USMLE Forums banner
1 - 17 of 17 Posts

·
Registered
Joined
·
590 Posts
Discussion Starter · #1 ·
A 52-year-old male with a previous history of diabetes mellitus and hypercholesterolemia presents with recurrent chest discomfort that is relieved after five minutes of rest. He is prescribed nitroglycerine tablets with instructions to put one under his tongue the next time an episode occurs, to see if that relieves the discomfort. Nitrogycerin is quickly denitrated, and the first nitric oxide induces vasodilation by acting on:
  • Endothelial cells to activate guanylyl cyclase to make cGMP
  • Endothelial cells to activate the calcium-calmodulin second messenger system
  • Smooth muscle cells by binding to a GPCR on the cell membrane to make cGMP
  • Smooth muscle cells to activate guanylyl cyclase to make cGMP
  • Smooth muscle cells to activate the calcium-calmodulin second messenger system
 

·
Registered
Joined
·
116 Posts
Answer is D.

Histamine, bradykinins, and acetylcholine stimulate NO synthase in enthothelial cells that forms NO from arginine. NO diffuse into smooth muscle cells, activates soluble guanylyl cyclase. Finally increased cGMP.
But NO from Nitrogycerin is synthesized in smooth muscle cells directly; not in endothelial cells.

one more concept tested about nitro compounds is why tolerance develops!
NO synthesis from Nitroglyc requires glutathione. glutathione stores r limited. so ur cells need some time to replenish glutathione stores. this is why u give nitro patches during day time and remove it during night time. u don't get angina during night and it helps cell to make glutathione, so that nitro can work next day.
u probably remember glutathione story from acetaminophen toxicity as well.

How does cGMP cause vasodilation? this is also tested.

dephosphorylation of mysosin light chain. there is one q about this in UW.
 

·
Registered
Joined
·
487 Posts
Answer is D.

Histamine, bradykinins, and acetylcholine stimulate NO synthase in enthothelial cells that forms NO from arginine. NO diffuse into smooth muscle cells, activates soluble guanylyl cyclase. Finally increased cGMP.
But NO from Nitrogycerin is synthesized in smooth muscle cells directly; not in endothelial cells.

one more concept tested about nitro compounds is why tolerance develops!
NO synthesis from Nitroglyc requires glutathione. glutathione stores r limited. so ur cells need some time to replenish glutathione stores. this is why u give nitro patches during day time and remove it during night time. u don't get angina during night and it helps cell to make glutathione, so that nitro can work next day.
u probably remember glutathione story from acetaminophen toxicity as well.

How does cGMP cause vasodilation? this is also tested.

dephosphorylation of mysosin light chain. there is one q about this in UW.
Very nice explanation.... Did you copy this from UW...?:sleepy:
 

·
Registered
Joined
·
590 Posts
Discussion Starter · #12 ·
Correct!

As drahmednawaz explained very nicely above, the NO would come from the vascular endothelial cell or from the nitrate drug. It's acting in the smooth muscle cell (since that's the kind of cell that does the contraction or relaxation). The NO enters the cell and activates guanylyl cyclase. That forms cGMP from GTP. The cGMP activates myosin light-chain (MLC) phosphatase, which dephosphorylates MLC and causes relaxation of the smooth muscle cell.

Slope Font Circle Parallel Terrestrial plant
click image to enlarge
image from Golan Pharmacology


Conversely, when the cell wants to contract, calcium comes in and forms a calcium-calmodulin complex that activates MLC kinase, which phosphorylates the light chain of myosin and provokes contraction.
 

·
Registered
Joined
·
21 Posts
A 52-year-old male with a previous history of diabetes mellitus and hypercholesterolemia presents with recurrent chest discomfort that is relieved after five minutes of rest. He is prescribed nitroglycerine tablets with instructions to put one under his tongue the next time an episode occurs, to see if that relieves the discomfort. Nitrogycerin is quickly denitrated, and the first nitric oxide induces vasodilation by acting on:
  • Endothelial cells to activate guanylyl cyclase to make cGMP
  • Endothelial cells to activate the calcium-calmodulin second messenger system
  • Smooth muscle cells by binding to a GPCR on the cell membrane to make cGMP
  • Smooth muscle cells to activate guanylyl cyclase to make cGMP
  • Smooth muscle cells to activate the calcium-calmodulin second messenger system
Thanks for posting such informative questions along with your excellent explanations.
Can you please elaborate option C, is this this the mechanism of action of ANP ? What is GPCR ?
 

·
Registered
Joined
·
116 Posts
NO activate the soluble guanylyl cyclase in the cytoplasm to increase cGMP, atrial natriuretic peptide acts on G protein-coupled receptors (GPCRs) in the cell membrane to activate membrane-bound guanylyl cyclase to do the same job for living.
 

·
Registered
Joined
·
590 Posts
Discussion Starter · #16 ·
Can you please elaborate option C, is this this the mechanism of action of ANP ? What is GPCR ?
As drahmednawaz wrote above, GPCR stands for G-protein coupled receptor, which are seven-pass transmembrane receptors coupled to a G-protein on the intracellular side, and one of the receptors that binds ANP is a GPCR. There are actually two different kinds of receptor for ANP: the GCPR is more of a clearance receptor - it binds the ANP and sequesters it ("job well done, ANP, that's enough for today"). There are also single-pass catalytic receptors which are associated with guanylyl cyclase on the intracellular side of the membrane. They act, in the end, much like a GPCR would, and as drahmednawaz described above: they bind ANP on the outside of the membrane, activate guanylyl cyclase on the inside of the membrane, leading to the same cGMP effects as NO.

Hope that helps!
 
1 - 17 of 17 Posts
Top