Roles of Circulatory System

• primary roles: distribution of dissolved gases, distribution of nutrient molecules
• secondary roles: fast chemical signaling(hormones and neurotransmitters), dissipation of heat for core to surface, mediation of inflammatory and host defense

Disease Caused by failure of

Circulatory System

• Congestive heart failure: heart as a pump
• thrombosis and embolism: blood as effective liquid organ
• Hemorrhage: vasculature as competent container
• Atherosclerosis: efficient distribution system

Cross Sectional Area of Vessels

• capillaries have the highest at 2500cm² 
• Aorta is the smallest with 2.5cm²
• second largest is venules
• Aorta has the highest velocity and capillaries the lowest(more exchange)
• Bloow flow=XSA x velocity
• XSA= cross sectional area

Three Kinds of Pressure Differences,

and their axes, in a blood vessel

• drving pressure: along the axis-between arterial and venous ends of systemic circulation
• transmural pressure: difference btw inside(intravascular) the vessels and just outside the vessel(tissue)
• hydrostatic pressure: difference in height
• fig 17.4 in book
• P=F/A

Viscosity of Blood

• high in center but low near the walls
• increasing hematocrit exponentially increases viscosity
• normal hemocrit is around 45 with a viscosity of around 4
• hemocrit is cells in the blood

Laminar Vs Turbulent Flow

• flow is laminar and increases as long as there is a pressure difference and no resistance
• however after a critical velocity, resistance increases and flow becomes turbulent
• Reynolds number(dimensionless quantity) determines the turbulent flow (exceeds 2000)
• examples branching points in aorta and stenosis

Pressure Oscicilltations of blood flow

• Mean Arterial Pressure= Diastolic pressure + 1/3 of systolic pressure
• systolic pressure is high number and diastolic the lower one

Compliance

• if you change the volume the pressure changes
• how much you can stretch as well as hold the volume
• Compliance = ^V/^P
• veins have high compliance (hold lots of volume with out change in pressure
• arteries have low compliance(high pressure for not as much volume)
• decreases with age

Anatomy and Function of vasculature

• aorta-billions of capillaries-single vena cava
• arteries: distribution system
• microcirculation: dffusion and filtration system
• vein: collection system 

Keyparameters of Circulation System

• number of vessels(1 arota to 4x10^10 cappilaries)
• radius of an individual vessel: declines
• cross sectional area
• mean linear velocity: decreases
• single vessle flow: decreases
• relative blood volume: systemic>pulmonary>heart
• circulation time: 1 min for complete journey, 10 sec for coronary circ
• presure profiles: higher in systemic then pulmonary
• elastic properties

Blood Vessel

Resistors and Capacitors 

• compliance
• resistors show a large increase in pressure with an increase in volume(more linear) (aorta)
• capacitors show a large increase in volume with a small increase in pressure (vena cava)

Wall Tension

• opposes transmural pressure
• T=^P x r
• wall tension increases with increase in radius in arteries but not in veins
• collogen fibers react more to a change in radius where as elastic fibers barely gain tension with a large increase in radius(intact artery btw)
• smooth muscle contraction reduces radius and wall tension

Microcirculature

• microcirculation serves both nutritional and non-nutritional role
• the two sides of blood vessels and capilaries in btw
• all contains endothelium
• metarteriold: shortcut in system w/ discont VSMC
• capillaries contain a single layer of ECs surround by BM
• precapillary sphincters: transition btw a cap. and arteriole or metarteriole
• capillaries fall into three groups based on degree of leakiness

Capillary Types

• continuous: most common with interendothelial junctions(10-15 nm wide)
• fernestrated: endothelial cells are thin and pnctured with fenestrations(mem.-lined, cylindrical conduits), most often surrounding epithelia(small intestine and renal glomeruli)
• discontinuous: with large gap and found in sinusoids(open por capillary, lack of diaphragm and few tigh jnx). large intercellular clefts increase permiability. found in liver

Capillary Exchange of Solutes

• lipid-soluble subs like O2 and C02 readily exchange across capillary ECs by diffusion
• water and electrolytes move across the endothellium primarly by bulk flow via interendothelial clefts(pores)
• vesicular transport mech. move large molecules across the endothelium (transcytosis)
• active transport mech. move ions and other small molecules across the endothelium

Krogh Model

**

• Explains PO₂ w/in the capillary and PO2 shape of profiles w/in the vessel and tissue
• arterial blood has high O2 level
• PO2 profile of the capillary depend on: 
• Free O2 in the arteriolar blood (dissolved in plasma) and O2 content of the blood (<2% of total O2 is dissolved)
• capillary blood flow (F)
• radial diffusion coefficient (D_r)
• capillary radius (r_c) and tissue cyclinder r. (r_t)(tissue cylinder radius is from capillary to capillary)
• O2 consumption by surrounding tissue (Qo₂)
• axial distance (X) along the capillary

