Flashcards in Two C Deck (28)
Describe the two types of mechanisms of local control
1. Rapid changes in local constriction of arterioles.
2. Occurs in seconds to minutes.
3. Maintenance of local blood flow.
1. Long term reconstruction of the vasculature by
increasing or decreasing sizes or numbers of vessels.
2. Occurs in days, weeks or months.
What two things will change local local blood flow?
1. Blood flow is affected by rate of tissue metabolism.
An eight-fold increase in metabolism results in a four-
fold increase in blood flow with flow increase lagging
behind increase in metabolic rate.
2. Blood flow is affected by oxygen availability.
Oxygen availability to tissues decreases at the top of a
mountain, in pneumonia, in CO poisoning or upon
exposure to cyanide requiring an alteration in blood flow
A decrease in oxygen saturation to 25% normal results in
a three-fold increase in blood flow.
What are two explanations of how decreased O2 and increased metab. lead to changes in blood flow?
Oxygen and other nutrients are required for maintenance of smooth muscle contraction.
2) Increase in metabolism or decrease in oxygen levels results in the production of a vasodilator (ATP, K+ etc)
What theory explains how released vasodilators are able to migrate upstream? What are two aspects of the theory?
a) Diffusive transfer from venules to a paired arteriole, or
b) Communication of the vasoactive response (e.g., change in membrane potential) along the vessel via gap junctions (conducted or propagated vasomotor responses)
Explain what reactive hyperemia is and how it works.
Reactive hyperemia – transient increase in blood flow in an organ following a period of circulatory arrest (occlusion of blood supply, ischemia). Longer the occlusion, greater the vasodilator response.
This makes sense b/c more blood flow means you'll receive more vasodilators and more time means they'll build up to a greater extent.
What is the autoregulation of blood flow? Where is it most pronounced? Where else is it prominent?
d) Autoregulation of Blood Flow: The tendency for organ blood flow to remain constant in the
face of local changes in arterial pressure.
Q = ΔP/R
If flow (Q) equals perfusion pressure (ΔP) divided by vascular resistance (R) then if ΔP rises
through the autoregulatory range (PA = 80-160 mmHg in brain and kidney), R must increase to
maintain constant flow.
It is most pronounced in brain and kidney and is prominent in the heart, skeletal muscle, intestine
What are two explanations of autoregulation?
Myogenic: Vascular smooth muscle contracts when stretched
Increase in intravascular pressure causes vessel distension
Vessel constricts to decrease flow
Metabolic: Delivery of nutrients
Increase in perfusion pressure increases flow
Delivery of nutrients or removal of waste products enhanced
Smooth muscle constricts
Define 3 types of long term blood flow regulation
Vasculogenesis – early embryonic growth, de novo formation of endothelial tubes.
Angiogenesis – growth of new vessels from existing vessels.
Arteriogenesis – remodeling of existing vessels.
What is the inducer, promotor, substrate, result, and time to completion of angiogenesis?
Promotor: hypoxia inducible factor (hif-1)
Substrate: preexisting capillaries
Result: increased capillary density
Time to completion: days
What is the inducer, promotor, substrate, result, and time to completion of arteriogenesis?
inducers : shear stress or inflammation
Promotor : shear stress responsive element
Substrate : preexisting arterioles
Result : new arteries
Time frame : days to weeks
Explain some steps that lead to SM contraction.
1. Depolarization of the vascular smooth muscle membrane resulting in the opening of calcium
2. Direct activation of membrane receptors inducing:
a) Opening of G-protein coupled calcium channels
b) Activation of phospholipase C that hydrolyzes
phosphatidyl-inositol 4,5-bisphosphate to
diacylglycerol and IP3.
c) IP3 releases calcium from sarcoplasmic reticulum
d) Diacylglycerol activates protein kinase C that in
turn phosphorylates a number of enzymes involved
The end-result is an increase in intracellular free
calcium that sets into motion a cascade of events
resulting in vasoconstriction.
CM = calmodulin
MLCK = myosin light chain kinase
MLCP = myosin light chain
are all also involved.
Give 6 examples of how physiologic substances act on SM cell state. Give 3 pharmacologic substances
Increased calcium ion: vasoconstriction via increase in calcium gradient.
