Paracrine signalling by local chemical messengers

Local chemical messengers are only active in the vicinity of the cells from which they are secreted. Extracellular enzymes rapidly destroy many of them or they are even very unstable of their own. Hence, they are quickly transformed into inactive metabolites so that they can only diffuse over a short distance. Some cells respond to signalling molecules that they themselves produce (autocrine signalling). In this respect, it is noteworthy that abnormal autocrine signalling frequently contributes to the uncontrolled growth of cancer cells. In this situation, a cancer cell produces a growth factor to which it also responds, thereby continuously driving its own proliferation.

Well-known local chemical mediators are histamine and prostaglandins. Histamine is secreted by mast cells (present in connective tissues throughout the body) when stimulated by injury, local infection or certain immunological reactions. It will cause local blood vessels to dilate and become leaky. This will facilitate the access of serum proteins (antibodies!) and phagocytic white blood cells to the site of injury.

Prostaglandins make part of the eicosanoids, a family of fatty acid derivatives, which also include prostacyclin and the thromboxanes (Figure 12). Many biological responses have been ascribed to these molecules, including smooth muscle contraction, platelet aggregation and inflammation. All eicosanoids are synthesized from arachidonic acid, which is formed from phospholipids.

The first step in the pathway leading to synthesis of either prostaglandins or thromboxanes is the conversion of arachidonic acid to prostaglandin H2. Interestingly,

Figure 12 Structure and synthesis of principal prostaglandins. Reprinted from L.B. Wingard, T.M. Brody, J. Larner and A. Schwartz (1991), Human Pharmacology: Molecular to Clinical, p.234. Copyright (1991), with permission from Elsevier.

Tunica media

(elastic tissue and smooth muscle)

Tunica intima

(endothelium and basement membrane)

Figure 13 Structure of an elastic artery. Reprinted from Seeley et al., Anatomy and Physiology 5th edn., © (2000), McGraw-Hill, with permission from the McGraw-Hill Companies.

Tunica media

(elastic tissue and smooth muscle)

Tunica intima

(endothelium and basement membrane)

Figure 13 Structure of an elastic artery. Reprinted from Seeley et al., Anatomy and Physiology 5th edn., © (2000), McGraw-Hill, with permission from the McGraw-Hill Companies.

the enzyme that catalyzes this reaction (cyclooxygenase) is the target of antiinflammatory drugs like aspirin. By inhibiting synthesis of the prostaglandins, aspirin reduces inflammation and pain. By inhibiting synthesis of thromboxane, aspirin also reduces platelet aggregation and blood clotting.

The vascular endothelial cells are now recognized to play an important paracrine role in controlling the contractile status of large blood vessels (which are composed of an internal layer of endothelial cells - facing the blood stream - and surrounding smooth muscle tissue) (Figure 13). In response to several external stimuli, they are able to produce a relaxing factor (EDRF, i.e. endothelium-derived relaxing factor), which diffuses to the surrounding smooth muscle. EDRF has been identified as the highly unstable nitric oxide radical (NO'). This area of research started with the discovery that, under specific conditions, the relaxation of pieces (strips) of aorta is strictly dependent on the presence of endothelium (which is usually not the case in isolated blood vessels unless special care is taken during preparation). Interestingly, organic nitrates have been used in clinical medicine for more than 100 years to produce vasodilatation and this action can now be explained by their ability to mimic the smooth muscle relaxing action of NO'.

When their level is increased in the endothelial cells, Ca2+ ions bind to nitric oxide synthase, an enzyme that acts on arginine to produce NO'. NO' diffuses out of the endothelial cell and into the smooth muscle cell where it combines with the guanylyl cyclase enzyme. This enzyme converts GTP to cyclic GMP, which causes the smooth muscle cell to relax (Figure 14).

Was this article helpful?

0 0

Post a comment