Blog 2.4

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

Endothelium cells respond to vasorelaxants by releasing soluble endothelium-derived relaxing factor (EDRF). EDRF acts on vascular muscle to cause relaxation. NO is the major bioactive component of EDRF. So Endothelium-dependent vasodilators increase the intracellular calsium levels in the endothelium. Endothelium-dependent vasodilation is stimulated by an increase in blood flow that increases shear stress on the endothelium, both in the resistance vessels conduit. 

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

iNOS are expressed through transcriptional induction when exposed to inflammatory mediators and this expression, and thus NO synthesis, is not regulated by calcium. eNOS and nNOS are expressed constituvely and NO synthesis is dependent on calcium regulation.

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

Sepsis is a systemic inflammatory response caused by  an infection. Endotoxins from the bacterial cell wall and other cytokines induce synthesis of iNOS in macrophages, neutrophils, T-cells, hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. The synthesis of NO cause aggravated hypotension, septic shock and death. 

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

NO

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

Intracellular glutathione protects against tissue damage caused by scavenging peroxynitrite Peroxynitritecause tissue damage during inflammation.

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

NO stimulates the synthesis of inflammatory prostaglandins by activating the COX-2 pathway. Prostaglandins have vasodilatory effects and together with NO, it can increase vascular permeability and it can lead to perivascular edema. Excessive NO production may lead to tissue injury.

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

Stroke, Parkinson's disease and Amyothropic lateral sclerosis