Increased magnesium ion: vasodilation via competition with calcium.
Increased potassium ion: vasodilation via general inhibition of smooth muscle contraction (hyperpolarization)
Increased sodium ion - mild arteriolar vasodilation via increase in osmolality of fluids.
Hydrogen ion - increase results in arteriolar dilation as does large decrease. Small decrease results in arteriolar constriction.
Carbon dioxide - Locally, it causes a moderate vasodilation in most tissues with marked vasodilation in the brain. However CO2 acting on the vasomotor center has a very powerful indirect vasoconstrictor effect that is transmitted via the sympathetic vasoconstrictor system.
Calcium channel antagonists limit entry of calcium into
smooth muscle preventing or limiting contraction, especially in vessels that have tone.
Activation of potassium channels hyperpolarizes the
smooth muscle cell inhibiting the entry of calcium via voltage-gated channels.
Activators of adenylate cyclase such as
epinephrine by increasing cAMP will result in
vasodilation due to phosphorylation of MLCK at a
site that interferes with its role in the
phosphorylation of myosin.
What are two routes by which substances can affect the activity of SM cells
1. Substances that are blood borne first encounter the endothelium. Upon contact, they will
either induce the production of a secondary product (prostaglandins, nitric oxide,
endothelium derived hyperpolarizing factor (EDHF)) or act directly on the smooth muscle
after passing through the endothelium (O2, CO2)
2. Substances produced in the tissue or at a nerve terminal reach the smooth muscle directly
without encountering the endothelium (adenosine, K+
What are eicosanoids? Where do they come from? Generally, What enzymes are used? What can enhance their synth. and how?
A diverse group of related compounds derived from 20-carbon essential fatty acids that contain 3, 4 or 5 double bonds derived from the fatty acid, arachidonic acid (AA). AA is liberated from membrane phospholipids by the actions of the enzyme phospholipase A2 (PLA2).
Hormones, autacoids and other substances can enhance the biosynthesis of eicosanoids by binding to plasma-
membrane bound G-protein coupled receptors, increasing cytosolic concentrations of Ca2+, thus
activating PLA2. Eicosanoids are produced from the now elevated levels of AA.
What are the 4 major classes of eicosanoids and what enzymes are used to produce them (1st step)?
There are four
major classes of eicosanoids:
Epoxides (cytochrome p450 monooxygenases)
What prostaglandins exist? Explain how each of them are formed (enzymes).
AA is converted to PGH2 by COX. PGH2 is quickly converted to something else. To PGE2, PGD2, or PGF2-alpha by prostaglandin endoperoxide isomerase. To PGI2 (prostacyclin) by prostacyclin synthase. To thromboxane (TXA2) by Thromboxane synthase.
List the various prostaglandins. Which receptors do they bind to and what action do they perform? Which are most important to vasculature?
PGI2 IP receptors - vasodilation/anti-platelet (incr cAMP)
PGE2 EP receptors (1-4) – vasodilation ( incr cAMP)
PGD2 DP receptors (1 and 2)- vasodilation (low conc, DP1 incr cAMP)/ vasoconstriction (high conc, DP2, PLC incr Ca2+)
PGF2a FP receptors – vasoconstriction (PLC incr Ca2+)
TXA2 TP receptors - vasoconstriction/platelet activation (PLC incr. Ca2+)
Prostacyclin and thromboxane most important to vasculature
What are the differences between COX-1 and 2? What drugs exist that target these pathways?
COX-1 constitutive enzyme – always present and active. Prominent form in endothelial cells and platelets
COX-2 inducible enzyme – induced by inflammatory stimuli – e.g. cytokines, growth factors
Non steroidal anti-inflammatory drugs (NSAID; aspirin, ibuprofen, naproxen, indomethacin, diclofenac) inhibit both forms of cyclooxygenase
COX-2 inhibitors: celecoxib (celebrex™) and rofecoxib (vioxx™ - withdrawn)
Glucocorticoid steroids (e.g. dexamethasone, hydrocortisone) inhibit induction of COX-2 and the activity of PLA2.
Name 3 other prostaglandin related drugs?