O₂ Extraction Ratio

**

• depends on blood flow and metabolic demand
• decreases as flow increases
• increases as O₂ consumption increases
• 2 equations 

Excercise Effect On Capillaries

• O2 consumption, vasodilation, blood flow, density of perfused capillaries and PO2(tissue) all go up
• tissue radius of Krogh cylinder, diffusion distance both go down
• PO₂ in the capillary lumen during excercise: will fall less sharply when increase F, but PO₂ actually fall deeply due to increase oxygen consumption, Qo₂: oxygen consumption overides flow here

Diffusion of water soluble solute

across a capillary wall

• controlled by mechanism of bulk flow with diffusion
• hydrophillic solutes smaller than albumin can transverse the capillary wall thru paracellular route such as clets, interendothelial junctions, gaps or fenestrae
• due to the property of lipid-insoluble, small polar molecules have a relatively low permeability, can only diffuse through water-filled pore

Permiability Coefficient

• used when calculating flux of a small water-soluble solute
• P_x=Dx/a
• the permibility coefficent is a parameter combined D_x (diffusion coefficient, cm²/s) and wall thickness, a(cm)
• thus  P_x expresses the ease with which the solute crosses a capillary by diffusion
• also affected by leakiness

Estimation of Capillary Permeability

• estimated by whole-organ extraction ration
• E_x = (Xa-Xv)/Xa :just like extraction ratio
• E_x depends on total organ blood flow(F) and (P_x)S
• E_x = 1- e^-(P_xS/F)

Small-Pore Effect

• small pores- 3nm of radius
• the permability coefficient of small polar molecules falls as molecular radius rises
• for lipid-soluble subs like CO2 and O2, which can diffuse thru the entire capillary cell, the permeability is much larger
• small polar molecules can diffuse only by paracellular path via inter-endothelial cleft, or other water filled pathways, which constitute only a fraction of total capillary area

Large-Pore effect

(transcytosis)

• caveoli (membrane invagination) are predominantly responsible for translocation of macromolecules (caveoli contain protein caveolin)
• process of vesicular transport governs transcytosis of macromolecules
• apparent permeability of typical capill. macromol. falls of steeply w/ inc. in molecular radius, feature of sieving

Transcellular vs Paracellular 

Capillary Exchange of Water

• trnacellulary pathway involves AQP1 (aquaporin, a water channel in EC)
• Paracellular pathway involves interendothelial clefts, fenestrae or gaps

Convection

• main mechanism for the transfer of fluid across the capillary membrane 
• two driving forces for convection of fluid or bulk water mvt: transcapillary hydrostatic pressure difference and effective osmotic pressure difference
• hydrostatic pressure is Capillary pressure vs Interstitial fluid pressure
• osmotic pressure is the amounts of protein in the capillary and in the interstitial fluid 

NDF

• net filtration pressure
• (P_c-P_if) - σ(∏_c-∏_if)
• NDF > 0, filtration (NDF > 0 at arterial end)
• NDF<0, reabsorption ( ex is at venous end)
• NDF= 0 no net fluid movements
• σ refelcts the permeability of capillary to the proteins responsible for generatic osmotic pressure

Beta-Adrenergic Receptors

• members of a superfamily of GPCRs
• can lead to cAMP or DAG, IP₃ secondary messangers
• seven transmembrane domains
• alpha, beta, and gamma gprotein subunits
• β1 - heart, β2 - vascular, pulmonary, GI smooth muscle, β3 -adipose tissue

Pharmacological Profile

of Beta 1 and 2 receptors

• NE and Epi have the same effect on Beta 1 receptors (heart)
• Beta 2 receptors do relaxation of smooth muscles, epinephrine has a greater effect, NE needs a higher concentration to have the same effect
• conc of NE usually does not reach level needed to have a beta 2 response

β1 Adrenergic Receptor Signaling

• activates Gs actives AC to increase cAMP levels
• cAMP activates PKA and I_f channel(HCN channel, SA node)
• PKA then targets L-type calcium channel, ryanodine receptor, troponin I, phospholamban in ventricular muscle
• PKA can also targe I_f channel

Phospholamban

• inhibits SERCA normally
• when PKA phosphoralates it, phospholamban becomes inhibited
• this allows SERCA to operate, increasing the rate of relaxation in the cell
• increases ionotrophy because with next contraction, theres more calcium in the SR

