Endothelial vasodil/vasoconst Flashcards

1
Q

Major mechanisms controlling peripheral vasc resistance

A
  • Vasoconstrictor receptors
    o incr [intra¢ Ca2+] => promote vasoconstriction
    o Respond to agonists from neurogenic, humoral, endothelial fct
     A1 adrenergic R => NE
     Ang II => vasoconstrictor + incr NE release
     ET-1 => released from damaged endothelium
  • Cyclic nucleotide vasodilatory system
    o cAMP/cGMP: inhibit vasoconstriction by inhibiting myosin light chain kinase
     B adrenergic stimulation=> incr cAMP
     NO => incr cGMP
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2
Q

Principal determinant of vasomotor tone (cellular pathways)

A

depends on final common pathway = cytosolic Ca2+ availability for muscle contraction
* Agonist => G-prot ¢ membrane R => phospholipase C =>
o Diacylglycerol (DG) => Ca2+ dependant prot kinase => Na/H exchanger
o Inositol triphosphate (IP3) => direct cytosolic Ca2+ from SR => available for myosin

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3
Q

Def of endothelial signaling

A

Small molecule locally produced in arterioles

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4
Q

Local vasodilators

A

NO
Prostacyclin
ET derived hyperpol factor
Adenosine

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5
Q

Local vasoconstrictors

A

Endothelin

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6
Q

Factors inhibiting vasodilators activity

A

Hypoxia
Thrombin
O2-derived free radicals

o Also incr ET1 release

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7
Q

Effect of NO release

A

released from endothelial ¢ lining blood vessels
 Reason why exercise induce vasodilation => vasodilatory local messenger
 NO release
* psymp stimulation
* Shear stress 2nd to incr blood flow in normal endothelium
 incr cGMP induced vasodilation

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8
Q

Effect of adenosine

A

 Act on adenosine R on vascular SM¢
 Inhibit release of NE

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9
Q

Effect of endothelin

A

release stimulated
 Shear stress if damaged endothelium
* Act on ETA R => vasoconstriction
 Low doses/physiologic = vasodilatory via ETB => NO release

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10
Q

CNS control of endothelium

A

Stimulation via
o Ao baro/chemo R => vagus nerve => medulla
 ChemoR less important for BP regulation => acidosis or hypercapnia => incr BP
o Carotid sinuses & bodies => glossopharyngeal nerve => medulla
o Cardiopulmonary R
o Stretch R in A, V, PA

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11
Q

Effect of decr BP on CNS

A

activation of symp + suppression of psymp => incr HR, contractility, arterial + venous vasoconstriction, renin release, Na retention

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12
Q

Effect of incr BP on CNS

A

carotid + Ao baroR => nucleus solitarius in brainstem => vagal nucleus => vagal stimulation => symp inhibition => decr HR and inotropy => decr CO => decr BP
o Expected reflex bradycardia in acute incr BP
o Carotid sinus massage can also initiate response

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13
Q

What are the neurotransmitter of symp system

A

 Norepinephrine (NE): stimulates
* Myocardial B adrenergic R => incr HR
o HR decr after initial transient incr because pressure sensitive control mechanism
* Vascular A adrenergic R => vasoconst
* Formed in variscosities of terminal nerves
o Dopa + dopamine => amino acid tyrosine

 Epinephrine: stimulates
* Myocardial B adrenergic R => incr HR
* Vascular B adrenergic R => vasodilation
o Overall effect: incr systolic BP and decr diastolic BP = stable mean BP
o = incr CO + incr limb blood flow

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14
Q

Type of R of symp system

A

 A adrenergic R
* A1 = vascular SM¢ => vasoconstriction
o Postsynaptic receptors (sarcolemma)
* A2 = adrenergic nerve terminal => inhibit NE release
o Feedback inhibition of its own release
o Presynaptic receptors

 B adrenergic R
* B1 = heart => incr contractility + HR
* B2 = sinus node => incr HR
= vascular SM¢ => vasodilation
* B3 = decr contractility
 A2 = adrenergic nerve terminal => inhibit NE release

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15
Q

Signaling of symp system once R activated

A

 NE bind to B adrenergic R => stimulatory G protein => activates adenylate cyclase => conversion of ATP => cAMP
* incr opening of Ca2+ channel => promotes Ca2+ entry
* incr release of Ca2+ by SR => incr [Ca2+] => incr contractility
 In sinus node: cAMP icnr rate of spontaneous pacemaking

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16
Q

Modulation of symp system

A

 Stimulate NE release: AngII
 Inhibit NE release: adenosine, NO, incr psymp activity

