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CVPR Unit 1 > Cardiac & Vascular Signaling Pathways > Flashcards

Cardiac & Vascular Signaling Pathways Flashcards

1
Q

Describe the structure of GPCRs

A

7-transmembrane-spanning integral membrane proteins

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2
Q

List some types of GPCRs

A

Alpha & beta adrenergic receptors,
adenosine receptors,
glucagon receptors,
angiotensin receptors

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3
Q

Briefly describe GPCR’s activation

A

Agonist binds receptor->GTP replaces GDP on alpha subunit of heterotimeric G protein->dissociation of alpha & betagamma G protein subunits->Both alpha & betagamma can be active signals

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4
Q

Briefly describe GPCR’s deactivation

A

Auto dephosphorylation of GTP to GDP by alpha subunit->reassociation with betagamma. rebinding of G protein to receptor causes inactivation

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5
Q

What are the families of G protein involved in cardiovascular function?

A

Gs, Gi/o, Gq

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6
Q

Gs method of action

A
  • stimulatory G protein
  • activates adenylate cyclase
  • Increases cAMP, activates PKA
  • Heart: increase chronotropy, inotropy, lusitropy, dromotropy
  • Skeletal muscle vascular beds: vasodilatation
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7
Q

Gi/o method of action

A
  • inhibitory G protein
  • inhibits adenylate cyclase
  • Decreases cAMP, inhibits PKA
  • Decreases chronotropy
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8
Q

Gq method of action

A
  • activates PLC and PKC
  • Increases Ca2+ (via IP3R activation & SR Ca2+ release)
  • Vasoconstriction
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9
Q

Briefly describe PKA

A

Has 2 regulatory and 2 catalytic subunits. 4 cAMP units bind, releasing the catalytic subunits which can phosphaorylate target proteins

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10
Q

How does the sympathetic system regulate inotropy?

A

Symp. neurons innervate heart, release norepinephrine that binds to Beta adrenergic receptors, increasing intracellular cAMP, activating PKA. PKA acts on 4 different proteins:

  • Phospholamban (PLB)
  • L-type Ca2+ Channels (LTCCs)
  • Ryanodine Receptors (RyRs)
  • Troponin I (TnI)
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11
Q

What is the counterpart of PKA?

A

Phosphatases that dephosphorylates targets

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12
Q

Effects of PLB phosphorylation?

A

relieves inhibition of SERCA
faster Ca2+ reuptake into SR.
Increases lusitropy by increasing SR Ca2+ uptake
Increases inotropy by increasing SR Ca2+ load.

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13
Q

Effects of RyRs phosphorylation?

A
  • Phosphorylation increases Ca2+ sensitivity, so that less Ca2+ is needed to evoke Ca2+ release
  • Increases inotropy by increasing SR Ca2+ release.
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14
Q

Effects of TnI phosphorylation?

A

-TnI decreases Ca2+ sensitivity of troponin C
allows faster dissociation of Ca2+ so faster filling = increased lusitropy (not inotropy)
-Imp @ high HR

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15
Q

Parasympathetic regulation of inotropy

A

parasympathetic innervation of the ventricle is sparse, so little parasympathetic regulation of inotropy

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16
Q

Effects of LTCCs phosphorylation?

A
  • Phosphorylation slows inactivation, increases entry of trigger Ca2+
  • Increased Ca2+-induced Ca2+ release increases inotropy
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17
Q

What is the effect of blocking M2 muscarinic acetylcholine receptors w/atropine?

A

Increased HR by inhibiting tonic parasympathetic activity

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18
Q

What is the effect of blocking Beta adrenergic receptors with propanolol?

A

Decreased HR by inhibiting tonic sympathetic activity

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19
Q

T or F: under normal conditions, the parasympathetic tone at rest is less than the sympathetic tone

A

False, parasympathetic tone is greater at rest

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20
Q

What are the molecular targets for sympathetic regulation of chronotropy?

A
  • HCNs
  • LTCCs
  • RyRs
  • NCX
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21
Q

Sympathetic Regulation of Chronotropy: HCN

A

Activity increased by sympathetic stimulation via cAMP binding
Net inward (depolarizing) current = cardiac “funny current,”
Promotes excitability and spontaneous action potentials
Highly expressed in sinoatrial myocytes

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22
Q

Sympathetic Regulation of Chronotropy: LTCCs

A

Activity increased by sympathetic stimulation
Net inward (depolarizing) current
Promotes excitability and spontaneous action potentials

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23
Q

Sympathetic Regulation of Chronotropy: LTCC & RyRs

A

Increase HR

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24
Q

Sympathetic Regulation of Chronotropy: NCX

A

Promotes excitability and spontaneous action potentials
Intracellular Ca2+ is extruded by NCX, which generates a net inward current (2 Ca2+ out, 3 Na+ in)
Serves to remove Ca2+ from cytoplasm

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25
Q

How is Parasympathetic Regulation of Chronotropy mediated?