Beta2 adenergic receptor signaling

• activation causes an increase in cAMP levels in the vascular smooth muscle
• this causes a reduction in MLCK activity 
• leads to a relaxation of the smooth muscle

Drugs that target β-ARs

• β-ARs agonists are epinephrine, norepinephrine, dopamine, isoproterenol, dobutamine(β1) and albuterol (β2)
• β-AR Antagonists are propranolol and metoprolol(β1)

Effects of β-AR blockade

• heart: decrease contractility, and heart rate

Therapeutic Uses: β-AR Agonists

• heart failure
• cardiac arrest
• asthma
• anaphylaxis

Therapeutic Uses: β-AR antagonists

• post-MI
• angina
• hypertension
• heart failure
• arrhythmias

Ca Channel Blockers-Classes

• dihydropyridines: Nifedipine
• Non-Dihydropyridines: Verapamil, diltiazem
• reduce contraction, heart rate, and something
• in smooth muscle they relax
• Heart: Verapamil>diltiazem>dihyrdopyridines
• Arteriolar Smoot M.:dihydropyridines> diltiazem> verapamil

Therapeutic Uses: Ca Channel Blockers

• hypertension, angina, arrhythmias
• CCBs can reduce cardiac contractility, heart rate, and conduction
• arteriodilation

Vasoconstrictor area of

Vasomotor Center

• located bilaterally in anterolateral portions of upper medulla; 
• fibers from these neurons are disrtibuted to all levels of spinal cord, excite preganglionic vasoconstrictor neurons of sympathetic nervous system

Vasodilator Area of 

Vasomotor Center

• located bilaterally in anterolateral portions of lower medulla
• fibers from these neurons project upwards to vasoconstrictor area 
• they inhibit vasoconstrictor activity resulting in vasodilation

Sensory Area of 

Vasomotor Center

• located bilaterally in posterolateral portions of medulla and lower pons
• neurons receive sensory nerve signals through vagus and glossopharyngeal nerves,
•  output signals from this area control activities of vasoconstrictor and vasodialator areas

Vascular tone

• contractive state of vessel or vascular region
• arteriolar tone: regulated by basal tone, local metabolic vasodialator factors, symp vasoconstrictor nerves(viaα1)
• venous tone: controlled by symp vasoconstrictor nerves, internal pressure, external compression
• basal arteriolar tone contributes to total peripheral resistance and arterial BP in resting ind
• flow in brain, cardiac and skeletal muscle under local metabolic control
• flow in kidney, skin, splanchnic regulated by symp nerve 

Sympathetic vasoconstrictor tone

• vasoconstrictor area continuously transmits signals to sympathetic vasoconstrictor nerve fibers, cause slow firing of these fibers -> continual firing is called symp vasoconstrictor tone
• causes continuous partial constriction of blood vessels, called vasomotor tone

Reflex Mech. for

controling arterial pressure

• baroreceptors
• chemoreceptors
• low-pressure receptors 

Baroreceptor reflex

• negative feedback reflex mechanism-primary purpose to stabilize minute by minute variations in arterial pressure
• initiated by stretch receptors called baroreceptors or pressoreceptors; located at specific points in walls of systemic arteries
• respond rapidly to changes in arterial pressure; geater response to rapidly changing pressure
• 2 main types: carotid baroreceptors (use herring nerve) and aortic baroreceptors

Baroreceptors during

changes in body posture

• upon standing, fall in arterial pressure in head and upper part of body leads to loss of consciousness
• falling pressure at baroreceptors initiates an immediate reflex resulting in strong sympathetic dischange -> increases arterial pressure back to normal

Chemoreceptors

• initiated by chemosensitive cells that are sensitive to oxygen lack and excess of CO2 and Hion concentration
• located in chemoreceptor organs: 2 carotid bodies and 1-3 aortic bodies (adjacent to aorta)
• excite nerve fibers passing through herings and vagus nerves into vasomotor center of brain stem
• only functional when presssure drops below 80mm Hg
• each carotid/aortic body has an abundant supply 
• can both speed up and slow down heart depending on O2 levels and other conditions

Atrial and Pulmonary Artery Reflexes

• stretch receptors called low-pressure receptors
• located in walls of atria and pulmonary arteries
• similar to baroreceptors, usually work in parallel to baroreceptors
• regulate differences in arterial pressure due to changes in blood volume
• atrial stretch causes reflex dilation of afferent renal arterioles, increasing glomerular filtration 
• also lowers secretion of ADH, decreasing water reabsorbtion
• net result: increase in fluid loss by kdineys, decreases blood volume back to normal

