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The purpose of the cardiovascular system is to pump blood to the periphery and return it
to the lungs and heart for further oxygenation and redistribution back to the periphery. In
addition to gas exchange, the blood also serves as a means to deliver nutrients, remove
wastes etc. In order to do this, the cardiovascular system is divided into 2 separate
systems that are in series: systemic and pulmonary. We often deal only with the systemic
circulation for simplicity.

   1) Heart is 2 pumps in series: Rt is pulmonary (low pressure), Lft is systemic (high
      pressure). Generally, output of left and right are equal-if not you will rapidly have
      serious problems. Ventricular systole: contraction and blood ejection. Ventricular
      diastole: relaxation and refilling with blood.
   2) Pulsatile ejection by heart during systole into aorta, large arteries, small arteries,
      arterioles, capillaries, venules, veins. The characteristics of these blood vessels are
      critical for efficient delivery of blood.

So, heart and vasculature are coupled physically and both are involved in determining the
CO (L/min) during different physical states.
We will look at …..
    1) Heart
    2) Vasculature
    3) Factors that couple the two

Layers of heart muscle:
   1) Endocardium is inner layer next to blood.
   2) Myocardium is the meat of the heart, so to speak, that genereates contrctile force
   3) Epicardium is outer layer of heart muscle
   4) Pericardium is membrane that envelops heart

Gross anatomy of heart: Atria, ventricles; valves.

Atria: thin walled chambers compared to ventricles; left receives input from pulmonary
vein (oxygenated blood) right recives return flow from the systemic circulation
(deoxygenated); feed into their respective ventricles
Ventricles: left much thicker because it has to generate more force to deliver blood
throughout body. The heart is organized so that as the atria contract, the ventricles relax
and vic versa. This is of great significance for the proper filling and pumping action.

Valves: valves are basically passive and simply respond to changes in pressure
   1) atrio-ventricular valves: rt side is called tricuspid, left side is “mitral” (bicuspid).
       As atrial pressure exceeds ventricular pressure, these open and the ventricle fills.

      As ventricle contracts, ventricular pressure exceeds atrial prssure and the valves
      slam shut. Valves do not blowback into atria due to chorda tendinae and papillary
   2) semilunar: connect left vetricle to aorta (aortic valve w/ 3 cusps) and rt ventricle
      to pulmonary artery. As ventricle contracts, pressure eventually exceeds aortic (or
      pulmonary arterial) pressure and the valve opens and blood leaves the ventricles.

  1) From SA throughout atrial fibers (via gap junctions): about 1m/sec
  2) From atria to ventricles via AV node: about 0.05 m/sec
         a) Ca++ blockers decrease AP amplitude and duration. So….conduction
              slows and AV delay increases
         b) exhibits pronounced RRP: at high rates of atrial depolarization 200/min,
              RRP may block every other AP from ventricle
         c) Parasympathetic slows AV conduction at the N region. Strong stimulation
              can lead to complete block.
         d) Sympathetic speeds up conduction
  3) From AV node to bundle of His, bundle branches, purkinje fibers: all high
     velocity. All these are very fast but purkinje is fastest (1-4 m/sec) because they
     are large (70-80uM vs 10-15uM for myocardial cells)
  4) Depolarize from endo to epicardium more slowly than purkinjes but still pretty
     fast. First septum, papillary muscles, then the rest.

Electrical properties: Different cells have different electrical properties that are
important for :
   1) pacemaker activity: SA and AV node
   2) conduction paths: AV node, bundle of his, purkinje’s
   3) contraction of myocardial fibers

Two basic types of Aps:
  1) Fast: myocardial cells, purkinje’s
  2) Slow: SA and AV node

Basis of slow vs fast AP:
   1) Fast has lower RMP
   2) Fast has faster phase 0-due to fast Na+ channels, slow has lower amp and depol
       due mostly to Ca++ channels
   3) Fast has phase 1 (notch)-inactivation of Na+ channels
   4) Fast has pronounced plateau-100 to 300 msec, due to balance between Ca++
       influx and K+ efflux, Ca++ activated at about –35mV; Ca++ critical for
       excitation-contraction coupling
   5) Both have phase 3 (repol)-due to Ca+ inactivation and K+ efflux

   6) Both have phase 4
   7) Both have relatively long ARP-compared to neurons
   8) Fast has shorter RRP

Why are refractory periods important?
  1) Electrical protection:
          a. Long plateau helps block spurious atrial depolarization that might make it
              through. Effective at low heart rates. AP duration shortens at higher heart
              rates. Protects against reentry or “circus” reexcitation of heart.
          b. At high heart rates, AV nodal cells have longer ARP and RRP.

