The Cardiovascular System

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The Cardiovascular System
The Pump
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Multifactorial control of the peripheral
vasculature
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COMPETING DEMANDS

• The cardiovascular system is organized to respond
  to multiple demands simultaneously, and
  especially to meet crises. Responses are
  mediated by multiple mechanisms.
• Intrinsic mechanisms regulate capillary flow and
  pressure of each organ.
• Extrinsic mechanisms, nerves and hormones
  coordinate functional needs of the organism as a
  whole.
• Bleeding causes neurally mediated constriction of
  most vascular beds.
• Generalized vasoconstriction helps to sustain
  blood pressure, and improves cardiac function.
• In the heart and striated muscle, intrinsic
  mechanisms can over ride the vasoconstrictor
  signals to allow the muscles to do the work of
  escaping from the big cat

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COMPETING DEMANDS

• Much of vascular physiology is organized to
  protect the brain in times of crisis.
• For example, the brain vasculature is protected
  from most vasoconstrictor stimuli by the
  blood-brain barrier.
• Furthermore, in times of crisis, the vascular
  function of all organs will be sacrificed to
  maintain the cerebral blood flow and to permit
  the animal (or person) to escape.

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VASCULAR SMOOTH MUSCLE (VSM)
VSM is capable of graded contraction, i.e.,
contraction is not all-or- nothing. This
means that vascular diameter can be precisely
controlled by graded contractions and
relaxations of the smooth muscle. Contractile
strength is determined by the level of
intracellular calcium and the degree of myosin
phosphorylation. Ca sources include
extracellular fluid, inner cell membrane, and
sarcoplasmic reticulum.
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The VSM intracellular Ca can be modulated by

• Membrane potential causing opening of L-type or
  T-type Ca channels
• K modifies smooth muscle contraction by changing
  in membrane potential
• Release of Ca from intracellular stores.
• norepinephrine can act directly on intracellular
  stores
• Phosphorylation of contractile proteins,
  channels, pumps, and IP3 receptors can all be
  modified by
• Myosin kinases and phosphatases
• Regulated by cyclic AMP and cyclic GMP

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VSM commonly manifests tone - a state of partial
contraction.

• All dilators work to reduce tone. Tone may be
  either
• Spontaneous - that is an inherent property of the
  muscle cells, perhaps due to a relatively high
  leak of Ca
• Induced - resulting from exposure to stimuli
• Agonist induced, e.g. norepinephrine from the
  nerve terminals
• Stretch induced the response to stretch is
  often referred to as the myogenic response.
• see autoregulation below

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SMOOTH MUSCLE - ENDOTHELIAL CELL COOPERATION

• The smooth muscle effect is terminated by
  phosphodiesterase 5
• removes the cGMP and allows intracellular Ca
  to rise
• Viagra (sildenafil) works by inhibiting
  phosphodiesterase5.
• Unfortunately nitro-vasodilators (e.g.
  nitroglycerine) also work by
• elevating cGMP. The combined effect of
  Viagra and nitroglycerine can
• be life threatening! http//www.youtube.com/
  watch?vviK121c8iZI

• NO diffuses from endothelium to VSM, activates
  guanylate cyclase to produce cGMP.
• cGMP, which reduces intracellular Ca by
  inactivating an L-type Ca channels. cGMP also
  sensitizes the myosin sensitivity to Ca.

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Smooth muscle integration of vasomotor signals
Note many of these stimuli can cause relaxation
() or contraction depending on location and dose
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Intrinsic regulation of blood flow
Three kinds of intrinsic regulatory
mechanisms Reactive hyperemia Autoregulation Fu
nctional hyperemia
Reactive hyperemia
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Intrinsic regulation of blood flow
Three kinds of intrinsic regulatory
mechanisms Reactive hyperemia Autoregulation Fu
nctional hyperemia
Autoregulation
Repays a flow debt incured during a time of
reduced perfusion
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Intrinsic regulation of blood flow
Three kinds of intrinsic regulatory
mechanisms Reactive hyperemia Autoregulation Fu
nctional hyperemia
Flow rises to supply the necessary O2 for work
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MECHANISMS INVOLVED IN THE INTRINSIC REGULATORY
PROCESSES

• MYOGENIC MECHANISM
• An inherent property of vascular smooth muscle.
• Stretch leads to contraction
• Probably most important in autoregulation and
  reactive hyperemia.
• METABOLIC MECHANISM
• Originating from an alteration in the balance
  between the metabolic demands of the tissue and
  the blood flow and O2 supply.
• Increased metabolism leads to dilation via the
  release of dilators like adenosine
• TISSUE PRESSURE
• Tissue pressure rises with more filtration and
  this reduces the filtration pressure back toward
  control values.
• It may be important in pathological states e.g.
  compartment syndrome
• Injury may increase vessel permeability
  sufficiently to cause major accumulation of fluid
  in tissue and vascular occlusion.