The Bainbridge Reflex

• nervous reflex of atria that controls heart rate
• initiated by stretch receptors of atria in response to increased blood volume
• acts as counterbalance to baroreceptor reflex in control of heart rate
• prevents damming of blood in veins, atria and pulmonary circ
• increases heart rate and strenght of heart contraction

CNS Ischemic Response

• arterial pressure elevation in response to cerebral ischemia (severely reduced blood flow to vasomotor center in lower brain stem)
• most powerful activator of sympathetic vasoconstrictor system
• excites vasoconstrictor and cardioaccelerator neurons in vasomotor center( causes drastic elevation)
• can lead to almost complete occlusion of peripheral vessels
• works only when MAP falls to below 60 mm Hg

Cushing Reflex

• specific type of CNS ischemic response resulting from increased pressure of CSF around brain 
• cushing reaction protects brian from elevated CSF pressure
• cushing triad
• widening pulse pressure (with elevated systolic and decrease/normal diastolic BP)
• bradycardia (slower heart rate)
• irregular respiration

Abdominal Compression Reflex

• when baroreceptor or chemoreceptor reflex is initiated 
• transmission of nerve signals to skeletal muscles
• compresses abdominal venous reservoirs, facilitating translocation of blood out of abdominal vascular reservoir to heart
• increases cardiac output and arterial pressure

Skeletal muscle contraction

during excersise

• compression of blood vessels translocates blood from peripheral vessels to heart resulting in increased cardiac output and increased arterial pressure

Inspiration and Arterial Pressure

• insipiration causes negative pressure within thoracic cavity, leading to expansion of blood vessels in chest
• leads to decrease in quantity of blood returning to left side of heart, momentary decrease in cardiac output and decrease in arterial pressure
• pressure changes in thoracic vessels following respiration excite vascular and atrial stretch receptors
• slight increase in arterial pressure during early part of expiration

determinants of myocardial oxygen 

demand

• heart rate
• after load or systemic vascular resistance
• myocardial wall stress (measured by preload)
• myocardial contractility
• coronary flow is 225ml/min at rest but can increase fourfold to sevenfold with strenuous exercise

Atherosclerosis

• a complex arterial disease in which cholesterol deposition, extracellular matrix, and thrombus formation play major roles
• a diffuse condition of ahterothrombosis invloving the heart(coronary arteries), brain(carotid, vertebral, cerebral arteries), aorta and peripheral arteries

σ coefficient

• the observed osmotic pressure is less then the theoretical one
• this coefficient helps rectify it
• if the capilary is impermeable to the protein then the coefficeint is 1
• if it is freely permeable then it is 0
• continuous cap. have one greater then 0.9 and discontinuous or fernestered is close to 0

Capillary Pressure

• determined by Pressure on artery and venule side, as well as pre and post resistance
• effect of elevations in venous pressure are much greater due to postcapillary resistance being much lower
• because Ra is higher, change in Pa is poorly transmitted downstream to the capillary
• precapillary upstream resistance exceeds the postcapillary downstream (Rv/Ra)=0.3

Other Factors to affect P_c

• high Pc needed for glomerular capillary for ultrafiltration
• high Pc is needed to keep the capillary patent in the face
• Low Pc pulmonary capillaries to minimize ultrafiltration and avoid edema
• Pc varies considerably from moment to moment
• gravity: a capillary bed below the level of the heart has a high Pc than a capillary bed at the level of the heart

Interstitial Fluid Pressure(P_if)

• slightly negative, except in encapsulated organ
• determined by interstitual fluid volume, and compliance of the tissue
• has slightly negative because of pumping into lympatic system
• Pif is sensitive to addition of fluid to interstitial compartment. adding more fluid disrupts the solid phase of collagen fibers, making interstitial compartment behaves like a high compliance system, so large volume can accumulate, and resulting in edema in loose tissue

Interstitial Fluid Colloid Osmotic Pressure

• lowest value is at the arteriolar end due to flitration(gain of protein-free fluid from the capillary)
• the highest value is near the venular end due to reabsorption(loss of protein-free fluid from IF)

Interstitial Edema and Edema Formation

• edema is characterized by an excess of salt and water in the extracellular space, or the fluid volume within interstitial compartment increase because filtration>reabsorption + lymph 
• increase capilary hydrostatic presure (heart failure or venous obstruction) 
• decreased plasma colloid osmotic forces
• increase capilary permeability
• lymphatic obstruction

