Actions of 5 Hydroxytryptamine

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Chapter: Essential pharmacology : 5Hydroxytryptamine, Its Antagonists And Drug Therapy Of Migraine

5HT is a potent depolarizer of nerve endings. It thus exerts direct as well as reflex and indirect


ACTIONS

 

5HT is a potent depolarizer of nerve endings. It thus exerts direct as well as reflex and indirect

5HT1 :     Autoreceptors; inhibit serotonergic neural activity in brain.

5HT1A—present in raphe nuclei and hippocampus; buspirone may act through these receptors.

5HT1B/1D—Constricts cranial blood vessels and inhibits release of inflammatory neuropeptides in them; sumatriptan acts through these receptors.

 

5HT2A :    Previously D type receptor; most important postjunctional receptor mediating direct actions of 5HT like vascular and visceral smooth muscle contraction, platelet aggregation, neuronal activation in brain; ketanserin blocks these receptors.

 

5HT3 :     Previously M type receptor; depolarizes neurones by gating cation channels; elicits reflex effects of 5HT—emesis, gut peristalsis, bradycardia, transient hypotension, apnoea, pain, itch; ondansetron acts by blocking these receptors.

 

5HT4 :     Mediate intestinal secretion, augmentation of peristalsis. Renzapride is a selective 5HT4 agonist effects. Tachyphylaxis is common with repeated doses of 5HT. The overall effects therefore are often variable.

 

CVS

 

Arteries are constricted (by action on smooth muscle) as well as dilated (through EDRF release) by direct action of 5HT, depending on the vascular bed and the basal tone. In addition, 5HT releases Adr from adrenal medulla, affects ganglionic transmission and evokes cardiovascular reflexes. The net effect is complex. Larger arteries and veins are characteristically constricted. In the microcirculation 5HT dilates arterioles and constricts venules: capillary pressure rises and fluid escapes. The direct action to increase capillary permeability is feeble.

 

Isolated heart is stimulated by 5HT: both directly and by release of NA from nerve endings. In intact animals, bradycardia is mostly seen due to activation of coronary chemoreflex (Bezold Jarisch reflex) through action on vagal afferent nerve endings in the coronary bed, evoking bradycardia, hypotension and apnoea.

 

BP: a triphasic response is classically seen on i.v. injection of 5HT in animals.

Early sharp fall in BP—due to coronary chemoreflex.

Brief rise in BP—due to vasoconstriction and increased cardiac output.

Prolonged fall in BP—due to arteriolar dilatation and extravasation of fluid.

 

However, 5HT is not involved in the physiological regulation of BP.

 

Smooth Muscles

 

5HT is a potent stimulator of g.i.t., both by direct action as well as through enteric plexuses. Several subtypes of 5HT receptors are present in the gut (See box). Peristalsis is increased and diarrhoea can occur (also due to increased secretion). It constricts bronchi, but is less potent than histamine. Action on other smooth muscles in man are feeble and inconsistent.

 


 


Glands

 

5HT inhibits gastric secretion (both acid and pepsin), but increases mucus production. It thus has ulcer protective property. Effect on other glandular secretions is not significant.

 

Nerve Endings And Adrenal Medulla

 

Afferent nerve endings are activated—tingling and pricking sensation, pain. Depolarization of visceral afferents elicits respiratory and cardiovascular reflexes, nausea and vomiting. 5HT is less potent than histamine in releasing CAs from adrenal medulla.

 

Respiration

 

A brief stimulation of respiration (mostly reflex from bronchial afferents) and hyperventilation are the usual response, but large doses can cause transient apnoea through coronary chemoreflex.

 

Platelets

 

5HT causes changes in shape of platelets and is a weak aggregator through 5HT2A receptors. However, it does not induce the release reaction.

 

CNS

 

Injected i.v., 5HT does not produce central effects because it poorly crosses bloodbrain barrier. However, it serves as a transmitter, primarily inhibitory. Direct injection in the brain produces sleepiness, changes in body temperature, hunger and a variety of behavioural effects.

 

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