Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using the Merrifield solid-phase method, we have synthesized 18 new 2-O-alkyltyrosine-substituted analogues (where alkyl = methyl and ethyl) of the arginine-vasopressin (AVP) vasopressor antagonists [1-deaminopenicillamine]-arginine-vasopressin (dPAVP), [1-(beta-mercapto-beta,beta-diethylpropionic acid)]arginine-vasopressin (dEt2AVP), and [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)]arginine-vasopressin (d(CH2)5AVP) and of their 8-D-arginine (d(R2)DAVP) analogues, their 4-valine (dR2VAVP) analogues, and their 4-valine,8-D-arginine (d(R2)VDAVP) analogues [where R = CH3 or C2H5 and 2R = (CH2)5]. These analogues were tested for agonistic and antagonistic activities in in vivo rat vasopressor and rat antidiuretic and in vitro rat uterus assay systems. Although many exhibit very low antidiuretic activities, none of the new analogues antagonize antidiuretic responses to AVP. They exhibit no evident pressor activities and are in fact all highly effective antagonists of the vasopressor responses to AVP. They are also potent antagonists of the in vitro oxytocic responses to oxytocin, both in the absence and in the presence of Mg2+. These analogues together with their corresponding antivasopressor pA2 values are as follows: 1. dPTyr(Et)AVP, 8.40 +/- 0.08; 2. dEt2Tyr(Me)AVP, 8.53 +/- 0.06; 3. dEt2Tyr(Et)AVP, 8.46 +/- 0.08; 4. d(CH2)5Tyr(Et)AVP, 8.47 +/- 0.04; 5. dPTyr(Me)DAVP, 8.31 +/- 0.08; 6. dPTyr(Et)DAVP, 8.27 +/- 0.06; 7. dEt2Tyr(Me)DAVP, 8.57 +/- 0.03; 8. dEt2Tyr(Et)DAVP, 8.33 +/- 0.06; 9. d(CH2)5Tyr(Me)DAVP, 8.41 +/- 0.05; 10. d(CH2)5Tyr(Et)DAVP, 8.45 +/- 0.05; 11. dPTyr(Me)VAVP, 8.36 +/- 0.07; 12. dPTyr(Et)VAVP, 8.07 +/- 0.13; 13. dEt2Tyr(Me)VAVP, 8.29 +/- 0.08; 14. dEt2Tyr(Et)VAVP, 8.42 +/- 0.06; 15. dPTyr(Me)VDAVP, 7.84 +/- 0.06; 16. dPTyr(Et)VDAVP, 8.46 +/- 0.03; 17. dET2Tyr(Me)VDAVP, 8.35 +/- 0.10; 18. dEt2Tyr (Et)VDAVP, 8.19 +/- 0.07. Seven of these analogues are clearly more potent vasopressor antagonists than their respective unalkylated tyrosine-containing parents. In the remaining 11, antagonistic potency was not changed significantly. In no instance did 2-O-alkyltyrosine substitution decrease antagonistic potency. With pA2 values equal to or greater than 8.40, nine of these antagonists (numbers 1-4, 7, 9, 10, 14, and 16) are among the most potent vasopressor antagonists reported to date. They could thus serve as additional valuable pharmacological tools in studies on the roles of AVP in the control of blood pressure in normal and in pathophysiological conditions. These findings may also provide useful clues to the design of more potent and selective antagonists of AVP.
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PMID:Synthesis and some pharmacological properties of 18 potent O-alkyltyrosine-substituted antagonists of the vasopressor responses to arginine-vasopressin. 404 23

