• What do you understand by the term “endothelium-dependent” vasodilation?  Explain.

Endothelium cells respond to vasorelaxants by releasing soluble endothelium-derived relaxing factor (EDRF). EDRF acts on vascular muscle to cause relaxation. NO is the major bioactive component of EDRF.

• When we talk about the NOS enzyme, what is meant by “constitutive” and “inducible” enzymes and what are the pathological and physiological implications thereof?

iNOS are expressed through transcriptional induction (inducible) when exposed to inflammatory mediators and this expression, and thus NO synthesis, is not regulated by calcium. eNOS and nNOS are expressed constituvely (=continuously produced regardless of cells' needs) and NO synthesis is dependent on calcium regulation. Cytosolic calcium forms complexes with calmodulin which then binds and activates eNOS and nNOS.

• Explain how NO contributes to the fatal pathology of septic shock.

Sepsis is a systemic inflammatory response caused by infection. Endotoxins from the bacterial cell wall along with endogenously generated TNF-alpha and other cytokines, induce synthesis of iNOS in macrophages, neutrophils, T-cells, hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. This widespread synthesis of NO cause aggravated hypotension, septic shock and death. 

• Which autacoids’ mechanism of action depends on effects on the guanylyl cyclase-cGMP system?

NO

• NO may be toxic to the cell.  Which mechanisms are available to the body to counter this detrimental effect of NO?

Intracellular glutathione protect against tissue damage caused by scavenging peroxynitrite (peroxynitrite=NO+superoxide; it inhibits protein function and cause tissue damage during inflammation).

• Name a way in which NO can act pro-inflammatory.  Give examples of where it will have advantages or disadvantages.

NO stimulates the synthesis of inflammatory prostaglandins by activating COX-2. The vasodilatory effects of prostaglandins along With NO leads to an increase in vascular permeability and thus lead to perivascular oedema. Excessive NO production may lead to tissue injury (iNOS induction.)

• In which possible neurological and psychiatric diseases is NO involved? 

- Stroke

- Parkinson's disease

-  Amyothropic lateral sclerosis