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Myogenic vs metabolic regulation

• Myogenic and the metabolic mechanisms are the
  most frequently activated.
• varies in different organs under different
  conditions.
• The strength of one or the other of the
  regulatory mechanisms varies in different organs
  under different conditions.
• Heart relies heavily on metabolic mechanism and
  kidney relies heavily on myogenic mechanism
• The importance of the metabolic mechanism is
  heavily influenced by the normal ratio of flow
  (F) to metabolic rate (MR) for a given tissue.

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CENTRAL REGULATORY RESPONSES OF THE HEART AND THE
VASCULATURE
Receptors
Effectors
chemoreceptors
baroreceptors
atrial receptors
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BLOOD PRESSURE SENSORS ARTERIAL
Baroreceptors respond to stretch Nerve impulses
over the vagus and glossopharyngeal to medulla
inhibit sympathetic nerve discharge and increase
parasympathetic.
Vasodilation due to reduced contraction of
arterioles. Decrease sympathetic activity also
decreases heart rate and contractility Parasympath
etic decreases rate.
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The baroreceptors are sensitive to both mean and
pulse pressure.
Experimentally change mean pressure and leave
pulse pressure the same. Note that the
baroreceptor nerve has a greater response to the
pulse pressure as the mean pressure is raised.
Recordings from the glossopharyngeal nerve
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BLOOD PRESSURE SENSORS - LOW PRESSURE SIDE

• Located in the atria, ventricles, and pulmonary
  artery
• Two types of atrial receptors
• Atrial A receptors - stimulated by atrial
  contraction
• Atrial B - stimulated by atrial distention
• Stimulation by stretch causes vasodilation
• These are especially important in blood volume
  control
• Stimulation also inhibits release of angiotensin,
  aldosterone, and vasopressin, all critical
  regulators of blood volume.

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Other receptors regulating CV function

• ENTERIC SENSORS - intestine
• Can produce both vasoconstriction and
  vasodilation
• Gut distortion or pulling causes a major fall in
  resistance.
• CUTANEOUS RECEPTORS
• Superficial receptors produce vasoconstriction
• Deep receptors cause vasodilation

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EXTRINSIC REGULATORY RESPONSES III - EFFERENT
NEURAL PATHWAYS- SYMPATHETIC ADRENERGIC FIBERS

• Transmitter released as a result of nerve
  activity is norepinephrine
• co-transmitters also released including ATP and
  neuropeptide Y (NPY).
• This is the dominant means of neural control of
  the peripheral circulation.
• Norepinephrine is one of a catecholamines and can
  stimulate two types of receptors on the blood
  vessels
• a receptors - contraction of the smooth muscle
• b receptors - relaxation of the smooth muscle
  cells
• Vessels stimulated with norepinephrine will
  normally show only the effects of a stimulation,
  because the b stimulating capacity of
  norepinephrine is weak.
• Epinephrine - more potent b stimulator,
  especially at low doses in striated muscle.
• low doses - relaxation
• higher doses - constriction.
• Arterioles and venules are both innervated. The
  capillaries are not.
• Norepinephrine release from sympathetic nerve
  terminals causes decreased flow, decreased
  capillary pressure, and decreased venous volume.

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CONTROL OF CAPILLARY FLUID EXCHANGE
Muscle or other tissue on a scale to measure
changes in either blood or interstitial fluid
volume
Initial rapid rise is accumulation of blood in
the tissue, i.e. distension of the vessels. Slow
secondary change has been shown to be due to
fluid filtering from the capillaries into the
space surrounding the tissue cells, the
interstitial space.
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EFFECT OF SYMPATHETIC STIMULATION ON BLOOD AND
INTERSTITIAL VOLUME
Sympathetic stimulation Constricts the veins
and forces blood out of the tissue and back
to the body Constricts the arterioles,
lowers capillary pressure and causes fluid
reabsorption from the interstitial space
into the blood
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RELATIVE SENSITIVITY OF RESISTANCE (arterioles)
AND CAPICATANCE (venules) VESSELS
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TISSUE DIFFERENCES IN RESPONSE TO SYMPATHETIC
STIMULATION
Kidney and intestine are more like skin
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SYMPATHETIC CHOLINERGIC FIBERS

• The dominant cause of neurally induced
  vasodilation is removal of sympathetic tone or
  passive dilation.
• However, there is a set of fibers that originate
  in the motor cortex, and pass through the
  hypothalamus where they synapse with fibers from
  other areas and then through the medulla and into
  the spinal outflow.
• Transmitter is acetylcholine and these may induce
  an active vasodilation).
• These sympathetic cholinergic fibers are not
  tonically active and they do not innervate the
  capacitance vessels.
• Activated by strong emotional influences and the
  anticipation of exercise. Function is not well
  established.
• May be activated during the initial transient
  response to baroreceptor stimulation to produce
  "active vasodilation."

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PARASYMPATHETIC DILATOR FIBERS

• Transmitter is acetylcholine
• Fibers of cranial origin supply head and viscera.
  