External measurements of electrical activities (ECGs)
Look at an ECG profile:
P= atrial depolarization
QRS= ventricular depol (atrial repol is lost in this)
T= vent repol
P-R interval= conduction time or AV delay; normally .12 to .2 sec
QRS length= process of depol; longer time or altered profile may indicate conduction
S-T interval=all ventricular cells depolarized (in plateau of AP)
Q-T= about .4 sec, decreases with increasing HR; “electrical systole”=length of AP and
length of contraction and relaxation of muscle

Heart rates and rhythms.
   1) HR
          a) Bradycardia=slower HR
          b) Tachycardia=faster HR
   2) AV blocks
          a) 1st degree: long P-R interval
          b) 2nd degree: during atrial tachycardia protects ventricles. Multiple Ps per
          c) 3rd degree: complete block so ventricles adopt own rhythm
   3) bundle blocks: portions of ventricles depolarize at different times so QRS is
       longer and sometimes notched

Cardiac cycle
   1) isovolumetric contraction
          a) starts w/ peak of R wave and 1st hart sound (closure of mitral valve)
          b) as vent contracts, pressure increases readily until vent P> aortic P and
              aortic valve opens

   2) ejection phase
          a) rapid ejection
                   i.)     vent and aortic pressures increase
                   ii.)    decrease in vent volume
                   iii.)   increase in aortic flow
          b) reduced ejection
                   i.)     aortic/vent P drops because flow from aorta to periphery is
                           greater than vent to aorta
                   ii.)    ends after T wave
                   iii.)   about 50% residual volume left in vent: if HR higher or
                           afterload less, then residual is less
                   iv.)    Note: during ejection, atria are in diastole and filling from
                           venous return so atrial pressure increases

   3) isovolumetric relaxation
          a) as muscle relaxes aorticP>>vent P so aortic valve closes (2nd heart sound)
          b) vent P drops but volume is same because both mitral and aortic valves are
               shut (no inflow or outflow)
   4) rapid filling
          a) most vent filling occurs here as vent P< atrial P and mitral opens
          b) atrial and vent P both decrease because muscle relaxes as chamber is filled
   5) diastasis
          a) slow filling as blood continues to flow from venous to atria to ventricle
          b) small increase in vent volume
   6) atrial systole
          a) atrial contraction soon after P wave but most vent filling occurs prior to
               atrial systole
          b) atrial contraction “tops off” vent filling; plays a greater role during high
               HR when diastasis is short

Control of Cardiac Output
Can affect CO by changing HR or SV

SV affected by intrsinsic and extrinsic factors
   1) Intrinsic
           a. Frank Starling: more venous return, more stretch, greater force… more
              volume is ejected during systole
   2) Extrinsic
           a. Increased SYMP output will enhance contractility
           b. More adrenal EPI will do the same
           c. Drugs that increase Ca++ in ICF too

HR affected by intrinsic and extrinsic also
  1) intrinsic
          a. pacemaker cells run at about 100 bpm
  2) extrinsic
          a. intrinsic rate under tonic PS inhibition
          b. increased PS will slow HR
          c. increased S will speed up HR
          d. ANS output depends on cardiovascular centers in medulla/hypothalamus

Reflex control of HR
   1) baroreceptors: in carotid sinuses and aortic arch
          a) Integrates cardiac output with arterial BP (negative feedback loop)
          b) Increased BP increases input to ANS centers and I) suppresses S, II)
              stimulates PS so that HR drops
   2) Atrial receptors: stretch receptors in walls of atria
          a) Integrates cardiac output with venous pressure (vent filling)
          b) Increased vent filling causes more stretch and activates S so that HR goes
          c) also called Bainbridge reflex

Effects of HR and SV: Up until now we’ve talked about CO in terms of changing
contractility OR SV but CO=HR x SV

