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

Endothelium-dependent vasodilation is when acetylcholine and bradykinin, act by increasing intracellular calcium levels in endothelial cells, leading to the synthesis of NO. NO diffuses to vascular smooth muscle, leading to vasorelaxation. Endothelium cells respond to vasorelaxants by releasing soluble EDRF. EDRF acts on vascular muscle to cause relaxation and gives a vaso-relaxing effect. An increase in blood flow stimulates endothelium-dependent vasodilation by increasing shear stress on the endothelium, both in conduit and resistance vessels

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

Constitutive enzymes are enzymes that are synthesized on a constant basis regardless of the physiological demand, so they have a greater physiological and pathological implication because they occur permanently in an area. Induced enzymes are enzymes that occur after a substance is added, so the enzyme is not present before the substance, which means that something has to be excreted by the body before that enzyme takes effect, so the implications are smaller.

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?

Nitric Oxide (NO)

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

NO is inactivated by reaction with oxygen to form nitrogen dioxide. NO reacts with superoxide to form peroxynitrite. Intracellular glutathione protect against tissue damage caused by scavenging peroxynitrite. Peroxynitrite 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.

When challenged with foreign antigen, TH1 cells synthesis Nitric Oxide, the importance of NO of TH1 cell is demonstrated by the impaired protective response to injected parasites after inhibition of iNOS. NO also stimulates the synthesis of inflammatory prostaglandins by activating COX-2. Through its effects on COX-2, its direct vasodilatory effects, and other mechanisms, NO generated during inflammation contributes to the erythema, vascular permeability, and subsequent edema associated with acute inflammation. 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? 

• Parkinson's disease, stroke and amyotrophic lateral sclerosis.