Physiology and Pharmacology 16: (Evans) role of endothelium

Question 1

What are endothelins? Function? 3 examples and where theyre found

Answer 1

ETs : 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis -> act on ETa and ETb receptors G protein PLC coupled

ET-1 : only in endothelial cells and expressed in a wide range of other tissues
ET-2 : present in kidney
ET-3 : present in brain, lung and adrenal gland

Question 2

Where/what level does endothelin (ET-1) regulation occur? Why?

Answer 2

Endothelial cells do not have storage vesicles -> regulation occurs at transcription level

Big precursors are processed, then cleaved by endothelin converting enzyme

Question 3

Describe pathway of Nitric oxide synthesis in endothelial cells -> molecules involved in artery relaxation?

Answer 3

L-arginine is catalysed by Nitric Oxide synthase (NOS)
-> forms citrulline + NO

• > NO diffusion into artery smooth muscle
• > stimulates guanylate cyclase -> increased GTP to cGMP

PKG is stimulated -> muscle relaxes

Question 4

example of a nitrovasodilator and its mechanism of action?

Answer 4

Sodium Nitroprusside (SNP)-> administered intravenously to induce rapid reduction of blood pressure (40ish sec half life)

SNP breaks down to produce NO inside smooth muscle cells

Question 5

What is the function of renin and where is it synthesised, stored and secreted?

Answer 5

Primary function to increase blood pressure -> leads to restoration of perfusion pressure in kidneys

synthesised, secreted and stored in granular juxtaglomerular cells

Question 6

What stimulates renin release in the kidney?

Answer 6

Decrease in NaCl in filtrate is sensed by the macula densa cells of distal tubule
-> stimulates renin release

Release also controlled by renal blood pressure -> increase in renal BP locally decreases renin secretion and vice versa

Stimulation of B1-adrenoceptors on juxtaglomerular cells also increases renin secretion

Question 7

How does renin interact with angiotensin? Following modifications and actions of angiotensin?

Answer 7

renin is an ‘angiotensinogenase’ -> cleaves off N-terminal of angiotensin (chopped small aa sequence = angiotensin I)

Angiotensin I converted to Angiotensin II via ACE

~ circulating renin acts on circulating angiotensin to produce angiotensin I in the plasma

Conversion of AI to AII in plasma/artery -> localised action

AII binds to AT GPCRs resulting in Ca release and contraction of smooth muscle

Question 8

Summary of Angiotensin II effects?

Answer 8

Vasocontriction
+ Production of aldosterone increases sodium uptake in kidney
+ production of ADH increases H20 uptake in kidney
Generates feeling of thirst

All lead to increased blood pressure through various mechanisms (water retention, increased blood volume, vasoconstriction)