In order to develop inhibitors of vasopressin (VP) and oxytocin (OXY) action on uterine activity, 1-deaminated vasotocin derivatives with modifications at positions 2, 4 and 8 were developed. Two of the most effective analogues in the rat, 1-deamino-2-D-Tyr(OEt)-4-Val-8-Orn-vasotocin (dE-VVT) and 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-vasotocin (dE-TVT) were now tested on human nonpregnant myometrium obtained at hysterectomy in fertile age and on pregnant myometrial tissue obtained at elective cesarean section. The effect was compared with that of a previously synthesized analogue 1-deamino-Tyr(OEt)-oxytocin (dE-OXY) which has already been tested in nonpregnant and pregnant women in vivo. Both of the new analogues competitively inhibited the action of the posterior pituitary hormones. On the nonpregnant uterus dE-VVT was about five times and dE-TVT almost twenty-five times more potent than dE-OXY in inhibiting the effects of VP. On pregnant myometrium, dE-TVT inhibited oxytocin action about as effectively as a five-fold stronger concentration of dE-OXY, and dE-VVT slightly less. A moderate agonistic effect of dE-OXY on pregnant myometrium was found, whereas it was minimal with dE-VVT and not detectable at all with dE-TVT. It appears that these two analogues, particularly dE-TVT, would be interesting for clinical testing both in dysmenorrhea, where increased VP secretion could be of etiological importance, and in premature labor where an increased myometrial concentration of OXY receptors has been demonstrated.
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PMID:The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin. 406 Oct 66

Neurophysins are part of the prohormones for vasopressin and oxytocin, and are localized with these hormones in the magnocellular cells of the neurohypophysis. New techniques have identified neurophysins in other areas within and outside the central nervous system, and we report here the isolation of neurophysins from the uterus of the rat. Using immunohistology the neurophysin immunoreactivity was localized to the epithelial lining cells of the uterus, and using radioimmunoassay was also present in uterine fluid suggesting secretion into the uterine cavity. The amount of uterine neurophysin increased in response to administered estrogen and was especially elevated in the pregnant uterus. The neurophysin-like material isolated from the uterus was similar to neurophysins from the neurohypophysis by radioimmunoassay, molecular sieve chromatography, isoelectric focusing and SDS gel electrophoresis. Both neurohypophyseal hormones, vasopressin and oxytocin, were also extracted from uterine endothelium and identified by radioimmunoassay and high pressure liquid chromatography.
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PMID:Isolation and localization of neurophysin-like proteins in rat uterus. 408 Jun 7

The effect of (+) IPNEA on various stimulant drugs was examined on isolated rat uterus. Addition of (+) IPNEA (1 times 10- minus 5 g/ml) to the organ bath, produced marked potentiation in the contractile responses of oxytocin and prostaglandins. Potentiation was less significant to 5-HT, vasopressin, angiotensin and bradykinin. (+) INPEA did not potentiate the responses of oxytocin on isolated rat mammary strip and the responses of prostaglandins on rat stomach (fundus) strip, guinea-pig tracheal chain and guinea-pig ileum. The significance of these findings has been discussed.
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PMID:Potentiation of oxytocin and prostaglandins-evoked responses by (+) INPEA on isolated rat uterus: its specificity and selectivity. 415 75

1. Metals potentiate the contractile effects of S-S polypeptides in depolarized rat uterus. Their order of potency is Co(++)>/=Co(+++)>/=Mn(++)>/=Ni(++)>/= Mn(+++)>Zn(++)>/=Mg(++)>Fe(++)>Fe(+++)>/= Ca(++)>Be(++)=Sr(++)=Ba(++)=Cu(++)=O.2. S-S polypeptides with relatively weak oxytocic activity such as lys-vasopressin, arg-vasopressin and orn-vasopressin are strongly potentiated by metals while highly active polypeptides such as oxytocin are weakly potentiated.3. Potentiation by metals was specific for S-S polypeptides; other polypeptides (bradykinin, hypertensin) as well as acetylcholine and isoprenaline were unaffected.4. Potentiation by metals occurs rapidly and is fully reversible. In all cases some activity was retained by S-S polypeptides even in the complete absence of metals.5. A scheme which could account for the observed effects has been formulated. This assumes the formation of a ternary complex between receptor, metal and polypeptide leading to improved alignment between polypeptide and receptor.6. Analogies are discussed between metal enzymes and the S-S polypeptide receptor for which the term metal receptor is proposed.
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PMID:The effect of metals on the S-S polypeptide receptor in depolarized rat uterus. 430 88

