Endothelial vasodil/vasoconst

Question 1

Major mechanisms controlling peripheral vasc resistance

Answer 1

• 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

Question 2

Principal determinant of vasomotor tone (cellular pathways)

Answer 2

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

Question 3

Def of endothelial signaling

Answer 3

Small molecule locally produced in arterioles

Question 4

Local vasodilators

Answer 4

NO
Prostacyclin
ET derived hyperpol factor
Adenosine

Question 5

Local vasoconstrictors

Answer 5

Endothelin

Question 6

Factors inhibiting vasodilators activity

Answer 6

Hypoxia
Thrombin
O2-derived free radicals

o Also incr ET1 release

Question 7

Effect of NO release

Answer 7

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

Question 8

Effect of adenosine

Answer 8

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

Question 9

Effect of endothelin

Answer 9

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

Question 10

CNS control of endothelium

Answer 10

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

Question 11

Effect of decr BP on CNS

Answer 11

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

Question 12

Effect of incr BP on CNS

Answer 12

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

Question 13

What are the neurotransmitter of symp system

Answer 13

 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

Question 14

Type of R of symp system

Answer 14

 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

Question 15

Signaling of symp system once R activated

Answer 15

 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

Question 16

Modulation of symp system

Answer 16

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

Question 17

Overall adrenergic effect on vascular bed

Answer 17

 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

Question 18

NT of psymp syst

Answer 18

Ach

Question 19

R and signal trasmission of psymp syst

Answer 19

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

Question 20

Effect of psymp activation on SA node

Answer 20

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

Question 21

Effect of psymp activation on vascular SM cells

Answer 21

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

Question 22

Vasoconstrictives hormones

Answer 22

Ang II
Vasopressine/ADH
ET1

Question 23

Ang II effect on circulation

Answer 23

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

Question 24

Vasopressine effect on circ

Answer 24

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

Question 25

ET1 effect on circ and R

Answer 25

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

Question 26

NO synthetized by

Answer 26

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

Question 27

NO signaling

Answer 27

* 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

Question 28

Vascular ations

Answer 28

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

Question 29

NO release triggered by

Answer 29

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

Question 30

Exogenous source of NO

Answer 30

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