1.What do you understand by the term “endothelium-dependent” vasodilation?  Explain
Vasodilation is caused  by vasodilators that originate from the endothelium and are synthesised there. Endothelium-dependent vasodilators such as Acetylcholine and bradykinin increase the intracellular calcium levels in the endothelium leading to the synthesis of NO an endothelial-derived relaxing factor in the endothelium. NO moves to the vascular smooth muscle to cause its vaso-relaxing effect.

2.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 constantly being synthesized regardless of physiological need, resulting in greater physiological and pathological importance. Induced enzymes are enzymes that appear after a substance has been added, so the enzyme is present before the substance, which means the body has to excrete something before the enzyme works, so the effects are small. Endogenous substances may also interact with constitutive enzymes more often due to their more permanent presence in cells than inducible enzymes. Constitutive NOS will have greater pathological and physiological implications than inducible NOS.

3.Explain how NO contributes to the fatal pathology of septic shock.
Sepsis is a systemic inflammatory response caused by infection. Components present on bacteria such as endotoxins, cytokines and tumour necrosis factor-α induce the formation of iNOS in macrophages, smooth muscle cells, neutrophils. This NO formation in a wide area leads to severe hypotension, shock and in some cases death.

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

5.NO may be toxic to the cell.  Which mechanisms are available to the body to counter this detrimental effect of NO?
Haemoglobin can react with NO in the body and oxidize it to nitrate, thereby deactivating it. NO can also be deactivated by reacting with O2 in the body to form NO2. NO also rapidly reacts with metals in the body which also deactivate it and thereby counteract its detrimental effect on cells. The body releases NOS enzyme inhibitors which bind competitively to arginine binding site in NOS therefore arginine is not converted to nitric oxide.

6.Name a way in which NO can act pro-inflammatory.  Give examples of where it will have advantages or disadvantages.
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. The NO and peroxynitrates produced are an important microbial agent. Function of the immune cell TH1, which synthesizes NO in response to an unknown substance. This is a good protective response, especially when iNOS is inhibited. NO also stimulates prostaglandin synthesis. The vasodilator effects of NO and the effects of COX2 play a role in inflammation, where it causes red skin color, increases vascular permeability and increases edema in acute inflammations. A disadvantage of NO in acute and chronic inflammation is that excessive NO production can lead to tissue damage, psoriasis lesions, airway epithelium in asthma and inflammatory bowel lesions.

7.In which possible neurological and psychiatric diseases is NO involved?
Myotrophic lateral sclerosis, Parkinson Disease and stroke.