1. A synthetic oxytocin analogue, [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), has been tested as an antagonist to the actions of oxytocin and vasopressin on the uterus, the mammary gland and blood pressure.2. The analogue inhibited the response of the isolated rat uterus to both oxytocin and vasopressin without itself stimulating the uterus to contract. The responses to equipotent doses of oxytocin and vasopressin were inhibited equally. There was little or no inhibition of the response to bradykinin. carbachol, angiotensin or 5-hydroxytryptamine with doses of the analogue up to 160 times that required to inhibit the response to oxytocin by 50%. The analogue caused a parallel displacement of the log dose-response curve for oxytocin; the pA(2) value (2 min contact) varied from 6.4 to 7.1 according to the ionic composition of the solution in the organ bath.3. The analogue inhibited the response of the rat uterus in situ to oxytocin but not to angiotensin or 5-hydroxytryptamine. It did not stimulate the uterus.4. When, in certain experimental conditions, spontaneous activity occurred in the isolated uterus or the uterus in situ, this activity was unaffected by the analogue but the increase in amplitude and frequency of contractions caused by oxytocin was inhibited. The regular rhythm of contractions induced in the quiescent uterus by the intravenous infusion of oxytocin was interrupted by intravenous injections of the analogue.5. The response of the isolated strip of rat mammary gland to the analogue depended on whether or not magnesium was present in the bath solution. In the presence of this ion, the analogue generally caused an increase in tension; in its absence, it acted as a pure antagonist. As on the isolated uterus, oxytocin and vasopressin were equally inhibited, and the analogue caused a parallel displacement of the log dose-response curve for oxytocin. With 0.9 mM Ca and 1.0 mM Mg, the mean pA(2) value (2 min contact) was 6.28 +/- 0.08 (S.E.)6. In the lactating rat, the analogue inhibited the milk-ejection response to oxytocin and vasopressin but not that to acetylcholine, bradykinin or 5-hydroxytryptamine. A milk-ejection response to the analogue itself was seen occasionally with retrograde arterial but not with intravenous injections.7. The analogue inhibited the avian depressor response to oxytocin and the rat pressor response to vasopressin.8. On all assay preparations, the degree of inhibition caused by the analogue was dependent on the dose, and the inhibition could be surmounted by increasing the dose of agonist. Recovery usually occurred within 15 min. These features, together with the parallel displacement of the dose-response curve for oxytocin on the isolated uterus and mammary strip, and the equal inhibition of the responses to oxytocin and vasopressin, suggest that carbamoyl-methyl-oxytocin acts as a specific competitive inhibitor of the neurohypophysial hormones.9. The structure-activity relationships of analogues of oxytocin having substituents in the terminal amino and phenolic hydroxyl groups, and some practical applications of the carbamoyl-methyl analogue, are discussed.
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PMID:Some pharmacological properties of a synthetic oxytocin analogue [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), an antagonist to the neurohypophysial hormones. 432 60

Research on the physiopathologic and biochemical nature of prostaglandins (PGs) suggest that PGs play a role in reproductive physiology. In vitro studies show that the PGE series decrease the motility of the human uterus, fallopian tubes, and ureter, and produce vasodilatation. PGFs cause vasoconstriction and increased motility of the uterus, fallopian tubes, ureter, and gastrointestinal muscle. PGs are also known to inhibit lipolysis, platelet aggregation, and gastric secretion. The exact mechanism of PGs are not fully understood, but evidence suggests that many responses can be attributed to interference with the enzyme adenyl cyclase, which catalyzes the formation of adenosine 3',5'-monophosphate (cyclic AMP) from adenosine triphosphate. The adenyl cyclase-cyclic AMP system mediates lipolysis, steroidogenesis, gastric secretion, certain smooth muscle motility responses, and increase in permeability due to vasopressin. Early studies of the myometrial effects of PGs showed that the PGE series inhibited the motility of the human myometrium in vitro while the PGF series produced mixed responses. The role of PGF2alpha in parturition has not been established but evidence suggests that it has a potential role as an oxytocic in cases of therapeutic abortion. In the area of human fertility, the physiologic role of PGs in seminal fluid is hypothesized to facilitate the migration of spermatozoa from the vagina into the uterine cavity. Karolinska Institute researchers have found that some infertile males have low PG levels in their ejaculates and are now working with methods of improving the PG levels to improve their fertility. Pickles et al. proposed a potential role for PGs in the etiology of dysmenorrhea, having found a significantly higher ratio of PGF to PGE in a series of patients with severe dysmenorrhea than in a comparable series of normal patients. The luteolytic and antinidatory effects of PGF2alpha are being investigated and studies appear encouraging. PGs have therapeutic potentials in induction of labor, treatment of infertility, morning-after conception, treatment of dysmenorrhea, and contraception by alteration of fallopian tube motility.
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PMID:The role of prostaglandins in reproductive physiology. 491 53

