autacoids

Question 1

What is endothelin?

Answer 1

a 21 amino acid residue peptide with a shepherd’s crook structure due to two internal disulphide bonds

Question 2

What are the 3 isoforms of endothelin?

Answer 2

endothelin 1, 2, 3

Question 3

What 3 distinct genes code for endothelin?

Answer 3

1) ET-1
2) ET-2
3) ET-3

Question 4

Which isoform is produced by endothelial cells?

Answer 4

ET-1

Question 5

What is ET-2 associated with?

Answer 5

1) kidneys

2) intestine

Question 6

What is ET-3 associated with?

Answer 6

1) brain
2) lung
3) intestine
4) adrenals

Question 7

What are the 2 ET receptor subtypes?

Answer 7

1) ETₐ

2) ET₈

Question 8

Where are ET receptors found?

Answer 8

throughout the body

Question 9

What is the ETₐ receptor associated with?

Answer 9

1) excitation of visceral smooth muscle (vasoconstriction + bronchoconstriction)
2) hormone (aldosterone) secretion
3) affinity: ET-1 = Et-2 > ET-3
4) selective antagonists: BQ-123, ambrisentan

Question 10

What is the ET₈ receptor associated with?

Answer 10

1) brain
2) kidney
3) intestine
4) adrenals
5) vascular endothelium
6) endothelium-dependent vasodilation (if on endothelium)
7) inhibition of platelet aggregation
8) affinity: ET-1 = ET-2 = ET-3
selective agonists: BQ-3020, sarafotoxin 6c
9) selective antagonist: BQ-788

Question 11

How is endothelin derived?

Answer 11

1) much larger 212 amino acid residue peptide precursor pre-pro-endothelin converted to the intermediate fragment 38 amino acid residue “big ET”
2) big ET is converted to endothelin by endothelin converting enzyme (ECE), a metalloprotease + endopeptidase

Question 12

What is endothelin stimulated by?

Answer 12

1) activated platelets
2) endotoxin
3) thrombin
4) certain cytokines + growth factors
5) angiotensin II
6) arginine
7) vasopressin
8) adrenaline
9) insulin
10) hypoxia
11) low (mechanical) shear stress at the endothelial surface

Question 13

What is endothelin inhibited by?

Answer 13

1) nitric oxide (NO)
2) prostacyclin (PGI2)
3) heparin
4) high shear stress
5) ECE inhibitors

Question 14

What are the actions of endothelin?

Answer 14

1) acts as a paracrine/autocrine mediator
2) extremely potent vasoconstrictor
3) regulation of regional blood flow + arterial blood pressure
4) concentrations in blood are very low
5) pathogenesis of pulmonary hypertension
6) helps drive the pregnancy hypertensive complication pre-eclampsia
7) underpins renal/cerebral/intestinal vasospasm + acute MI

Question 15

How can pulmonary hypertension be treated?

Answer 15

1) ambrisentan

2) macitentan/bosentan (ETₐ + ET₈ receptor blockers)

Question 16

What are autacoids?

Answer 16

biological mediators/signalling molecules that act locally (close to sites of production) in autocrine (on the same cell that released them), paracrine (on a neighbouring cell), or intracrine (within the same cell that produced them) manners