• Fibers of sacral origin supply genitalia,
  bladder, and large bowel.
• In general, activation of these fibers results in
  vasodilation of digestive and reproductive
  organs.
• In the salivary glands, activation of the
  parasympathetic nerves produces a unique
  collaboration between intrinsic and extrinsic
  mechanisms
• Bradykinin is one of the most powerful
  vasodilators.
• In the penis, there is also a non-adrenergic,
  non-cholinergic nerve that releases NO which
  relaxes the smooth muscle of the arterioles and
  of the corpora cavernosum.

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EXTRINSIC MECHANISMS IV -- HUMORAL PATHWAYS

• ADRENAL MEDULLARY HORMONE
• mainly epinephrine.
• release is stimulated by decrease pressure in the
  baroreceptors, emotion, exercise, and a variety
  of chemical stimuli.
• Activation of the sympathetic nervous system is
  manifested primarily by the effects of the nerves
  rather than the hormonal epinephrine
• Circulating levels of epinephrine at times of
  stress are in a concentration range that causes
  dilation of the striated muscle vasculature and
  constriction of the cutaneous vessels, obviously
  ideal in time of danger.

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EXTRINSIC MECHANISMS IV -- HUMORAL PATHWAYS

• ADRENAL CORTICAL HORMONES
• Corticosterone
• Synthesized and released by the adrenal cortex
• As in the heart a permissive role in maintaining
  reactivity to other hormonal and neural
  transmitters.
• By permissive, one means that the adrenal
  cortical hormones have little effect by
  themselves, but rather they create conditions in
  which the other vasoactive materials are active.
• Aldosterone
• Major action is on the kidney
• Increases salt and water retention, and thereby
  expands extracellular volume
• Tends to elevate blood pressure

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EXTRINSIC MECHANISMS IV -- HUMORAL PATHWAYS

• ANGIOTENSIN II
• One of the most complex vasoactive substances in
  the cardiovascular system
• An octapeptide formed from Angiotensin I by
  converting enzyme
• Formation initiated by low sodium chloride and
  low blood pressure in the kidney
• Potent vasoconstrictor
• Inhibition of synthesis by angiotensin converting
  enzyme (ACE) inhibitors is a common treatment for
  hypertension
• Highly involved in body salt and water balance

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EXTRINSIC MECHANISMS IV -- HUMORAL PATHWAYS

• ANTIDIURETIC HORMONE (ADH)
• Also known as vasopressin
• Peptide released by the posterior pituitary
• Potent vasoconstrictor
• Major role is in control of water balance
• important in hemorrhage and also in maintenance
  of normal blood pressure
• HISTAMINE
• Released by mast cells following injury and
  allergic responses
• Dilates arterioles, constricts venules
• Increases capillary permeability

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EXTRINSIC MECHANISMS IV -- HUMORAL PATHWAYS

• PROSTAGLANDINS AND PROSTACYCLINS
• Synthesized from arachidonic acid breakdown
• Synthesized on demand not stored
• Synthesis is blocked by aspirin or other
  cyclooxygenase inhibitors
• Release is frequently associated with injury
• Many types dilate vessels, constrict vessels,
  modify sympathetic nerve transmission

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Non-steroidal anti-inflammatory drugs

• NSAIDs are generally indicated for the
  symptomatic relief of the following conditions!
• Rheumatoid arthritis
• Osteoarthritis
• Inflammatory arthropathies (e.g. ankylosing
  spondylitis, psoriatic arthritis, Reiter's
  syndrome)
• Acute gout
• Dysmenorrhoea (menstrual pain)
• Metastatic bone pain
• Headache and migraine
• Postoperative pain
• Mild-to-moderate pain due to inflammation and
  tissue injury
• Pyrexia (fever)
• Ileus
• Renal colic

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(No Transcript)
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Cardiac output determines venous return
determines cardiac output determines venous
return determines venous return determines
cardiac output
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Troponin I stimulation of an inhibitor

• Troponin C in cooperation with tropomyosin
  regulates myocyte contractile force.
• Phosphorylation of troponin I by protein kinase A
  causes a reduction in the Ca affinity of
  troponin C. The resulting desensitization of the
  myofilament response to Ca increases the rate
  of relaxation.

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Viagra the long and the short of it

• Relaxation causes inflow of blood and filling of
  the vessels to produce erection
• decrease of sympathetic vasoconstrictor outflow
  to the penis
• activation of parasympathetic, non-adrenergic,
  non-
• cholinergic (NONAC) neruons and release of
  nitric oxide
• NO, via cGMP and protein phosphorylation
  reduces smooth
• muscle Ca and desensitizes the contractile
  proteins
• response to Ca
  relaxation of the muscles controlling penile
  blood flow and the sinuses of the corpora
  caveronosa erection
• Effects are reversed by phosphodiesterase
  5
• Viagra inhibits the phosphodiesterase and
  prolongs the
• erection

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              Health Library
HEALTH LIBRARY
Report Viagra may help enlarged hearts Sunday,
January 23, 2005 Posted 451 PM EST (2151 GMT)
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