5 – hydroxytryptamine and purines Serotonin was the name given to unknown vasoconstrictor substance found in the serum after blood has clotted. It was identified chemically as 5- hydroxytryptamine (5-HT) in 1948 and shown to originate from the platelets. It was later found in the gastrointestinal tract and central nervous system (CNS) and shown to function both as neurotransmitter and as a local hormone in the peripheral vascular system.

Distribution, biosynthesis and degradation 5-HT occurs in the highest concentrations in three situations in the body. 1) In the wall of the intestine : About 90% of the total amount in the body is present in enterochromaffin cells. (mainly in the stomach and small intestine. Some 5-HT also occur in nerve cells of the myenteric plexus, where if functions as an excitatory neurotransmitter 2) In blood : 5-HT is present in high concentration in platelets, which accumulate it from the plasma by an active transport system and release it when they aggregate at site of tissue damage.

3) In the CNS : 5-HT is a transmitter in the CNS and is present in high concentrations in localised regions of the midbrain.

5_HT is often stored in neurons and chromaffin cells as a co – transmitter together with various peptide hormones, such as somatostatin, substance P or vasoactive intestinal polypeptides (VIP). Degradation of 5-Ht occurs mainly through oxidative deamination, catalysed by monoamine oxidase, followed by oxidation to 5- hydroxyindoleacetic acid (5-HIAA), the pathway being the same as that of noradrenaline catabolism. 5-HIAA is excreted in the urine and serves as an indicator of 5-HT production in the body. This is used, for example, in the diagnosis of carcinnoid syndrome

Pharmacological effects 1) Gastrointestinal tract : 5 –HT stimulates gastrointestinal motility. 5- HT also stimulates fluid secretions and elicts nausea and vomiting by stimulating smooth muscle and sensory nerves in the stomach. 2) Smooth muscle : else where in the body (e.g. uterus and bronchial tree) smooth muscle is contracted in some species.

3) Blood vessels : 5-HT constricts both arteries and veins. Activation of 5-HT receptors causes constriction of large intracranial vessel, dilation of which contributes to headache. 5-HT can also cause vasodilation, partly by acting on the endothelial cells to release nitric oxide and partly by inhibiting noradrenaline release from sympathetic nerve terminals. Platelets : 5-HT causes platelet aggregation. If the endothelium is intact, 5-HT release from adherent platelets cause vasodilation, which helps to sustain blood flow; if it is damaged ( e.g. by atherosclerosis ), 5-HT causes constriction and impair blood flow further.

Nerve endings : 5-HT stimulates nociceptive ( pain – mediating ) nerve endings. Central nervous system:

It was shown in 1929 that adenosine injected into anaesthetised animals causes cardiac slowing, a fall in blood pressure, vasodilation and inhibition of intestinal movements, and purines are now known to participate in many physiological control mechanisms; Such as the regulation of coronary flow and myocardial function, platelet aggregation and immune response and neurotransmission, in both the central and peripheral nervous system. Nucleosides, especially adenosine, and nucleotides, especially ADP and ATP, produces a wide range of pharmacological effects that are unrelated to their role in metabolism Purines

ATP as a neurotransmitter ATP is a transmitter in the periphery, both as a primary mediator and as co-transmitter in noradrenergic nerve terminals. ATP is contained in synaptic vesicles of both adrenergic and cholinergic neurons, and it accounts for many of the actions produced by stimulation of autonomic nerves that are not caused by acetylcholine or noradrenaline. These include effects such as relaxation of intestinal smooth muscle evoked by sympathetic stimulation, and contraction of the bladder produced by parasympathetic nerves.

Suramin, a drug shown to block ATP receptors, blocks synaptic response. ATP released from cells is rapidly dephosphorylated by a range of tissue – specific nucleotidases, producing ADP and adenosine, both of which produce a wide variety of receptor mediated effects. The role of intracellular ATP in controlling membrane potassium channels, which is important in the control of vascular smooth muscle and of insulin secretion, is quite distinct from its transmitter function.

Adenosine as a mediator Adenosine differs from ATP in that it is not stored by and released from secretary vesicle. Rather, it exist free in the cytosol of all cells and is transported in and out of cells mainly via a membrane transport. Adenosine performs many pharmacological role especially as protective agent when tissue are threatened, based on its ability to inhibit cell function and thus minimise the metabolic requirement of cells.

Purine receptors P 1 receptors P 2 receptors