A

The release of acetylcholine from vagal nerve ending in the SA node, activates M2 muscarinic ACh receptors coupled to Gi/o heterotrimeric G protein which releases 2 signals: Galphai/o & Gbetagamma subunit complex

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26
Q

Targets of parasympathetic inhibition of chronotropy

A
  • GIRKs (G-protein coupled inwardly-recitifying K+): Gbetagamma binds directly and stabilizes Vm near K+ Eq, dampening excitation: Primary mode
  • HCN, LTCCs, RyRs (Galphai/o inhibits adenylyl cyclase): secondary mode
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27
Q

Characteristics of VSMCs

A

Small mononucleate cells
No sarcomeres = smooth, not striated
No troponin complex, no tropomyosin
Different contractile mechanism vs. striated muscle (Ca2+ release from SR not required)
Rate of contraction slower than striated muscle, but can be sustained

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28
Q

Triggers of smooth muscle contraction:

A

Contraction triggered by mechanical, chemical, or electrical stimuli (APs not required)

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29
Q

List the steps in VSMC activation

A
  1. Ca2+ enters cytoplasm from SR and/or plasma membrane Ca2+ channels
  2. Ca2+ binds to Calmodulin (CaM)
  3. Ca2+- CaM binds to Myosin Light Chain Kinase (MLCK), to activate it.
  4. Activated MLCK phosphorylates the myosin head – permits cross bridge cycling
  5. MLC dephosphorylated by Myosin Light Chain Phosphatase (MLCP), to halt contraction
    Note: cAMP (via PKA) inhibits MLCK – causes VSMC relaxation
30
Q

What are the 3 methods of vasculature control?

A
  • Neural
  • Intrinsic
  • Humoral
31
Q

What constitute neural control of vasculature?

A

Sympathetic regulation
Baroreceptor reflex
CNS control center

32
Q

What is the result of sympathetic regulation of vasculature?

A

Vasoconstriction by direct activation of VSMC, INDEPENDENT of membrane depolarization

33
Q

How does Sympathetic stimulation directly activates VSMC contraction ?

A
  • Sympathetic terminals release NE – activates aARs on VSMCs (mainly a1 also some a2)
  • aARs in VSMCs are coupled to Gq
  • Gq activation causes IP3 production.
  • IP3 increases cytosolic Ca2+ by activating SR Ca2+ release via IP3 receptors (similar to ryanodine receptors)
34
Q

T or F: NE released by sympathetic neurons act on alpha1 receptors to cause vasoconstriction in all vascular beds

A

True, however Circulating epinephrine can activate b2ARs on VSMCs in skeletal muscle, causing vasodilation via cAMP/PKA inhibition of MLCK.

35
Q

What are baroreceptors?

A

Pressure sensitive neurons found in in aortic arch and carotid sinus (High pressure); in atria and vena cavae (Low pressure)

36
Q

What is the function of high pressure baroreceptors?

A

respond to increases in arterial pressure by increasing firing rate.

37
Q

How are baroreceptors activated?

A

Stretch of arterial walls activates mechanosensitive eNac Na+ channels on baroreceptor cell membranes. Inward current causes depolarization, triggers APs in neurons

38
Q

What is the Baroreceptor reflex?

A

SHORT TERM and rapid negative feedback mechanism for sudden changes in blood pressure (increase). The end result is a decrease in HR, decrease in inotropy, and decreased vascular tone by decreasing sympathetic tone and increasing parasympathetic tone output from cardiovascular center.

39
Q

Where do the high pressure baroreceptors project?

A

Carotid sinus baroreceptors project to the “cardiovascular control center” in the medulla via glossopharyngeal nerve. Aortic arch baroreceptors project via the vagus nerve.

40
Q

What mediated the “Bainbridge Reflex” ?

A

Low pressure baroreceptors

41
Q

Describe vasculature control by vasoactive metabolites

A

-Vasoactive metabolites produced by metabolically active tissue = local feedback control of blood flow.

42
Q

what is the PRIMARY MECHANISM TO MATCH BLOOD FLOW IN CAPILLARIES TO METABOLIC DEMAND?

A

Vasoactive metabolites (intrinsic control mechanism)

43
Q

What are the vasoactive metabolites?

A
  • decreased PO2
  • increased PCO2 (decreased pH), partially due to lactic acid
  • increased extracellular K+
  • increased adenosine (byproduct of ATP hydrolysis): binds to A2 purinergic receptors on VSMCs. A2 receptors are GPCRs coupled to Gs = increased cAMP, vasodilation via inhibition of MLCK
44
Q

What is the myogenic response?

A
  • Feedback mechanism to maintain constant flow despite changes in pressure
  • Increased pressure increases flow initially (Q = DP/R), but myogenic response counters by producing vasoconstriction to reduce flow.
45
Q

T or F: Myogenic response can be overcome by vasoactive metabolites

A

True

46
Q

How is the myogenic response mediated?

A

Stretch-activated ion channels of Trp family in VSMC membrane :

  • non-selective cation channels, many isoforms
  • inward current depolarizes cell, also direct Ca2+ entry
47
Q

What are the 2 mechanisms of endothelial-mediated regulation?

