Two C Flashcards
Describe the two types of mechanisms of local control
Acute:
- Rapid changes in local constriction of arterioles.
- Occurs in seconds to minutes.
- Maintenance of local blood flow.
b. Chronic:
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?
- 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.
- 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
to compensate.
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?
Vasodilatory 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
and liver.
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?
Inducer: ischemia 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.
- Depolarization of the vascular smooth muscle membrane resulting in the opening of calcium
channels
- 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
in contraction.
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
phosphatase
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.
Pharmacological Agents:
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
- 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)
- Substances produced in the tissue or at a nerve terminal reach the smooth muscle directly
without encountering the endothelium (adenosine, K+
, norepinephrine).
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:
Prostaglandins (Cyclooxygenases)
Thromboxanes (dyclooxygenases)
Leukotrienes (5-lipooxygenases)
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?
EDRF=NO
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.
