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Cardiology BMSc > Endothelium and Nitric Oxide (Prof Khan) > Flashcards

Endothelium and Nitric Oxide (Prof Khan) Flashcards

1
Q

Describe intrinsic local blood flow control factors

A

Originate from the vessel itself or surrounding tissue- Endothelial fators, myogenic mechanisms, local hormones (bradykinin, histamine), metabolic by-producs/hypoxia.

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2
Q

Describe extrinsic blood pressure regulation factors

A

Originate from outside of the organ or tissue in which the blood vessel is located- sympathetic nerves and circulating Ang II.

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3
Q

List the 8 main functions of the endothelium

A

1) Diffusion/permeability barrier
2) Regulate homeostasis and immunogenic processes
3) Regulate vascular tone
4) Regulate inflammation
5) Regulate oxidative stress
6) Regulate vascular growth/remodelling
7) Sense shear and tangential stress
8) Modulates vasoactive substances

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4
Q

Describe laminar blood flow

A

Blood in the centre of the blood vessel travels with least peripheral resistance

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5
Q

How does endothelium react to blood flow

A

Detect direction of blood flow and the endothelial cells move according to which way the blood flows (the endothelial cells move compared with no flow, 6 hours of flow and then 24 hours of flow)

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6
Q

List some risk factors for endothelial damage

A

Vasospasm, DM, hyperlipidaemia, HF, hypertension, inactivity, adiposity, oxidative stress, inflammation/infection and passive smoking

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7
Q

List the two main types of endothelium-derived chemicals and what molecules are included in these

A

1) Vasodilators: Endothelium-derived relaxing factor; nitric oxide, prostaglandins (PGI2, PGE2) and endothelium-derived hyperpolarising factor (CO, EETs, H2O2, NO and PGI2.
2) Vasoconstritors: Endothelin and prostanoids (thromboxane, PGG2 and PGH2.

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8
Q

How do they test the effects of ACh on the vascular wall

A

ACh was shown to relax a strip of aorta precontracted with noradrenaline. This is done with an arterial sample organ bath.

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9
Q

List the three types of nitric oxide synthase

A
  • NOS I: Neuronal (nNOS): in neurons
  • NOS II: Inducible (iNOS): Macrophages, neutrophils, fibroblasts, VSMC
  • NOS III: Endothelial (eNOD): Endothelial cells, cardiac myocytes, osteoblasts, osteoclasts, airway epithelium
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10
Q

What is the chemical reaction that forms nitric oxide

A

L-arginine, NADPH and O2 react with nitric oxide synthases to produce NO, NADP and L-citruline

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11
Q

Subcellular locations of nNOS, iNOS and eNOS

A 
nNOS = Largely cytosolic
iNOS = Cytosolic
eNOS = Membrane bound
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12
Q

Regulation of expression of nNOS, iNOS and eNOS

A

nNOS = Constitutive
Upregulated by SEX hormones and after nerve injury

iNOS = Not normally present
Expression induced by cytokines/endotoxins

eNOS = Constitutive
Upregulated by sex hormones and shear stress

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13
Q

Which NOS types are calcium calmodulin binding dependent

A

nNOS and eNOS are both activated when calcium is above a normal resting concentration of the cells

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14
Q

Major function of nNOS, iNOS and eNOS

A

nNOS = Neuronal messenger, cell communication

iNOS = Immunocytotoxicity

eNOS = Relaxation of vascular smooth muscle

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15
Q

What are the actions of NO

A

1) Scavenged by O2 to form OONO > Nitrate (NO3)
2) Combines oxyhaemoglobin
3) Activates guanylate cyclase in VSMC
4) Lowers intacellular calcium by SERCA uptake into intracellular stores in VSMC
5) Indirect effects: Inhibits PDE, inhibits ET-1 and inhibits renin release

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16
Q

Actions of NO via cGMP

A
  • Stimulate sodium potassium ATPase causing hyperpolarisation
  • Inhibits Rho kinase causing reduced contraction
  • Modulate calcium
17
Q

Role of calcium in muscle contraction

A

1) Increased calcium
2) Increased CaM
3) This changes MLCK to MLCK CaMCA2+
4) This turns mysoin into myosin P
5) To contract, myosin-P binds with actin to form actomyosin-P

18
Q

Describe local changes in calcium

A

1) Calcium sparks-activated by calcium entry through VGCC
2) Calcium sparks caused by coordinated opening of RyRc
3) Calcium sparks acts as positive feedback to increase smooth muscle contractility
4) A lot more…

19
Q

Actions of NO on calcium

A
  • Downregulating IP3 formation (inhibits PLC)
  • Decreasing calcium mobilisation through IP3 receptor
  • Promoting calcium sequestration in SR
  • Reducing calcium influx
  • Increasing calcium efflux
20
Q

Examples of NO donor drugs

A

Sodium nitroprusside, diethylamine/NO and diethylenetriamine and S-nitrosothiols

21
Q

CV agents modulating endogenous NO bio activity

A
  • ACEi
  • Calcium channel blockers
  • Statins
  • Beta blockers
  • Phosphodiesterase inhibitors
22
Q

Examples of NO synthesis inhibitors

A
  • Asymmetric dimethylarginine (ADMA)- This is naturally occurring
  • Arginine analogues:

1) NG-monomethyl-L-arginine (L-NMMA)
2) NG-nitro-L-arginine methyl ester (L-NAME)

23
Q

Describe endothelium-derived hyperpolarising factor

A

Causes an increase in endothelial calcium and activates endothelial SK and IK calcium channels

24
Q

Describe hyperpolarisation of endothelial cells

A

Spread to SMC (via gap junctions) and activtaes SMC sodium potassium and/or potassium channels

25
Q

Describe endothelin

A

ET1, 2 and 3 are produced on demand through mRNA synthesis. Is induced by Ang II, adrenaline, hypoxia and oxLDL. Is inhibited by shear stress, NO and PGI2

26
Q

What pathway does endothelin cause vasoconstriction

A

IP3 pathway

27
Q

Describe the lead up to ET-1

A

Pre-pro-ET-1 -> Big ET-1 -> ET-1

28
Q

What receptors are expressed on the endothelium that initiate ipro-inflammatory signalling pathways

A

Toll like receptors

29
Q

Describe TLRs

A
  • TLRs control cytokine production

- Healthy arteries express low levels of TLR2 and 4

30
Q

Deletion of TLRs prevent what

A

Atherosclerosis

31
Q

How to assess endothelial function

A
  • An endothelial -dependent vasodilator (ACh, substance P, bradykinin, serotonin)
  • This causes a dilation via the endothelium
  • Then a nitrovasodilator is given (GTN or SNP) and this donates NO directly (out with use of endothelium)
32
Q

What does TLR signalling in macrophages activate

A

Mitogen and stress-activated protein kinase MSK1 and MSK2

33
Q

What do MSKs promote

A

Transcription of genes with anti-inflammatory functions (IL-10 and IL-1 receptor antagonists)

Cardiology BMSc (4 decks)

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