Local Control Mech

Microcirculation

• myogenic regulation refers an intrinsic mode of control of activity
• chemical factors: interstitial PO2, pH, ect
• in the case of local control, increased interstitial metabolism vasodilates vessels 
• blood flow activates local feed back system, inducing vasomotion

Vasoactive Compounds

• endothelium of capilary bed is the source of vasoactive compounds, NO, EDHF and endothelin

Vasodialation in VSMCs

• nitric Oxide(NO)(inhibits platelet aggregation, platelet adhesion
• endothelium-derived hyperpolarizing factor(EDHF)
• prostacyclin(PGI2): increases cAMP and phosphorylation of MCLK

Vasoconstriction in VSMCs

• endothelins(promoted by acute and chronic pathological conditions, including hypoxia (binds to PLC to generate IP3 and raise Ca2+ level
• thromboxane A₂ (TXA2) opens ltype channels
• EDCF: an endothelium dependent putative factor mediating vasoconstriction. EDCF2 could be superoxide anion radical 

Vascular bed Autoregulation

• despite large changes in systemic arterial pressure, vascular beds maintains local blood flow in a narrow range
• vascular beds behave like a rigid vessel at very low and very high perfusion pressures
• increase in pressure lead to increase in resistance to keep blood flow within a range
• contraction of VSMCs are autonomous and independent of neural and endocrine mech
• both myogenic and chemical factors play an important role in adjusting smooth muscle tone during autoregulation
• autoregulation is very important for heart, brain and kidney, that is very sensitive to ischemia or hypoxia

Angiogenesis

• dissolution of venular basement membrane
• activation and proliferation of quiescent endothelial cells
• the new cells, attracted by G.F. migrate to form a tube
• the budding tubes connect each other, allowing the flow of blood and the development of vascular smooth muscle as the new microvascular network establishes itself

Angiogenesis Promoters

• VGEF and FGF are the principle peptides inducing angiogensis
• VEGF: produced by fibroblasts and cancers:promoted by activated coagulation factor VII
• FGF mediates many cellular responses during embryonic, fetal, postnatal development 
• both interact EC specific receptor tyrosine kinase
• both promot NOS expresion, generating NO promotes proliferation and migration of ECS and differentiation of vascular tubes
• avastin mAb against VGEF-A, used as anti cancer drug

Coronary Artery Disease

• aprox 15 million americans have coronary artery disease
• remains leading cause of death in US
• one of every 5 deaths
• 1.3 million hospitalized
• 0.81 million acute MI, remainder are unstable

Epicardial Stenosis

• blockage
• blood flow at rest is maintained by compesatory dilation of the coronary bed beyond the stenosis
• diminished coronary reserve results in an inability to meet oxygen requirements as myocardial demand increases, it creates a supply/demand mismatch

Coronary Artery Disease

(CAD)

• various presentations of CAD, including stable angina pectoris or acute chest pain syndromes (unstable angina, acute myocardial infarction) are most commonly related to atheromatous plaque in the coronary arteries
• progression of coronary atheromata typically results in symptoms when a coronary artery is narrowed-70%

Coronary Heart Disease

• cholesterol LDL, HDL, Triglycerides
• smoking
• obesity
• hypertension
• diabetes
• genetic predisposition
• lack of exercise

Positive Stress Test

• New ST segment depression
• inability to exercise more then 2 mins
• decreased systolic blood pressure with exercise
• development of heart failure or sustained ventricular arrhythmias
• prolonged interval after exercise cessation before ST segments changes return to baseline

ABCDE

• aspirin
• beta blockers
• calcium channel blockers, cholesterol(statins), cigarette smoking
• diet(low cholesterol, decrease salt intake)
• excersize

Unstable Angina

• plaque is narrowing or intermitantly rupturing and blocking
• pain longer then 20 mins and brought on at rest or minimal eertion
• being severe and described as pain
• occurring with a crescendo pattern

Acute MI

• 600,000 persons in US experience an MI each year
• 320,000 will have a recurrent MI
• patients with STEMI are 30-40% of cases
• remainder are NSTEMI
• average age of first MI 64.5 years in men; 70.4 years in women
• 156 billion per year
• in hospital mortality declined from 11.2% in 1990 to 9.4 in 1999 to like 6% now

Plaque Rupture

• mild to moderate immature plaques
• thin fibrous caps
• lipid rich cores
• rupture in setting of inflammation
• sequence of platelet aggregation fibrin deposition and vasoconstriction

Clinical Definition of myocardial infarction

• two of the following
• characteristic symptoms
• elevation in cardial biomarkers
• characteristic electrocardiographic (ECG) changes