Iloprost-Longer half life and all the same activities as PGI2
Treatment for certain peripheral vascular diseases (Raynaud’s phenomenon). May also be useful in Myocardial Infarction
Prostaglandin-Short half life-pulmonary hypertension (vasodilation)
PGE1 analog alprostadil - vasodilator used in neonates also indicated for erectile dysfunction – increases blood flow and oxygenation
What leukotrienes exist? How are they formed? What role do they play?
Microvasculature activity – inflammation –
low concentrations - fluid flux across membrane and plasma exudation
higher concentrations cause constriction and reduce plasma exudation. LTC4 and LTD4 most active at vasculature.
AA forms HPETE by 5-lipooxygenase, which forms LTA4 by LTA synthase which forms LTB4 by LTA4 hydrolase and LTC/D/E/F4 by Glutathione-S-Transferase.
What epoxides exist? How are they formed?
AA forms various EETs by Cytochrome P450 Monooxygenase
Waht is endothelial derived relaxing factor? What does it do? What releases it? Where is it released from?
Potent vasodilator substance with a short half life. Released from endothelium upon stimulation by a variety of agents (e.g acetylcholine, ATP) and shear forces.
How is NO formed? What are the different isoforms of the enzyme?
NO is formed when the amino acid L-arginine is converted to L-citrulline by nitric oxide synthase (NOS)
e-NOS – constitutive enzyme located in endothelial cells – always present and active – Ca2+/Calmodulin dependent
i-NOS – inducible enzyme expressed in smooth muscle, immune and many other cell types in response to inflammatory mediators - Ca2+ independent
n-NOS –constitutive enzyme located in the nervous system - always present and active – Ca2+/Calmodulin dependent
How does NO work? What does it do? What limits its activity?
Physiological regulator of vascular tone
– inhibit NOS in vivo - blood pressure increases.
Explains the vasodilator abilities of numerous agonists – important concept
Half-life very short (sec)
– superoxide anion limits activity. Also binds to heam groups (Hb e.g.)
NO causes vasorelaxation by increasing intracellular cGMP leading to:
Inhibition of calcium entry into the cell, and decreased intracellular Ca2+ concentrations by Ca2+ sequestration into the SR
Stimulation of a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to smooth muscle relaxation.
What are 3 types of therapeutic agents that use NO pathways? Give examples of each. What are they used to treat?
Sildenafil (viagra™), Tadalafil (cialis™), Vardenafil (levitra™) – PDE-5 inhibitors – prolong the actions of NO by preventing the breakdown of cGMP. Erectile dysfunction, pulmonary hypertension
Nitroglycerin and Sodium Nitroprusside – NO donors – angina, acute hypertension, congestive heart failure.
NO hybrid drugs – NO-losartan (AT1 receptor antagonist)
What is bradykinin? What does it do? How does it do it? What roles does it play? What are its receptors? What does each do?
Kinins are small polypeptides that are split from plasma alpha2 globulins by proteolytic enzymes.
Of particular importance is
kallikrein which, when activated,
results in the release of the kinin
kalliden which is then converted
by tissue enzymes to bradykinin.
Bradykinin is a nine amino acid
peptide that causes a very potent
arteriolar vasodilation (via NO
and PGI2 release from
endothelial cells) as well as an
increase in capillary permeability
Bradykinin may play a very important role in regulating blood flow and capillary leakage in
inflamed tissue as well as blood flow in the skin, salivary gland and glands in the gastrointestinal
tract. There are two bradykinin receptors, B1 and B2. The B1 subtype of receptor is expressed at
very low levels normally and is upregulated in inflammation. The B2 receptor subtype is found on
blood vessels where it is linked to NOS activity to increase NO production as well as PLA2
activity to increase PGI2 production.
When is ATP released? What effect does it have on vasculature? How?
ATP – released from endothelial cells in response to shear stress
ATP – released from red blood cells in response to low pO2, low pH and mechanical deformation
ATP – acts indirectly as a vasodilator by stimulating the release of both NO and PGI2 from endothelial cells in the periphery, and EDHF from cerebral endothelium. P2y receptor action (PLC, PLA2 stimulation in EC, NO, PGs produced).
ATP can also cause vasoconstriction by acting directly on P2x receptors (Ligand gated Ca2+ ion channel) on the vascular smooth muscle