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What are the 3 general levels of vascular control and their components?
- Extrinsic autonomic: baroreceptor reflex
- Extrinsic hormonal: Epi, Ang II, Vasopressin, Natriuretic peptides
- Local control: nitric oxide, endothelin, prostaglandins, kinins/histamine
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Describe the functions of:
Nitric oxide
Endothelin
Prostaglandins
Kinins/histamine
- NO- vasodilator
- Endothelin- vasoconstrictor
- Prostaglandins- vasocontriction and dilation
- Kinins/histamine- vasodilator
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Venoconstriction increases ____________, promotes __________, and pools _______________.
capillary hydrostatic pressure; tissue/interstitial edema; blood volume away from the heart
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How do parallel vascular circuits affect resistance?
decrease total resistance
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The site of greatest pressure drop in circulation.
across the arterioles
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How is reflex vasodilation achieved?
decrease in tonic vasoconstriction
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Describe the affects of the different SNS autonomic receptors in the vasculature. (3)
- alpha 1 and 2- vasoconstriction
- beta2- vasodilation
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Describe the process of vasoconstriction at the cellular level.
- 1. NE binds alpha receptor and activates G protein
- 2. Phospholipase C activated, activating second messenger IP3
- 3. Ca2+ enters cell via L-type Ca2+ channel
- 4. Ca2+ binds Ryr receptor on SR, releasing stored Ca2+ from Sr; IP3 also causes more Ca2+ release from SR
- 5. Ca2+ binds myosin light chain kinase (MLCK)
- 6. MLCK phosphorylates myosin light chains, allowing them to interact with actin
- 7. muscle contraction and vasoconstriction
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Patients unresponsive to catecholamine infusions (for vasoconstriction) may respond to an infusion of ____________.
vasopressin
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__________ is a precursor to NE and is a _________ agonist.
Dopamine; alpha and beta receptor
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ACE is also called __________ and breaks down the vaso________, __________.
kininase; vasodilator; bradykinin
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Nitric oxide is increased by... (3)
parasympathetic activity, exercise, and by some drugs.
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Increased activity of SERCA leads to ___________.
vasodilation
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When phospholamban is inhibited, __________ has increased activity and there is ____________.
SERCA; vasodilation (by increased reuptake of Ca2+ into the SR and less contraction)
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Phosphodiesterase (PDE) inhibitors function as ___________ because...
vasodilators; PDEs break down cAMP and cGMP, which are inhibitors for myocellular contraction
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Natriuretic peptides serve as ____________ because...
vasodilators; they induce renal loss of sodium and water
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Causes of hypotension. (8)
volume depletion (dehydration), cardiac muscle depression (anesthetics), severe bradycardia, severe heart failure [ultimately all cause decreases CO]; excessive vasodilation caused by anesthetics, sepsis, severe acidemia
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How does sepsis cause excessive vasodilation?
causes high levels of NO
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How does severe acidemia cause excessive vasodilation?
alpha-receptors of severely acidemic patients do not respond appropriately to NE
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Therapies for hypotension.
- 1. fluid replacement therapy
- 2. Drugs: NE, phenylephrine
- 3. vasopressin (esp. patients with sepsis or acidemia)
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What are the most common causes of systemic hypertension in animals? (4)
- CKD, glomerular disease, Cushing's disease (dogs), hyperthyroidism (cats)
- [Less common: adrenal tumors secreting Epi or aldosterone]
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What are the clinical consequences of systemic hypertension? (4 targets)
- Brain: cerebral edema, hemorrhagic stroke
- Eyes: retinal edema and detachment, blindness
- Heart: LV hypertrophy
- Kidneys: urinary protein loss, kidney failure
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The main longterm therapies for systemic hypertension. (4)
ACE inhibitors, Ca2+ channel blockers, +/- sodium nitroprusside (IV) or prazosin
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How do ACE inhibitors work?
