism can lead to stroke
- high probability of restenosis within 1-2 years (plaques can reform)
- try to reduce VSM proliferation or vasoconstriction using iNOS
what happens during coronary artery bypass grafting (CABG)?
- open heart surgery
- heart is arrested and cooled
- circulation bypassed using a heart-lung machine
- artery with plaque physically removed, replaced with piece of saphenous vein from leg or mammary artery
- very invasive and expensive
- risk of bypass surgery
- still doesn’t fix the cause
- new blood vessels can develop atherosclerosis
what defines the extent of damage due to myocardial ischemia?
- vessel affected
- transmural location
- location and extent of block
how can a supply and demand mismatch cause myocardial ischemia?
- anoxia (total O2 deprivation), hypoxia
- decreases FFAs
- decreased glucose
- build up of metabolites (CO2, lactate, K+, H+)
what are the consequences of ischemia?
- decreased beta oxidation due to decreased O2 availability -> decreases ATP production
- decreased glucose oxidation increases pyruvate conversion to lactic acid -> increased lactic acid decreases pH, causing acidosis
- increases CO2 waste increases H+ -> decreases pH and causes acidosis
- peroxidation of lipids (membrane and mito damage)
- hypocontractility and increased incidence of arrhythmia
what are the effects of acidosis and low ATP?
1) electrical remodelling
2) altered Ca2+ handling
3) reduced force of contraction
how does acidosis cause electrical remodelling?
protons inhibit many ion channels; net effect:
- decreased Na+ channel, voltage-gated K+ channel, and Ca2+ channel activity
- altered ion channel activity may be pro-arrhythmogenic, particularly if conduction pathways are affective (ex. bundle branches)
how does acidosis alter calcium handling?
- lowers systolic Ca2+: inhibition of Cav1.2 reduces Ca2+ entry; inhibition of RYR reduces SR Ca2+ release
- increases diastolic Ca2+:
- inhibition of NCX decreases Ca2+ extrusion
- intracellular protons leads to Na/H exchange = increased Na+ = Ca2+ entry via NCX (reversal of NCX)
- inhibition of SERCA reduces SR uptake of Ca2+
net effect: cytoplasmic Ca2+ rises
- but Ca2+ is elevated even during diastole, causing tonic contraction (contraction during diastole)
- elevated Ca2+ activates protease enzymes (ex. Calpain), causing protein breakdown
how does acidosis reduce force of contraction?
hypocontractility (reduced force of contraction):
- decreased myofilament Ca2+ sensitivity - need more Ca2+ to produce contraction (TnC)
- decreased cross-bridge cycling (decreased ATPase activity)
what are the effects of ischemia on Na+ and K+?
decreased Na-K-ATPase activity (decreased ATP and increased H+ - directly reduces ATPase activity)
- extracellular K+ accumulation causes Ek and RMP to become more depolarized
- intracellular Na+ accumulation reverses NCX activity, causing Ca2+ entry
net effect:
- elevated intracellular Na+, elevated extracellular K+, and elevated RMP
- increased excitability - proarrhythmic
