Uterus oxytocin action

Ki of 6 nM against a guinea-pig uterine oxytocin preparation and at least 100-fold selectivity over rat vasopressin tissue preparations. These molecules show a pseudo-irreversible pharmacology, with an extended action against spontaneous contractibility of rat uterus 24 h post partum. 

Oxytocin (OT) is a nonapeptide in which six amino acids form a ring closed by a disulfide bridge, while the ring itself forms an antiparallel pleated sheet. The tail portion of the peptide, composed of Pro-Leu-Gly-NHj, is also rigidly held in a folded conformation. Oxytocin causes the powerful contraction of some smooth muscles and plays a vital role in milk ejection (not to be confused with milk secretion, which is regulated by prolactin). It also has uterotonic action, contracting the muscles of the uterus, and is therefore used clinically to induce childbirth. 

Isothebaine (2,11-dimethoxy-l-hydroxyaporphine) was isolated for the first time by Gadamer and Klee (394) from P. orientale L. In isolated normal intestine of rabbits and rats and in that tonicized by enterotonine smaller doses of isothebaine brought about a rise of the muscle tonus whereas higher doses produced relaxation (395, 396). Experiments carried out on the rat uterus in situ showed that isothebaine amplified the tonus and contractions but it did not affect the action of oxytocin. It slowed down significantly the frequency of respiration and the pulse rate. In mice it decreased the motor activity... 

Q8 During pregnancy, contractions of the smooth muscle of the uterus are suppressed because of actions of progesterone. But at the end of pregnancy the concentration of progesterone declines and the high oestrogen concentration increases the density of oxytocin receptors in the myometrium. 

Ergometrine and oxytocin differ in their actions on the uterus. In moderate doses oxytocin produces slow generalised contractions with full relaxation in between ergometrine produces faster contractions superimposed on a tonic contraction. High doses of both substances produce sustained tonic contraction. It will be seen, therefore, that oxytocin is more suited to induction of labour and ergometrine to the prevention and treatment of postpartum haemorrhage, the incidence of which is reduced by its routine prophylactic use (generally i.m.). 

The other main class of agent used for contractile actions on the uterus are the prostanoids. They may be used together with oxytocin for the induction of labour. Some are also used for therapeutic abortion e.g. gemeprost. See prostanoid RECEPTOR AGONISTS. 

The relaxant activity of obaberine was examined in isolated rat uterus and its inhibitory potency compared with that of tetrandrine. Obaberine was observed to relax KCl-depolarized rat uterus and to totally or partially inhibit oxytocin-induced rhythmic contractions. Obaberine inhibited sustained K+-induced contraction with the same potency as tetrandrine when extracellular calcium is present, but the rhythmic contraction induced by oxytocin was diminished to a much lesser extent. This observation indicates that the relaxant mechanism of obaberine may be mainly related to Ca+2 influx, possibly through voltage-operated channels. In Ca+2-free medium, obaberine relaxed oxytocin- and vanadate-induced uterine contractions, while tetrandrine did not. These results suggest that obaberine has an intracellular site of action, and may interact with a stereospecific receptor site within the cell [307]. 

The primary stimulus for oxytocin release is suclding. Stimulation of tactile receptors located around the nipples of the breasts initiates an action potential that propagates along afferent nerve fibers through the spinal cord and mid-bram to the hypothalamus. The cell bodies in the paraventricular nucleus are then stimulated, resulting in the episodic release of oxytocin. Stretch receptors in the uterus and possibly in the vaginal mucosa may also initiate action potentials in afferent nerve fibers that ultimately stimulate the release of oxytocin from the neurohypophysis. Estrogens enhance the response of oxytocin to these stimuli. The influence of other parts of the brain on the release of oxytocin has been reported emotional stress, for instance, inhibits lactation. 

The pr-MDI and bu-MDI (5x10 - - 10 M) blocked the spasmogenic action on the estrogenized rat uterus of PGF2a> PGE2, oxytocin, barium, acetylcholine, and ergonovine in a concentration-... 

Oxytocin is synthesized in the cell bodies of supraoptic and paraventricular neurons and, then, transported (complexed with neurophysin) in membrane-bound vesicles to the posterior lobe of the pituitary gland, where it may be released by a reflex mechanism or mechanisms, initiated or amplified by genital stimulation, coitus, parturition, or suckling of the infant. Suckling also releases prolactin. The action of oxytocin on the uterus (muscular contraction and parturition) and mammary glands (contraction of myoepithelial cells and milk secretion) is a direct one and is not influenced by the autonomic nervous system. 