17
Q

Overall adrenergic effect on vascular bed

A

 A1 effects of NE opposed to B2 effects of EPI
 NE can stimulate B2 as well
* Major vasoconstrictive effect via A1 because
o A1 anatomically closer vs B2
o # of A1 receptors > vs B2

18
Q

NT of psymp syst

A

Ach

19
Q

R and signal trasmission of psymp syst

A
  • Activation via muscarinic/cholinergic R
    o Inhibitory G protein => decr adenylate cyclase activity => decr cAMP
     decr contractile force
20
Q

Effect of psymp activation on SA node

A

decr rate of depolarization
o Directly inhibit SA node + indirectly via decr cAMP formation
o Act on inward rectifying K+ channels

21
Q

Effect of psymp activation on vascular SM cells

A

o Bradykinin release => vasodilation
o Inhibit NE release => indirect vasodilation

22
Q

Vasoconstrictives hormones

A

Ang II
Vasopressine/ADH
ET1

23
Q

Ang II effect on circulation

A

o Sympathetic activation + baroR in renal vascular bed => renin release => cleave to angiotensinogen => angiotensin I => angiotensin II
o Act on 2 receptors (AT1 and AT2)
 Heart: AT2/AT1 ratio = 2/1
* Positive inotrope
* Stimulate myocardial hypertrophy
 Vasculature: AT1 => vasoconstriction
 incr symp activity: block reuptake + facilitate release of NE
 Stimulate secretion of aldosterone => incr Na + H2O retention => incr preload

24
Q

Vasopressine effect on circ

A

o Secreted by posterior pituitary gland
 OsmoR in hypothalamus
* Dehydration => incr blood osmolality => ADH secretion => incr H2O reabsorption (V2)
 Ang II triggered => decr BP or CHF => atrial R => vasoconstriction (V1)
o Receptors: V1 and V2
 V1 => vasoconstriction
 V2 => renal H2O retention

25
Q

ET1 effect on circ and R

A

o Released by endothelial ¢: ET1 produced by vascular endothelium
 Potent vasoconstrictor, incr HR, contractility, hypertrophy
 Increased by NE and AngII
o Receptors: ETA and ETB
 ETA: affinity ET1+ET3>ET2
 ETB = equal affinity

26
Q

NO synthetized by

A

by endothelial ¢
o From A.A L-arginine + O2
o Action of NO synthetase enzyme => activated by incr [Ca2+]
 2 endothelial forms:
* Constitutive: constant production under normal conditions
o Activity is Ca2+ and calmodulin dependent
o Stimulated by Ca2+ release from SR storage
* Inducible: low basal activity in normal conditons
o Activation is Ca2+ independent
o Stimulated by inflammation by bacterial endotoxins/cytokins: TNF, IL
 Co-factors: O2, NADPH, tetrahydrobipterin, flavin adenine nucleotide

27
Q

NO signaling

A
  • Paracrine + autocrine signaling
    o Only act locally => limited circulating ½ life
     Superanion w high affinity for NO => decr bioavailability

o Diffuse in adjacent vascular SM¢ => activate guanylyl cyclase => incr cGMP => vasodilation
 Induce vasodilation by
* Inhibit Ca2+ entry => decr [Ca2+]
* Activate K+ channels => hyperpolarization
* Stim cGMP dependent PK => activate myosin light chain phosphatase
 PDE5 rapidly inactivate cGMP in physiologic conditions

28
Q

Vascular ations

A

o Direct vasodilation: flow dependent, R mediated
o Indirect vasodilation:
 decr vasoconstrictor influences (Ang II, adrenergic)
 Mediate psymp induced vasodilation
* incr Ach release from nerve terminal
* decr NE release
o Anti thrombotic effect => inhibit platelets adhesion
o Anti inflammatory effect => inhibit leuco¢ adhesion
o Anti proloferative effect => inhibit SM¢ hyperplasia

29
Q

NO release triggered by

A

o Adenosine, Ach, bradykinin, substance P
 R linked to R-operated Ca2+ channels
o Shear stress: stretch sensitive Ca2+ channels

30
Q

Exogenous source of NO

A

Nitrates
* Short lived free radical => enzymatic release of NO => cGMP stim => decr Ca2+ => vasodilation
o Chronic use => tolerance
 Prolonged therapy: formation of peroxynitrite => decr NO synthase activity
* Coronary + peripheral vasodilatory effects
o Preferentially dilates large arteries => decr afterload
o Venodilation => incr venous capacitance => pooling of blood => decr venous return => decr preload
 Better venodilator
* Antiaggregatory effects: reverse platelet aggregation via classic pathway