A
  • Nitric Oxide (NO) System

- Endothelin System

48
Q

What is NO? Where is it produced?

A

A potent vasodilatation gas, produced by vascular endothelium vis nitric oxide synthase
-Labile, short half-life (10-60 s) = local effects

49
Q

What is the function of NO?

A

-Basal NO release helps set resting vascular tone
-Nitric oxide is a major physiological mechanism for vasodilation.

50
Q

Describe the action of NO in VSMC

A
  • NO diffuses across membranes to VSMCs, where it activates guanylate cyclase to produce cGMP
  • cGMP activates PKG
  • PKG reduces intracellular Ca2+ via activation of SERCA, and inhibition of L-type Ca2+ channels
  • Decreased Ca2+ causes vasodilation via reduced MLCK activity
51
Q

What is Endothelin?

A

potent vasoconstrictor, produced by vascular endothelium, synthesized by Endothelin Converting Enzyme (ECE) and inhibited by NO & ANP

52
Q

How does endothelin work?

A
  • Endothelin released from vascular endothelium binds to ET receptors on VSMC (GPCRs coupled to Gq): vasoconstriction via IP3 and increased Ca2+
  • Negative feedback via ET receptors on endothelial cells = NO production.
53
Q

What is the natural counterpart to NO?

A

endothelin

54
Q

What are the humoral systems of vasculature control?

A

Renin-Angiotensin-Aldosterone

Atrial Natriuretic Peptide

55
Q

What is the Primary system for long-term control of blood pressure?

A

Renin-Angiotensin-Aldosterone System

56
Q

What is Renin? function?

A

-Proteolytic enzyme released by renal juxtaglomerular cells

57
Q

What promotes the release of Renin?

A

sympathetic stimulation, decreased blood pressure in renal artery, and decreased Na+ reabsorption

58
Q

What is ANGIOTENSIN CONVERTING ENZYME (ACE)?

A
  • Cleaves Angiotensin I into Angiotensin II, a vasoconstrictor
  • ACE inhibitors & Angiotensin II receptor blockers = Therapeutics for treatment of hypertension & heart failure
59
Q

Effects of Angiotensin II:

A

Direct effect = systemic vasoconstriction via binding to GPCRs on VSMCs.
Indirect effects: Stimulates sympathetic activity and release of aldosterone, endothelin, and ADH

60
Q

What is aldosterone?

A
  • Steroid hormone produced by the adrenal cortex
  • Promotes reabsorption of Na+ and water in kidney collecting duct
  • Increases blood volume and blood pressure
61
Q

What is ADH?

A

ANTI-DIURETIC HORMONE (ADH, Arginine Vasopressin)

  • Peptide hormone formed in hypothalamus, released by pituitary
  • Increases water reabsorption in kidney
  • Can also bind to receptors in vasculature to cause vasoconstriction.
62
Q

What stimulates the release of ADH?

A

Release stimulated by hypovolemia, hypotension, high osomolarity, Angiotensin II, and sympathetic stimulation.

63
Q

What is Atrial Natriuretic Peptide (ANP)?

A
  • Vasodilator peptide released by atria (mostly right) in response to stretch
  • Natriuretic = sodium excretion
64
Q

What is the function of ANP?

A

-Long-term regulation of Na+ and water balance
-ANP increases glomerular filtration rate and secretion of Na+ and water (natriuresis and diuresis).

65
Q

How does ANP function?

A

ANP binds to Natriuretic Peptide Receptors
Receptor guanylate cyclases (not GPCRs), produce cGMP
cGMP activates SERCA, stimulates Ca2+ uptake, decreases cytoplasmic Ca2+

66
Q

What happens when someone stands up?

A

Blood pools in veins, decreased CO, decreased arterial pressure leads to activation of a compensatory reaction:

  • Baroreceptor reflex: increased sympathetic tone. increased HR, CO, vasoconstriction.
  • Myogenic Response: vasoconstriction due to increased pressure.
67
Q

What are the main systems in Integrated Cardiovascular Response to Exercise?

A
  • Central commend mechanism: Increased sympathetic and decreased para= increased CO, HR, inotropy, and increased arterial resistance in non-exercising muscles
  • Local responses: vasodilatation due to vasoactive metabolites
68
Q

How is there an increase in SV during exercise?

A

Activity of skeletal muscle increases venous return, Increase stroke volume via Starling’s Law

69
Q

Acute blood loss results in what?

A

decreased mean arterial pressure (MAP), which results in decreased CO.

70
Q

How does the body respond to acute blood loss?

A
  • Baroreceptor reflex: Increased sympathetic tone due to decreased firing, also decreased para. resulting in increased HR and inotropy and vasoconstriction
  • The renin-angiotensin system: activated by low BP, AII increases vascular tone, promotes ADH release to increase blood volume .
  • Decreased capillary hydrostatic pressure: reabsorption from interstitial fluid, increasing blood volume.
71
Q

What happens to max HR with Age?

A

decreases along w/ intrinsic HR

CVPR Unit 1 (27 decks)

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