Blog#2.4

 

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

Endothelium-dependent vasodilators such as e.g. Acetylcholine and bradykinin increase the intracellular calcium levels in the endothelium leading to the synthesis of NO an endothelial-derived relaxing factor (EDRF) in the endothelium. From there, NO moves to the vascular smooth muscle to cause its vaso-relaxing effect.

• 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 has been added, so the enzyme is not present before the substance, which means that something has to be secreted by the body before that enzyme takes effect, so the implications are smaller.

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

Sepsis is a systemic inflammatory response caused by an infection. Components present on bacteria such as endotoxins, cytokines and tumor necrosis factor-α induce the formation of iNOS in macrophages, smooth muscle cells, neutrophils etc. This NO formation in a wide area leads to severe 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?

For example, it prevents too much NO from being present.

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

Response to injury or infection leads to the activation of leukocytes and release of inflammatory mediators. This causes an increase in iNOS levels and activity in leukocytes. The NO as well as peroxynitrates produced are an important microbial agent. NO also plays an important role in the function of the immune cell TH1, which synthesizes NO in response to an unknown substance. This is a good protective response especially if iNOS is inhibited. NO also stimulates the synthesis of prostaglandins (activates COX2). NO's vasodilating effect and the effects of COX2 play a role in inflammation where it causes the red color of skin, increases vascular permeability and edema in acute inflammation. A disadvantage of NO in acute and chronic inflammation is that excessive NO production can cause tissue injury.

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

Stroke, amyotrophic lateral sclerosis and Parkinson's disease which are a cause of overactivation of NMDA receptors leading to excessive synthesis of NO and thus excitotoxic neuronal death.