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

Nitric Oxide is a potent vasodilator.  NO mediates its regulatory vasorelaxing effects through guanilyl cyclase activation. Also, thiol S-nitrosation by NO is increasingly evident as an effector mechanism. An increase in blood flow stimulates endothelium-dependent vasodilation. This is done by increasing shear stress on the endothelium.

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 – Any enzyme that is formed at a constant rate and in constant amount in a given cell, regardless of the metabolic state of the cell or organism.

Inducible - Inducible NOS is not usually expressed in cells, but its expression can be induced by bacterial lipopolysaccharide, cytokines, and other agents. Although primarily identified in macrophages expression of the enzyme can be stimulated in virtually any cell or tissue, provided that the appropriate inducing agents have been identified. Once expressed, iNOS is constantly active and not regulated by intracellular Ca²⁺ concentrations.

Constitutive enzymes are said to have a greater physiological effects than inducible enzymes.

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

In sepsis, nitric oxide synthesis is dysregulated with exaggerated production leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity whilst at the same time impaired microvascular function may be driven in part by reduced nitric oxide synthesis by the endothelium. Nitric oxide (NO) is believed to play a key role in the pathogenesis of septic shock, although many aspects of NO's involvement remain poorly defined

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

Nitrogen Monoxide

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

If NO reacts with oxygen it will form NO2 which thereby deactivates NO to ensure no toxic effects. If NO reacts with haemoglobin the body will oxidize it to a nitrate which therefore also deactivates NO and the toxic effects. NO also reacts with metals in the body.

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

NO is considered as a pro-inflammatory mediator that induces inflammation due to over production in abnormal situations. NO is synthesized and released into the endothelial cells by the help of NOSs that convert arginine into citrulline producing NO in the process. Oxygen and NADPH are necessary co-factors in such conversion. NO is believed to induce vasodilatation in cardiovascular system and furthermore, it involves in immune responses by cytokine-activated macrophages, which release NO in high concentrations. The response to injury or infection leads to the activation of leukocytes and the release of inflammatory mediators, resulting in an increase in iNOS levels and activity in leukocytes.

Nitric oxide and its oxidation products are toxic and can cause tissue injury. The endocrine system can protect against nitric-oxide-mediated tissue damage by producing corticosteroids, growth factors, and cytokines that are potent inhibitors of nitric oxide production.

In which possible neurological and psychiatric diseases is NO involved? 

Stroke, amyotrophic lateral sclerosis and Parkinson’s disease.