The direct stimulatory effect of oxytocin is prominent in the gravid uterus during the late stage of pregnancy. Its action is augmented by estrogen and inhibited by progesterone. Oxytocin s effect is specific for uterine muscle, as little effect is observed on intestinal muscle or coronary arteries. 

Oxytocin is a cyciic 9-peptide that, iike somatostatin, contains a ring that encompasses a disuifide bridge (Fig. 7.15). Oxytocin has uterotonic action, contracting the muscies of the uterus during gestation, and piays an important roie in miik ejection (not miik secretion, which is reguiated by the peptide hormone proiactin) from the mammary ducts into the nippies. 

Neurohypophysial hormones a group of hormones produced in the hypothalamus (not, as the name suggests, in the neurohypophysis see Hypophysis). The action spectrum of these phylogenetically ancient hormones, Oxytocin (see) and Vasopressin (see), extends from an effect on the smooth muscle of the uterus, mammary gland and blood vessels, to an alteration of the permeability of the skin, urinary bladder and kidney tubules. The carrier protein of N.h. is Neurophysin (see). N.h. are small molecules (nonapeptides) and they represent an ideal model for the study of the mechanism of hormone action at a molecular biological level. 

The seeds of Foeniculum vulgare have been used in traditional remedies for the treatment of dysmenorrhea, an action attributed to the antispasmodic effect of the essential oil. An in vitro experiment demonstrated that fennel essential oil inhibited oxytocin- and prostaglandin Ej (PGEj)-induced contractions of isolated uterus the former was considered to have a similar activity to diclofenac, a nonsteroidal anti-inflammatory drug. The overall mechanism of action is still unknown (Ostad et al 2001). 

The hypothesis that calcium is crucially involved in the mechanism of action of vasopressin seems to be attractive for different reasons It has been known for long that calcium is very important for the permeability to water of a number of animal membranes (e. g. Fukuda 1935, Bozler 1959). It has been shown by Lassiter et al. (1965) that calcium inhibits the permeability to water in the distal part of the nephron but not in the more proximal parts where the hormone presumably does not act on the water permeability. It is known that calcium is crucial for the action of oxytocin on the uterus. The concentration of calcium is crucial for the inhibitory action of certain analogues of oxytocin (Rudinger 1964). 

Oxytocin. The action of oxytocin on the uterus shows species variations and is influenced by sex hormones. The uterus isolated from rat or guinea-pig contracts in the presence of oxytocin. The sensitivity of the human uterus to oxytocin increases with the duration of pregnancy so that an intravenous injection of 1 mU/ min has the same action at the end of pregnancy as 16 mU/min at the beginning. The pregnant uterus shows rhythmic contractions, the rate of which depends upon the dose of the peptide. The non-pregnant human uterus shows almost no response to oxytocin, even in large doses. Paradoxically it is much more sensitive to vasopressin which causes the symptoms of dysmenorrhoea. 

Thiols at a concentration of 10 to 40 mM also act as antagonists to the action of neuropeptides on rat uterus, but not to their pressor effect Such a difference could be due to a difference in the receptors. Thioglycollate (10 mM) and cysteine (10 mM) inhibit the permeability response of the toad bladder to oxytocin or vasopressin. Gluthathione has a similar effect These actions of the peptides are also inhibited after incubation of the tissues in the presence of either N-ethyl- or N-phenylaleimide which form covalent bonds with sulphydryl groups or complex mercury mercaptides (p-hydroxy-mercury-benzoate, p-chloro-mercury-benzoate). These results show that the receptor presents in its constitution some functional sulphydryl groups. 

In the uterus, the production of 3, S -cyclic AMP is induced by the activation of the /7-adrenergic receptors and followed by inhibition of the electrical and mechanical activities. The action of oxytocin may be partly due to its ability to prevent the formation of cyclic AMP. The role of the reactive disulfide groups in the peptide receptors has already been discussed. The complexity of the receptor structure is pointed out by the observation that metals potentiate specifically the action of S-S polypeptides on the rat uterus, in such a way that it becomes very sensitive to vasopressin when the perfusion fluid contains a metal The order of metal potency is... 

For labor induction, all of the aforementioned modes of administration of prostaglandins have been used successfully ° . In addition, orally administered PGEg and PGFaa are effective for labor induction , whereas the larger doses required for orally induced therapeutic abortion produce marked levels of gastrointestinal side effects . Karim showed that the action of prostaglandins on the human uterus is not mediated throvigh the release of oxytocin . 

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