Retinopathy of Prematurity

• retrolental fibroplasia in infans
•  explosive out growth of retinal vessels in to vitreous humor leading to blindness
• will be scar formation
• hypoxia (low 02) -> causes release of H1F1α -> leads to VEGF (vascular endothelial growth factor) ->induction of angiogenesis
• (tumor uses similar kind of mechanism)

Angiogenesis

• formation of new blood vessels from existing vessels
• mech of long term regulation change in tissue vascularity
• physiological angiogenesis consists of fetal growth, menstral cycle, and wound healing
• pathological (excessive) angiogenesis can consist of diseases like diabetic retinopathy and tumor growth
• pathological(insufficient) heart disease, stroke, ulcers

Membrane Metalo proteinases

• degrades basement membrane of vasculature
• used in begining of angiogenesis

Anti-angiogenic molecules

• natural ones are: angiostatin(fragment of plasminogen) and endostatin (fragment of Collagen XVII)
• drugs are: Avastin (AMD; cancer), and lucentis (AMD)
• both drugs are antibodies to VEGF

Low Pressure Baroreceptors

• B-Fibers: increase in volume, causes these to increase heart rate (thus increasing cardiac output)
• also A-Fibers

Factors Affecting Cardiac Output

• basic level of body metabolism
• person activity(exercise)
• age (highest around 10, and goes down hill from here)
• size of the body

Mean Systemic Filling Pressure

(MSFP)

• about 7mm Hg
• when cardiac output, and thus venous return is zero, right atrial pressure equals this (MSFP)

Effect of Changes 

in Blood Volume on vascular functions

• a decrease in blood volume decreases venous return and decreases the RAP, as well as the Man systemic filling pressure (MSFP)
• increase in blood volume does the opposite

Effect of Changes 

in arteriolar tone on vascular functions

• has same Mean systemic filling pressure regardless of vasoconstriction or vasodialation
• Vasoconstriction has less venous return and vasodialation more
• this means maximums higher but x intercept is the same for this graph

Steady State Point

• when venous return and cardiac output are both are 5 liters/ min
• this happens around 2 mm Hg for Right Atrial Pressure
• if you increase RAP, you increase cardiac output and decrease venous return momentarily 
• shifting one of the curves does not effect the other (increasing heart rate of venous return) ***

Starlings Law

• stroke volume of the heart increases in response to an increase in the volume of blood filling the heart
• preload or venous return 
• this is true as long as all other measures remain constant
• Cardiac output = SV x HR

Blood Flow to cardiac muscles

• during exercise: CO is 4-5X in normal people and 6-7X in athletes 
• rates of blood flow through muscles: rest:3-4ml/min; athlete during exercise: 100-200 ml and endurance:400 ml/min
• blood flow is low during contraction and high in between(rhythmical)
• some capil. have little flow at rest but open during exercise, increasing flow 2-3 fold

Local Regulation of blood flow

in skeletal muscles

• decreased oxygen leads to production of vasodilators such as adenosine
• other vasodilatory factors: k+, ATP, lactic acid, CO₂

Arterial Pressure and Exercise

• increases due to: vasoconstriction of non-muscular arterioles, increased pumping activity, increases systemic filling pressure due to venous constriction
• important because: increase blood pushing force almost 30 times, increase stretch on walls of vessels and release of vasodilators, increasing local blood pressure(tense situations:MAP to 170mm Hg)

Coronary Circulation

• right coronary artery, left coronary artery that branches to left circumflex and left anterior descending branches
• normal coronary flow is 5% of cardiac output
• during exercise cardiac output increases 6-7X but blood flow increases only 3-4 fold to the heart
• coronary blood flow highest at diastole

Heart Ischemia

• 70% of energy is consumed from fatty acids at rest
• during ischemia/anaerobic conditions: energy is derived from glycolysis
• lactic acid cause of the cardiac pain during cardiac ischemia
• ATP is the convery of energy during contraction (adenosine is vasodilator)
• half of adenosine can be lost in 30 min and syn rate is only 2% (one of the major cause of death during myocardial ischemia)

Acute Coronary Occlusion

• type of acute coronary ischemia
• atherosclerosis(plaque build up)
• plaque formation caused by monocyte catching a damaged endothelium and taking up lipoprotein particles to become macrophage foam cell (adhered on endothelium)
• plaque can rupture and occlude vessels
• statins: inh. of HMG-CoA (rate limiting enzyme in cholesterol syn) can inhibit atherosclerosis
• can cause coronary embolus(thrombosus breaks away and blocks a distal peripheral vessel
• or secondary thrombus(atherosclerotic plaque could cause spasm in the muscle which may lead to secondary thrombus

