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.

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.

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

Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor-alpha and other cytokines induce synthesis of iNOS in macrophages, neutrophils, and T cells, as well as hapatocytes, smooth muscle cells endothelial cells and fibroblasts. This widespread generation of NO results in exaggerated hypotension, shock, and in some cases death.

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

Nitric Oxide

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

Phosphodiesterase enzymes that degrade cGMP, thus leading to NO having no or less effect.

NOS inhibitors and sGC inhibitor methylene bluein humans reduce or reverse the effects of NO.

NO is inactivated by reaction with oxygen to form nitrogen dioxide. NO reacts with superoxide to form peroxynitrite.

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. Excess NO production in acute or chronic inflammatory conditions may exacerbate tissue injury.

In which possible neurological and psychiatric diseases is NO involved?

Excessive NO synthesis is linked to excitotoxic neuronal death in several neurologic diseases including stroke, amyotrophic lateral sclerosis and Parkinson’s disease