Oxytocin and prostaglandins

In isolated rat uteri, treatment with fennel essential oil reduced the intensity of contractions induced by oxytocin and prostaglandin 2- The oil also reduced the frequency of contractions induced by prostaglandin E2 but not by oxytocin (Ostad et al. 2001). 

As previously mentioned, medical management of obstetric bleeding after delivery is conducted by using drugs such as uterotonic drugs (oxytocin) and prostaglandin Ej agonist. The latter has a vasoconstrictor effect and thus causes arterial spasm (Fig. 9.6). 

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). 

Many hormones and other blood-borne substances (including drugs) also alter contractile activity of smooth muscle. Some of the more important substances include epinephrine norepinephrine angiotensin II vasopressin oxytocin and histamine. Locally produced substances that may alter contraction in the tissue in which they are synthesized include nitric oxide prostaglandins leukotrienes carbon dioxide and hydrogen ion. 

MOA Synthetic oxytocin is identical to natural oxytocin and binds to the oxytocin receptor on the uterine myometrium, causing contractions. Prostaglandins are also naturally synthesized by the body and cause uterine contractions. 

The mechanism of labor onset has been elucidated in mammalian and nonhuman primate systems, but the sequence in humans is still unclear. The transition from phase 0 (quiescence) to phase 1 (activation) may be explained by the loss of inhibition of uterine activity mediators, such as progesterone, prostacyclin, and others. Once activation occurs, oxytocin, prostaglandin E2, and prostaglandin P2a increase and stimulate contractions of the uterus. ... 

Fig. (5). The effect of "zoapatle s brew" (ZACE), grandiflorenic acid (AC) and verapamil (Ve) on the responses elicited by oxytocin (OT), prostaglandin F2 alpha (PGp2a) and acetylcholine (Ach) on isolated rat uterus. Arrows indicate the additions of compounds. For detetils of the study see reference [33].

Oxytocin is well established as an inducer of labour and is frequently used clinically for this purpose. Oxytocin acts by both direct and indirect mechanisms to stimulate uterine contraction. Firstly, it acts directly on the myometrium to cause uterine contractions and secondly, oxytocin acts to stimulate the production of other mediators of uterine contractions, most notably prostaglandins [8]. 

Luteolysis The structural and functional degradation of the corpus luteum that occurs at the end of the luteal phase in the absence of pregnancy caused by the hormones prostaglandin-2(X and oxytocin. Communication between the corpus luteum and uterine endometrium is necessary for luteolysis. 

These messengers also play a role in regulating contraction of myometrium, which consists of smooth muscle fibres. Contraction is controlled by increases in the concentration of cytosolic Ca ions. Prostaglandins activate Ca ion channels in the plasma membrane of the fibres oxytocin activates release of Ca from intracellular stores. The increase in concentration of Ca ions leads to activation of myosin light-chain kinase which leads to crossbridge cycling and contraction (as described in Chapter 22 Figure 22.12). 

Release of oxytocin at this stage of parturition promotes prostaglandin production, particularly of the E and F series, within the decidua these prostaglandins are powerful myometrial stimulants and thus further enhance uterine contractions. The prostaglandin concentration in maternal serum and amniotic fluid increases with the progression of labor. 

Induction of labour PG s do not have any advantage over oxytocin for the induction of labour. The adverse effects of the prostaglandins are slightly higher than that produced by oxytocin. PGF has more gastrointestinal toxicity than PGE and is a bronchoconstrictor also. Oral PGE is superior to oral oxytocin. PGE PGF is used in place of oxytocin in renal failure patients. 

F. Role in therapy According to Micromedex, oxytocin is routinely used for the induction of labor at term and postpartum for the control of uterine bleeding. Oxytocin is not the drug of choice for induction of labor for abortion. Oxytocin infusion has been used following prostaglandin or hypertonic abortifacients to shorten the induction to abortion time when inducing second-trimester abortion, inducing abortion when a patient has failed to respond to the abortifacient, or to induce abortion after membranes have ruptured. 

Studies with knockout mice have confirmed a role for prostaglandins in reproduction and parturition. COX-l-derived PGF2K appears important for luteolysis, consistent with delayed parturition in COX-l-deficient mice. A complex interplay between PGF2E and oxytocin is critical to the onset of labor. EP2 receptor-deficient mice demonstrate a preimplantation defect, which underlies some of the breeding difficulties seen in COX-2 knockouts. 

Theoretically, PGE2 and PGF2K should be superior to oxytocin for inducing labor in women with preeclampsia-eclampsia or cardiac and renal diseases because, unlike oxytocin, they have no antidiuretic effect. In addition, PGE2 has natriuretic effects. However, the clinical benefits of these effects have not been documented. In cases of intrauterine fetal death, the prostaglandins alone or with oxytocin seem to cause delivery effectively. 

Oxytocin acts through G protein-coupled receptors and the phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine contraction. Oxytocin in small doses increases both the frequency and the force of uterine contractions. At higher doses, it produces sustained contraction. 

The action of HA is indirect, mediated primarily via activation of corticotropin-releasing hormone (CRH) originating in parvocellular neurons in the PVN and secondly via vasopressin (AVP) originating in parvo- and magnocellular neurons in the PVN and in the SON [18-24]. The effect of CRH is predominantly mediating in character (i.e. HA releases CRH which subsequently stimulates ACTH secretion) [18] while the effect of AVP seem to be mediating as well as permissive in character (i.e. AVP has to be present in order for HA to exert its effect on ACTH secretion) [25]. Besides these two important mediators, prostaglandins are involved in HA-induced release of the POMC-derived peptides from the anterior lobe [26], whereas catecholamines, oxytocin (OT) and serotonin (5-HT) do not participate [27-28, Willems et al. (unpublished observations)]. 

Prostaglandin therapy can cause electroencephalo-graphic abnormalities (105). Convulsions, which occur occasionally, are a particular risk in epileptic patients (5,104,105). The combination of prostaglandins and oxytocin can be complicated by tonic-clonic seizures (106). 

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