Myocardial Infarction

• type of acute coronary ischemia
• infarction:area of muscle with zero or little blood flow and can not sustain cardiac muscle function
• subendocardial muscle is more prone to infarctiion
• causes decreased CO, damming of blood in pulmonary vessels, fibrilation and rupture of heart

Cardiac Shock

• happens during myocardia infarction
• failure to pump blood to the peripheral arterial truee due to infarction 
• leads to cardiac failure and death of the peripheral tissue

Damming of Blood Vessels

• cause of death of myocardial infarction
• when heart is not pumping blood forward
• causes dammin of blood in atria and the blood vessels of lungs or systemic vessels
• decreased blood flow to the kidney-less urine secretion-increasing blood volume
• eventually leading to acute pulmonary edema

Fibrillation of Ventricles

• cause of death of myocardial infarction
• majority of death of MI: 2 dangerous periods: 10 mins and after 1h
• factors are loss of blood supply depletes K+ in muscle but increase ECF levels, ischemic muscle cause injury current: fail to repolarize making outside of membrane negative, powerful symp reflexes inc irritibiliy, increased dilation of ventricles inc length of the impulse conduction

Rupture of the Infarcted Area

• cause of death of Myocardial infarction
• degeneration of dead muscle fibers makes heart wall thin
• systolic stretch bulges the ventricle and rupture the infarcted area
• loss of blood into pericardial space
• rapid compression of heart by blood collecting in pericardial space(cardiac thamponade)
• death

Angina Pectoris

• can be caused when ischemia increaseds production of lactic acid or histamins, kinins; which stimulate pain nerve endings
• appearance of cardiac pain whenever the work load on the heart is too great compared to the available coronary blood flow
• treatment: nitroglycerin, nitrate, vasodilators, sympathetic beta-blockers

Surgical Treatment of

Coronary Artery Disease

• aortic-coronary bypass is grafting of subcutaneous vein from arim or leg to the root of the aorta to theside of a peripheral artery beyond the atherosclerotic blockage point(1-5 grafts)
• coronary angioplasty: procedure to open blocked artery before it became totally occluded (Stint)

Cerebral Blood Flow

• supplied by 4 large arteries: 2 carotid, 2 vertebral arteries
• circle of willis (at base of brain and made from the 4 arteries)
• normal rate of cerebral blood flow: 50-65ml/100g brain tissue/min (750-900ml/min)
• brain recieves 15% of resting cardiac output (brain only 2% of body weight)

Regulation of Cerebral Blood flow

• CO₂ concentration
• H-ion concentration
• O₂ concentration
• substances released from astrocytes(specialized non-neuronal cells that couple neuronal activity with local blood flow regulation)

Cerebral Blood Flow and CO₂ and H+

• CO₂ + H2O leads to H2CO3 which leads to an increase in H-ions
• excess Hions (lower brain pH) cause vasodilation of cerebral vessels
• true for build up of any acedic subs that lead to increase in Hions(lactic acid, pyruvic acid ect)

Oxygen Deficiency and 

Cerebral Blood Flow

• O2 deficiency causes vasodilation to incease brain blood flow
• important protective response against diminished cerebral neuronal activity a nd mental derangement
• decrease in cerebral tissue P_O2 below 30 mm Hg (normal 35-40mm Hg) increases blood flow
• fall in cerebral PO2 below 20 mm Hg can lead to coma

Astrocytes and Blood Flow

• astrocytes are star shaped non-neuronal cells that support and protect neurons, provide nutrition
• provide a potential mechanism for neurovascular communication
• increased neuronal activity causes vasoactive metabolites to be released from astrocytes (nitric oxide, metab. of arachidonic acid, potassium ions, adenosine)
• causes increase in cerebral blood flow

Sympathetic NS and Cerebral Blood Flow

• cerebral circ system has strong symp innervation
• increased in mean arterial pressure->symp nervous system constricts brain arteries to prevent high pressure from reaching small brain blood vessels
• important for preventing vascular hemorrhage in brain
• important for prevent cerebral stroke

Cerebral Microcirculation

• overall metabolic rate of brain grey matter 4x greater then white
• number of capil. and rate of blood flow-4x greater in grey matter
• brain capillaries are less leaky than blood capil, due to glial feet -prevent overstretching of capil.
• walls of small arterioles leading to brain capil are thickened in hypertension- these arterioles rmain constricted to prevent transmission of high pressure to capilaries

Formation of Cerebrospinal Fluid

• formed at rate of 500ml/day(3-4X total fluid volume in CSF system)
• about 2/3 or more orginates as secretion from choroid plexus in the 4 ventricles
• additional small amounts secreted by ependymal surface of ventricles and arachnoidal membranes
• also from perivascular spaces in the brain surrounding blood vessels passing through the brain