1. Contractions of guinea-pig isolated proximal colon produced by vasopressin are not affected by methyloxytocin (a compound that blocks pressor effects of vasopressin).2. Vasopressin contractions are inhibited by replacement of sodium with mannitol or sucrose, elevation of potassium or magnesium concentrations, the presence of the metabolic inhibitors sodium azide and triethyl tin or tetrodotoxin in the bathing fluid. Contractions produced by histamine or choline esters are comparatively insensitive to these procedures.3. Contractions of rat isolated uterus following vasopressin, oxytocin and methacholine are equally affected by replacement of sodium, increase of potassium or magnesium or addition of sodium azide.4. Neither vasopressin contractions nor contractions caused by transmural stimulation were consistently affected by morphine (10(-6) g/ml.) or hyoscine (10(-7) g/ml.) although both were reduced by anoxia or cooling the tissue. Morphine did not reduce the output of acetylcholine from stimulated colon.5. It is concluded that the action of vasopressin on proximal colon is unlike its action on other smooth muscle and is mediated by nervous tissue.
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PMID:Studies on the mode of action of vasopressin on the isolated proximal colon of the guinea-pig. 534 54

1. Protein fractions were prepared from serum and various organs of pigs following the methods used to extract and purify neurophysin from posterior pituitaries.2. Protein fractions extracted from porcine kidney, uterus, mammary gland or serum, which contain antigen reacting with anti-neurophysin serum, form non-dialysable complexes with oxytocin and/or lysine vasopressin.3. Protein from uterus or mammary gland bound oxytocin but not lysine vasopressin, while protein extracted from kidney bound lysine vasopressin but not oxytocin: protein from serum bound both hormones.4. Protein fractions prepared in the same way from porcine liver, spleen, skeletal muscle and brain, which do not contain antigen reacting with anti-neurophysin serum, did not form complexes with neurohypophysial hormone.5. The formation of complexes between the renal or uterine protein fractions and lysine vasopressin or oxytocin is inhibited by the addition of 1.0 x 10(-6)M-CaCl(2).6. 1-Desamino 8-arginine vasopressin is not bound by neurophysin prepared from porcine posterior pituitaries or the protein from porcine kidneys, while 8-arginine vasopressin does form non-dialysable complexes with proteins from both sources.7. A protein fraction extracted from guinea-pig kidney by similar preparative methods also bound lysine vasopressin and the binding was inhibited by addition of CaCl(2).
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PMID:The distribution of proteins that bind neurohypophysial hormones. 569 50

1. An oxytocic substance has been isolated from ox hypothalamus by successive gel filtration on Sephadex G-25 and Sephadex G-50, and its pharmacology has been examined on three smooth muscle preparations.2. The substance has the same order of potency on rat uterus, guinea-pig ileum, and hen rectal caecum.3. The action of the substance on rat uterus was not abolished by thioglycollate.4. Atropine (1.0 mug/ml.), phenoxybenzamine (0.1 mug/ml.) and mepyramine (1.0 mug/ml.) did not block the smooth muscle action of the substance.5. Drug action, relative potency, and log dose-response relationships distinguish the substance from 5-hydroxytryptamine, acetylcholine, oxytocin, vasopressin, angiotensin amide, bradykinin, and purified preparations of substance P.
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PMID:The pharmacology of a new oxytocic principle from ox hypothalamus. 581 85


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