  1) higher heart rates=shorter cycle length. This decreases systole and diastole but has
     a greater shortening effect on diastole. Thus, less filling and decreased SV (CO).
  2) Higher heart rate could also increase afterload and decrease SV and, hence, CO

So, effects of HR are a balancing act between increased beats per minute and reduced
filling time that could lead to decreased stroke volume.
Keep in mind that normal sympathetic activation would not only increase HR but ALSO
increase contractility and thus SV could increase up to a point despite reduced filling time
at very high HR………


So, blood is ejected from heart in a pulsatile fashion but tissues want a uniform delivery
of O2 and nutrients.

How does the body translate a pulsatile pump into fairly constant blood flow to tissues?

Key: arterial system acts as a hydraulic filter: aorta and lg arteries are elastic and store
energy for delivery during diastole, arterioles provide resistance to modulate and slow

flow, caps provide low velocity flow/small diameter/large surface area system for
efficient diffusion

Important blood vessels: you should know the anatomy of different types of vessels from
lecture and tables in lecture. Relate the structure to the functions described in lecture and
        1) Large arteries are highly compliant and elastic so they can absorb pulsatile
           energy of systolic ejection and use it during diastole to maintain BP. Due to a
           fair amount of elastin.
        2) Small arteries and arterioles are critical resistance vessels where changes in
           smooth muscle regulate distribution of blood and peripheral resistance.
           Peripheral resistance is the force against which the heart has to work and a
           major determinant of BP.
        3) Capillaries respond passively to changes in arterioles; at rest many caps are
           collapsed and are ”recruited “ as changes in pressure occur.
        4) Venous side: critical vessels for “capacitance” or reservoir. Compliance of
           venous side about 20 times that of arterial side so most of blood resides in
           venous side.

Types of BP
   1) pulse pressure=diff between Ps and Pd or Pa=Ps-Pd
          a) a measure of change in arterial pressure over one cardiac cycle
   2) Mean pressure=arterial pressure averaged over time
          a) measure area of curve/time of curve
          b) mean Pa=Pd+(Ps-Pd)/3

Compliance (Ca)=ability of artery to expand (elasticity)=change in vol/change in P

   1) as blood ejected during systole, a compliant arterial system expands
   2) this dampens the pressure during systolic ejection AND stores some energy in
      arterial wall
   3) during diastole the potential energy stored in expansion of walls is released as
      elastic recoil to help maintain BP
   4) in a compliant artery this helps maintain relatively constant BP and delivery of
      blood to periphery
   5) compliance decreases with age due to increased collagen and decreased elastin
   6) arteriosclerosis reduces Ca

Factors that determine BP
Physiological factors: CO (inflow) and Peripheral Resistance (outflow-regulated by
Physical factors: Arterial Blood Volume (determined by CO and resistance) and

Mean P is the average over time so only the inflow and outflow over time determines it.
Thus, an increase in CO will increase mean P. Similarly, an increase in resis. will
increase mean P.

Pulse press (Pa) is diff between Ps and Pd so both SV and Ca affects the Pa.
Increase SV increases Ps and decreases Pd so higher Pa
Decreased Ca increases Ps and decreases Pd so higher Pa

How does the structure-function of the arterial system affect delivery to capillaries?
The compliance of the arterial system coupled with increasing resistance to flow as the
blood goes from lg arteries to arterioles results in ……
    1) a major drop in BP by the time the blood hits the caps. This is good so caps don’t
        rupture plus it keeps the flow rate low enough for efficient capillary exchange.
    2) an absence of Ps and Pd by the time the blood hits the caps. This keeps constant P
        and more constant flow rate
As the arterial system branches into smaller classes of vessels, the cross sectional area of
each individual vessel decreases. HOWEVER, the numbers of smaller vessels is so vast
that the TOTAL CROSS-SECTIONAL AREA of each class of vessel increases to a
maximum in the capillaries. Since the velocity of flow is inversely proportional to the
total cross sectional area of a class of vessels, the velocity of flow is lowest in the

If the peripheral resistance results in such a drop in BP, how do we get blood from
the veins in our legs back to the heart (against gravity)?
    1) venous P is low but rt atrial P is very low so there is still a P gradient driving flow
    2) skeletal muscle pump and valves in the veins assist
    3) respiratory pump