block kininase (ACE) and inhibit AngI--> AngII (which causes vasoontriction)
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Give examples of specific ACE inhibitors. (2)
["_____pril"] enalapril, benazepril
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How do Ca2+ channel blockers work?
inhibit Ca2+ entry into vascular smooth muscle, preventing vasoconstriction
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Give examples of specific Ca2+ channel blockers? (1)
["_____pine"] amlodipine
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How does Prazosin work?
alpha-1 blocker, vasodilation
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How does Sodium Nitroprusside work?
nitrate; increasing nitric oxide--> vasodilation [used as acute therapy for HTN]
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What are the effects of beta-receptor agonists, and what are 2 examples of specific drugs?
vasodilation; dobutamine, isoproterenol
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What are examples of specific PDE inhibitor drugs? (2)
pimobendan, sildenafil
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How is nitric oxide produced? Why is this clinically relevant?
produced by the action of nitric oxide synthase on L-arginine [this AA is sometimes given therapeutically to enhance NO synthesis]
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What is thromboxane? What does it cause? What drug reduces it?
eicosanoid synthesized in platelets; vasoconstriction and clotting; reduced by aspirin
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What is prostacyclin? What does it cause? What drug is it reduced by?
eicosanoid produced by endothelium; vasodilation an inhibits platelets; reduced by aspirin.
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How does nitric oxide lead to vasodilation?
NO signals via guanylate cyclase --> increased cGMP--> inhibition of Ca-MLCK interaction--> decreased contraction--> vasodilation
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How does Ach cause vasodilation?
Ach binds muscarinic receptor--> activated guanylate cyclase--> increased cGMP--> inhibition of Ca-MLCK interaction--> decreased contraction--> vasodilation
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Describe the vasodilatory mechanism of cyclic nuecleotides.
cyclic nucleotides (cAMP and cGMP) inhibit the Ca-MLCK interaction--> less contraction--> vasodilation
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How are cyclic nucleotide modulated by drugs to cause vasodilation.
PDEs degrade cyclic nucleotides, allowing Ca to interact with MLCK and cause vasoconstriction--> PDE inhibitors prevent breakdown of cG/AMP--> vasodilation
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Describe the RAAS system.
renin released in kidney--> cleaves angiotensinogen to AngI--> circulation and gets to pulmonary circulation--> ACE cleaves AngI to AngII--> AngII causes systemic vasoconstriction, cardiac/vascular hypertrophy, thirst/inc plasma volume, renal Na+ and water retention, aldosterone release from adrenal, ADH release from pituitary--> aldosterone and ADH also cause Na+ and water rentention
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What are the results of AngII formation from the RAAS system? (6)
- systemic vasoconstriction
- cardiac/vascular hypertrophy
- thirst/increased plasma volume
- renal Na+ and water retention
- aldosterone release from adrenal (Na+ and water retention)
- ADH release from pituitary (water retention, vasoconstriction)
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What are triggers for renin release? (3)
decreased renal blood flow, increase SNS traffic of beta-receptors, decreased Na+ delivery to macula densa
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What are triggers for release of vasopressin?
- Osmotic trigger: dehydration, high serum [Na+]
- Non-osmotic trigger: low BP sensed by atrial stretch receptors
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What are the vascular and renal effects of vasopressin?
- Vascular: vasoconstriction via V1 receptorsÂ
- Renal: acts on renal V2 receptors to increase Na+ free water retention and lower serum [Na+]
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Give an example of a drug that is a muscarinic agonist and its effects in the vessels.
Bethanecol- vasodilation
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Give an example of a drug that is a muscarinic antagonist and its effects in the vessels.
Atropine- vasoconstriction, increased HR
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Describe the role of cAMP in the heart versus in the vessels.
- in the heart, cAMP activates PKA, increases Ca2+ release from the SR, and increases contractility
- in the vessels, cAMP inhibits the interaction b/w MLCK and Ca2+, leading to vasodilation
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