Properties vasopressin

D. M. Gash and G. Boer, eds.. Vasopressin Principles and Properties, Plenum, New York, 1987. 

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

As noted above, MDA is a potent stimulator of monoamine release (see Table 7.1), and recent reports indicate that a number of MDMA metabolites are bioactive. For example, Forsling et al.61 showed that the metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA) is more potent than MDMA as a stimulator of vasopressin secretion from rat posterior pituitaries in vitro. The neuroendocrine effects produced by in vivo administration of MDMA metabolites have not been examined. Monks et al.62 demonstrated that catechol metabolites of MDMA and MDA, namely, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), exhibit neurotoxic properties when oxidized and conjugated with glutathione. Further characterization of the biological effects of MDMA metabolites is an important area of research. 

In order to review these putative relationships it is first useful to define a subset of well-characterized hormones and neurotransmitters that have been implicated in behavior. The chemicals selected for discussion here are among those for which a robust relationship with behavior has been proposed, including steroids (estrogens, progestins, androgens and glucocorticoids), proteins (prolactin) and the neuropeptides (oxytocin and vasopressin). All of these chemicals may act as hormones, neurotransmitters and/or neuromodulators. In addition, to understand the action of these hormones, it is helpful to be familiar with some of the more common neurotransmitters (described below). Space does not permit a discussion of the behavioral effects of many additional compounds with endocrine or paracrine properties. 

The permeability properties of the distal convoluted tubule are regulated by antidiuretic hormone (ADH, or vasopressin). In hypotonic conditions, ADH secretion by the posterior pituitary is suppressed and the distal convoluted tubule is impermeant to water. Conversely, in hypertonic or volume-contracted states, ADH is released by the posterior pituitary and increases the permeability and water reabsorption by the distal convoluted tubule. 

Ox ocin is a nonapeptide which is structurally related to vasopressin. It stimulates rhythmic uterine contractions and is widely used by intravenous infusion of a diluted solution to induce labour and to treat postpartum bleeding. In large doses, it may cause relaxation of vascular smooth muscle causing hypotension in patients with cardiac disease or who are dehydrated. It has water-retaining properties and when given for prolonged periods to patients whose intake is electrolyte-free it causes overhydration and hyponatraemia. This may result in convulsions in the newborn with the risk of cerebral damage. 

Uterine contractions and fetal heart rate should be monitored during oxytocin administration (SEDA-13, 1310) (1,2). There is no significant increase in uterine complications or in fetal morbidity or mortality in women with a previous cesarean section, although oxytocin-treated patients had a higher rate of failed trial of labor for reasons that are unclear (3). Oxytocin is structurally similar to vasopressin, and like the latter has water-retaining properties when used in pharmacological doses. 

Vasopressin, a hypothalamic octapeptide that is secreted by the ncurohypophysis, has both antidiuretic and vasoconstrictor properties. Its short half-life (about 10 minutes) necessitates continuous intravenous infusion or frequent nasal application. 

Desmopressin has little vasoconstrictor effect but has potent antidiuretic action, through renal vasopressin V2 receptors, and at high doses hemostatic properties, by increasing concentrations of factor VIII and von Willebrand factor in the blood. 

Vasopressin is a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure. Vasopressin possesses antidiuretic and vasopressor properties. A deficiency of this hormone results in diabetes insipidus (see Chapters 15 and 17). 

Fassina G, Zamai M, Brigham-Burke M et al. Recognition properties of antisense peptide to Arg-8-vasopressin/bovine neurophysin II biosynthetic precursor sequences. Biochemistry 1989 28 8811. 

P Dreyfuss. Synthesis and some pharmacological properties of 8-e-hydroxy norleu-cine-vasopressin. J Med Chem 17 252-257, 1974. 

The ANF hormones, which derive from higher-molecular-weigth precursors (atriopeptigens), have diuretic properties, i.e. an administration of ANF in the rat increases diuresis and natriuresis (the release of Arg-vasopressin is inhibited) and at the same time the vessels are dilated, apparently by inhibition of catecholamines and angiotensin II. In addition, it has been shown that under volume loading the ANF peptides are released from the atria and develop their effects as hormones in renal, vascular, and other tissues. They can be considered as functional antagonists of the renin-angiotensin system. 

Intracellular Messengers from Phosphatidylinositols When the hormone vasopressin stimulates cleavage of phosphatidylinositol 4,5-bisphosphate by hormone-sensitive phospholipase C, two products are formed. What are they Compare their properties and their solubilities in water, and predict whether either would diffuse readily through the cytosol. 

Because of the pressor properties of vasopressin, this compound has been modified to desmopressin [dez moe PRESS in] (1-desamino-8-D-arginine vasopressin). This analog is now preferred for diabetes insipidus and nocturnal enuresis because it is largely free of pressor effects and is longer-acting than vasopressin. Desmopressin is conveniently administered intranasally. However, local irritation may occur. 

For [8-Arg]-vasopressin, see Meienhofer J, Trzeciak A, Havran RT, Walter R. Solid-phase synthesis of [8-arginine]-vasopressin through a crystalline protected nonapeptide intermediate and biological properties of the hormone. J. Am. Chem. Soc. 1970 92 7199-7202. 

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