                                 Capillaries and Diffusion

Caps: 5-10uM diameter; no active regulation, respond to changes in arterial and
venous P
      1) sometimes only 1 RBC thick
      2) low velocity flow ~1mM/sec for efficient exchanges
      3) caps have pores and fenestrations that are gaps between endothelial cells
      4) diff cap beds have different porosity and, hence, rates of diffusion and
      5) renal and hepatic are highly porous, brain has “blood-brain” barrier due to
          absence of pores and presence of tight junctions
      6) venous ends of caps beds are more permeable

Cap Exchange: Transfer of Solutes and water.
  1) Diffusion: lipid soluble and small, insoluble solutes
  2) “Transcytosis”: endocytotic processes by endothelial cells
  3) Bulk flow: movement of water and solutes trapped in water

           a. Filtration: caps to ISF
           b. Reabsorption: ISF to caps

Diffusion of Lipid Insoluble
   1) Flow-limited: very small molecules move rapidly through pores to interstitial
       fluid and cells. So, rate of delivery to tissues is limited only by flow rate to caps
   2) Larger molecules don’t diffuse as rapidly and can in theory become limited be the
       rate of diffusion. Very large molecules (>60,000MW) have to move by
   3) Normally most small molecules are flow-limited but if a tissue has very low cap
       density or edema the diff. Distance is so great that it can be diff-limited

Diffusion of Lipid-Soluble
   1) O2 and CO2 most important
   2) So rapid that it is determined by O2 press in blood vs. tissues and is also flow-
       limited under normal circumstances

Filtration of Water: Governed by Hydrostatic and osmotic forces.
Hydrostatic forces
    1) Blood hydrostatic pressure (BHP) is due to capillary BP and is opposed by
        interstitial fluid hydrostatic pressure (IFHP) (about 0 unless tissue edema is
    2) Higher BHP favors filtration flow out of CAPS; higher at arterial end, higher in
        lower limbs due to gravity
    3) regulate BHP by……
             a) increase arterial/venous P, increases HP
             b) increase venous resist, increases HP
             c) increase arterial resist, decreases HP
    osmotic forces:
    1) the reason that BHP doesn’t filter out all of your plasma volume is that there is
        higher osmotic P in caps than ISF so this acts to reduce filtration.
    2) total osmotic P in caps ~6000mM Hg and is due to electrolytes and plasma
        proteins; portion due to protein called the oncotic or blood colloid osmotic
        pressure (BCOP) (due mostly to albumin; lg. MW so don’t readily diffuse to ISF)
    3) since conc. of electrolytes in plasma and ISF are about equal, the plasma prot.
        provide the osmotic gradient that favors absorption of H2O
    4) across most caps, oncotic pressure is pretty constant (except kidney) and rate of
        filtration or absorption hinges on small changes in arteriole resistance and, hence,
        hydrostatic P
    5) pulmonary caps: low hydrostatic (8mMHg) vs oncotic P of abut 25mM. This
        favors reabsorption and prevents pulmonary edema that would prevent efficient
        gas exchange

Net filtration pressure (NFP)= BHP+IFOP-BCOP-IFHP

                           Control of Peripheral Circulation

Dual Control:
       1) Intrinsic
       2) Extrinsic
Act together to shunt blood flow from areas of low activity to high activity
Importance of intrinsic vs extrinsic vary with tissue and physiological state