Absorption of Cerebrospinal Fluid

• occurs through arachnoidal villi
• arachnoidal villi microscopic finger-like inward projections of arachnoidal membrane through walls and into venous sinuses
• arachnoidal granulations conglomerates of archnoidal vili forming macroscopic structures
• endothelial cells covering villi allow flow of CSF, dissolve protein molecules and RBC, WBC into venous blood

Cerebral Spinal Fluid Pressure

• normal pressure(when lying down) 130mm of water
• normal healthy person = 65-195 mm of water
• regulation of CSF mediated via arachnoidal villi
• arachnoidal villi-function like valves allowing CSF to flow readily into blood of venous sinuses while preventing backflow
• valve function activated when CSF pressure = 1.5mm Hg greater than blood pressure in venous sinuses

Net Characteristics of CSF

• osmotic pressure, aprox. equal to that of plasma 
• Na-ion concentration, aprox equal to that of plasma
• Cl-ions, 15% greater than in plasma
• K-ions, 40% less than plasma
• glucose, 30% less than plasma

Cerebral Stroke

• severe blockage of cerebral blood vessels resulting in severe disturbances in brain function
• arteriosclerotic plaques in feed arteries to brain are primarly responsible for strokes
• high BP initiates bursting of blood vessels causing hemorrhage
• blockage of middle cerebral artery can block nerve conduction in major pathways btw brain and spinal cord(causing snesnory and motor abnormalities)
• blockage of posterior cerebral artery-infarction of occipital pole resulting in vision loss

Papilledema(edema of optic disc)

• high CSF pressure pushes fluid into optic nerve sheath and then along space btw optic nerve fibers to interior of eyeball
• high pressure decreases outward fluid flow in optic nerves-> leads to accumulation of excess fluid in optic disc at center of retina
• pressure in optic nerve sheath impedes blood flow in retinal vein-> increase in retinal capillary pressure resulting in retinal edema
• can be visualized using a microscope

Hydrocephalus

• excess water in cranial vault due to impaired CSF absorption
• communicating hydrocephalus: blockage of fluid flow in subarachnoid spaces around basal regions of brain; blockage of arachnoidal villi
• non-communicationg hydroceph: fluild flow out of one or more ventricles is blocked(resulting from closure prior to birth or from blockage by brain tumor); increased volume in ventricles flattens brain into a thin shell against skull
• net result would be increased fluid accum. in  brain and tremendous swellin of head(can lead to brain damage)

Symptoms of Hydrocephalus

• sunken eyes
• seizures
• headaches 
• lack of coordination
• restricted movement and growth
• urinary incontinence, muscle spasms
• progressive dementia   

Brain Edema

• major complication of abnormal cerebral fluid dynamics
• accumulation of excess fluid in brain compresses blood vessels-> decrease in blood flow and destruction of brain tissue
• common causes of brain edema: increased capil. pressure or damage to capillary wall causing fluid leak
• brain concussion resulting in traumatization of brain tissues and capillaries and excessive fluid leak into traumatized tissues
• fluid taken up by nuronal and nonnuronal cells and swell

Vasogenic Cerebral Edema

• due to breakdown of endothelial tight junctions in blood brain barrier
• increased fluid leak, large number of intravascular proteins leak into brain ECF

Cytotoxic Cerebral Edema

• inadequate functioning of Na/K pumps in the glial cells cause increased cellular retention of Na/water
• this water is retained in nuronal cells and astrocytes

Osmotic Cerebral Edema

• occurs when the brain fluid osmolality exceeds that of plasma(eg. when the plasma gets diluted due to excessive water intake)

2 vicious cycles of Brain Edema

• compresses vasculature-decrease blood flow and brain ischemia-dilation-furthur increase capil. pressure-more edema fluid-progressive worsening of edema
• reduced cerebral blood flow-decrease in O2 delivery-increase in cap permeability resulting in more fluid leakage-turns off Na pumps of neuronal cells allowing swelling of these cells

Measures to overcome Brain Edema

• IV infusion of concentrated osmotic substance(mannitol sol) - pulls fluid by osmosis from brain tissue and breaks up vicious cycle
• rapid removal of fluid from lateral ventricles of brain by ventricular needle puncture- to relieve intracerebral pressure

Hypoglycemia

• caused by overtreatment of diabetic patients
• leads to decreased availability of glucose in blood to suppy neurons
• leads to severe derangement of mental function, coma, mental imbalance, psychotic disturbances