Regulation of Blood

Question 1

How is the nitric oxide pathway used to cause vasodilation.

Answer 1

• The stimulus (Ach or stress) activates a GPCR on the endothelial cell which causes the phosphorylation of IP3 which further phosphorylates Ca2+ sensitive IP3 channels on the ER, releasing Ca2+ into the cells. This triggers calmodulin.
• Calmodulin activates NO synthases which catalyses arginine to citrulline and NO.
• NO travels through the sub-endothelial space where it enters smooth muscles activating guanylyl cyclase that converts GTP into cyclic GMP.
• This causes the activation of protein kinase C causing muscle dilation.

Question 2

How does Endothelin-1 used as a vasoconstrictor.

Answer 2

• The main vasoconstriction produced by the endothelium.
• Starts as a prepro hormone then a pro which is cleaved into ET-1 via ECE-1.
• This leaves the endothelium and acts on smooth muscles via binding to ETA/ETB which are g-coupled receptors. IP3 produced and muscles contract via the increase in Ca2+ intracellularly.
• In a healthy individual NO and ET-1 inhibit each other. However during times of infection ET-1 is produced by macrophages at sites and superoxide species produced reduce the bioavailability of NO.

Question 3

What are the uses of angiotensin 2 and endothelial derived hyperpolarising factor.

Answer 3

1. Angiotensin II: Another vasoconstrictor. It is not endothelial derived but produced from the kidney and liver. Angiotensinogen (Pre-prohormone) is converted to Angiotensin I by renin, and angiotensin I is converted to Angiotensin II by ACE (angiotensin converting enzyme).
   - Angiotensin II can cause vasoconstriction by the same mechanisms as ET-1.
2. Endothelial derived hyperpolarising factor: It works by opening K+ channels causing potassium to leave the SM and this causes relaxation.
   - EDHF can work in the absence of NO, so relaxation can still occur, and mainly works in smaller vessels in vascular beds.