   1) Autoregulation or myogenic mechanisms: adaptive response to changes in
       blood pressure that ensures a relatively constant flow to tissue; resistance of
       arterioles change n response to changes in BP.
   2) Endothelium effects: high flow velocity (due to high BP) creates shear or stress
       on endothelial cells; release “endothelium-derived relaxing factor” or nitric oxide
       that causes vasodilation and reduces the shear (decreases BP). PGI2 or
       prostacyclin is also produced and is a vasodilator
   3) Metabolic effects very important: if local metabolism high (muscle activity),
       local oxygen levels decrease and vasodilator substances are released.
           a. Candidates include lactic acid, CO2, H+, K+ adenosine, NO
           b. Critical for directing flow towards area of high metabolism and,
               hence, increased need
           c. Metabolic and myogenic mechanisms are dominant intrinsic factors
               that modulate basal “tone” or contractile state of arteriole smooth
               muscle. Helps keep arterial pressure and total peripheral resistance
               (TPR) lower. Reduces work heart must do to effectively circulate
   1)      Sympathetic vasoconstriction centers in brain are tonically active:
           increased frequency causes more constriction, decreased frequency
           causes relaxation; act via -adrenergic receptors predominantly.
           a. Act on arteries, arterioles, veins but not caps
           b. Less effect on larger vessels
           c. Venous tone is low so the venous side acts as an expandable, low-pressure
               reservoir that holds most of blood volume. Symp activity during exercise
               constricts veins and increases venous pressure and, hence, venous return to
               heart and cardiac filling (Increases preload)
           d. Arteriole constriction due to symp input causes an increase in
               peripheral resistance (increased blood pressure/afterload)
           e. Capacitance vessels are hypersensitive to symp input compared to
               arterioles (i.e. the same freq of stimulation elicits greater vasoconstriction
               in venules than in arterioles) but don’t respond to vasodilator substances

   2)     Parasympathetic innervation mostly of head and visceral blood vessels
          not of skeletal muscle and skin which are major blood reservoirs. So not
          many arterioles are regulated and not much effect on peripheral
   1) baroreceptors in carotid sinus, aortic arch. As BP increases, this activates stretch
      receptors which inhibits vasoconstrictor regions in the medulla so that
      sympathetic inputs to arterioles decreases. This causes vasodilation and a decrease
      in BP. This acts in concert with baroreceptor-triggered decreases in HR.
          a. Baroreceptors adapt so they are more important in shorterm adjustments to
              changes in BP due to changes in blood volume, CO, resistance. (i.e. during
          b. Long-term regulation of BP involves fluid balance (in take and output:
              renal function).
   2) Chemoreceptors: in carotid body (where internal and external carotid branch),
      aortic arch. Minor role, more important in respiration.
          a. Sense PaO2, PaCO2, H+.

Intrinsic and Extrinsic dominance vary between tissues: see handout from lecture
   1)      Brain and heart: intrinsic mechanisms are dominant. Why? Can’t tolerate lack
           of blood flow.
   2)      Skin: extrinsic dominate
   3)      Skeletal muscle: nice interplay between the two.
           a. At rest, extrinsic regulates basal tone.
           b. During exercise, generalized increased in sympathetic activity: increases
               CO and increases vasoconstriction so peripheral resistance (afterload)
               increases. Increased afterload is counterproductive for a state in which
               increased CO is desired!!!
           c. Local metabolic factors in areas of high metabolic activity kick in and
               cause vasodilation in areas that need lots of gas exchange and nutrients
           d. Intrinsic overrides extrinsic so blood flow shunted to active muscles while
               symp vasoconstriction shunts away form areas of low activity. Intrinsic
               factors also reduce total peripheral resistance so afterload isn’t too

Coordinated Interplay between Central and Peripheral Factors: Exercise

So let’s put this together with a real life example…exercise. Fig. see handout from class.
    1) During exercise the body needs higher CO to supply muscles and experiences an
        overall increase in S activity and decreased PS activity.
    2) Heart effects
            a) increased HR, increased contractility and increased CO

      b) in isolation, this would elevate arterial BP (afterload) and reduce CO.
          Offset by metabolic dilation of arterioles
      c) in isolation, this would also decrease venous pressure (preload) and reduce
          CO. Offset by metabolic effects on arterioles and vasoconstriction of
3) Vascular effects
      a) increased S activity would normally cause arteriole vasoconstriction
      b) in isolation this would normally increase TPR, Pa and afterload and, thus,
          reduce CO. This would also reduce blood flow to active tissues-Not a
          good thing! This is offset by metabolic effects on precapillary arterioles.
      c) Increased S input to veins increases Pv and return of blood to heart and
          veins do not respond to vasodilatory substances (metabolic effects). This
          is a good thing.
4) So Metabolic affects help keep mean Pa down and actually reduces TPR. This
   means the heart can increase CO with less work than if it had to work against a
   huge afterload.


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