Vascular endothelium

Question 1

What are the functions of endothelial cells?

Answer 1

• permeability
• synthesize collagen and proteoglycans
• synthesize and secrete molecules which promote protective thrombus formation ( like Factor 8)
• synthesize and secrete molecules with minimise pathological thrombus formation ( nitrous oxide )
• secrete vasoactive factors controlling blood flow
• produce molecules which mediate the acute inflammatory reaction (interleukins 1,6,8 etc)
• produce some growth factors- fibroblast growth factor etc.

Question 2

In particular what is the role of the endothelium on hemostasis?

Answer 2

• Secretes NO, PGI2 to inhibit platelet activation
• Prevents exposure of platelets to sub-endothelial matrix components such as collagen
• Produces heparin to inhibit the coagulation cascade (heparin is expressed on endothelial cell surface)
• Produce thrombomodulin which, when bound to thrombin, can generate activated protein C which degrades FVa and FVIIIa. (expressed on endothelial cell surface)
• Secretes tPA and urokinase to degrade formed clots. (secreted into plasma in vicinity of intact endothelium)

Question 3

nitric oxide is a what?

endothelin is what?

Answer 3

nitric oxide = vasodilator

endothelin A = vasconstrictor

Endothelin B = vasodilator

Question 4

What are prostacyclins?

Answer 4

they are vasodilators

• is a product of arachidonic acid produced by cyclooxygenase
• inhibits platelet aggregation and promotes blood vessel dilation
• it’s counterpart is thromboxane 2 which is produced by platelets and promotes platelet aggregation and cuases blood vessel constriction in hemostasis

Question 5

what is endothelium derived relaxing factor?

Answer 5

it is a NO free radical and is therefore unstable with a very short half life - it can be produced enzymatically or chemically -

it is a potent vasodilator -used in the treatment of angina as it helps with ischemic pain by decreasing the cardiac workload - it is also an air pollutant produced by cigarette smoke, automobiles and power plants -

Question 6

What is ‘good nitric oxide synthase’?

Answer 6

eNOS or NOS 3= found in endothelial cells

Question 7

What is ‘bad’ Nitric oxide synthase?

Answer 7

iNOS or inducible nos= inducible in many tissues and innapropriately oxidizes things like LDLs

Question 8

what are the physiological effects of nitric oxide/cyclic GMP?

Answer 8

• Vascular effects include vasodilation & inhibition of platelet aggregation
• Immunological effects include inhibition of neutrophils & monocytes
• In blood vessels, cGMP causes relaxation of vascular smooth muscles lead to vasodilation and increased blood flow.

Question 9

the actions of nitric oxide and cyclic GMP are terminated by what enzyme?

Answer 9

phosphodiesterases - regulate the localization, duration, and amplitude of cyclic nucleotide signalling

* they are very localized enzymes which makes them great drug targets*

Question 10

what kind of drugs are PDE 5 inhibitors?

Answer 10

Sildenafil= viagra

Tadalfil

Vardenafil

Question 11

what is the difference between an on-target and off-target side effect?

Answer 11

on target= on the right ezyme, but producing the wrong effect

off target = on the wrong enzyme and causing the wrong effect

Question 12

what are nitric oxide synthase inhibitors used for?

Answer 12

•Inhibitors of NOS, while widely used in experimental research, are still in under investigation for clinical applications

Question 13

What are endothelins?

Answer 13

•Endothelin is a family of 21 amino acid peptides

–ET-1 is found in endothelial cells, brain and kidney

–ET-2 is found in the kidney and intestines

–ET-3 is found in the brain, lung, intestines and adrenal glands

• endothelins are the strongest vasoconstrictors known
• There are three isoforms with varying regions of expression and two key receptor types, ETA and ETB.

Question 14

What is the synthesis of endothelin inhibited by?

Answer 14

by NO and prostacyclin

Question 15

What are the two types of endothelin receptors?

Answer 15

•ETA

–ETA receptors stimulate phospholipase C

–ETA receptors are found in the smooth muscle tissue of blood vessels

–binding of endothelin to ETA increases vasoconstriction and the retention of sodium ->increased blood pressure.

•ETB

–ETB: Activate phospholipase C

–ETB receptors located on the endothelial cells

–ETB receptors linked to increased natriuresis and diuresis and the release of nitric oxide (NO), all mechanisms that lower the blood pressure.

Question 16

What drug is an ETA/B receptor antagonist?

Answer 16

–Bosantin is an ETA/B receptor antagonist

–used in the treatment of Pulmonary Hypertension

Question 17

Name a drug that is an ETA selective antagonist

Answer 17

–Ambrisentan and Sitaxsentan are ETA selective antagonist

–ETA selective antagonists decrease the vasoconstrictive actions and allow an increased beneficial effects of endothelin B stimulation, such as nitric oxide production

Question 18

All endothelin drugs can have what side effect?

Answer 18

–All endothelin antagonist drugs can induce liver damage and need to be monitored closely

Question 19

What is the effect of endothelium derived hyperpolarizing factors?

Answer 19

• Induces relaxation of smooth muscle due to hyperpolarization
• Diffuse from the endothelium
• Is not NO or prostacyclin
• Activated by Ga subunit
• Unlikely to be CO
• EDHFs have a short half life

Question 20

what vasoactive agents are released by the endothelium to regulate vascular tone?

Answer 20

•

–NO (vasodilator)

–Prostacyclin (vasodilator)

–EDRF (vasodilator; = NO)

–Endothelin (vasoconstrictor)

–EDHF (vasodilator)

•In a healthy individual, a delicate balance between vasoconstriction and vasodilation is maintained by endothelin, calcitonin and other vasoconstrictors on the one hand, and nitric oxide, prostacyclin and other vasodilators on the other.

Question 21

when do we use prostacyclin?

Answer 21

used intravenously - as a vasodilator in sever Raynaud’s phenomenon or ischemia of a limb -