Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P01178 (oxytocin)
15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vasopressin, vasopressin analogs, forskolin and 8-bromo-cyclic AMP (8Br-cAMP) were studied for their effects on transepithelial water flux in toad urinary bladder. Arginine vasopressin, arginine vasotocin, oxytocin, desamino-8-D arginine vasopressin, forskolin and 8Br-cAMP stimulated hydro-osmotic water flux in a dose-dependent fashion. The rank order of potency was arginine vasotocin greater than arginine vasopressin greater than oxytocin greater than desamino-8-D-arginine vasopressin greater than forskolin greater than 8Br-cAMP. The vasopressin analogs [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-(O-methyl)tyrosine,8-arginine]vasopressin (SK&F 100273), [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-(O-methyl)tyrosine,4-valine,8-arginine]vasopressin (SK&F 100501), [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-D-tyrosine,4-valine,8-arginine]vasopressin (SK&F 100885), [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-(O-ethyl)tyrosine,4-valine,8-arginine]vasopressin (SK&F 100398), [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-D-isoleucine,4-valine,8-arginine]vasopressin (SK&F 101485), [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-(O-ethyl)-tyrosine,4-valine,8-arginine]vasopressin (SK&F 101498), [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-(O-ethyl)D-tyrosine,4-valine,8-arginine,9-desglycine]vasop ressin (SK&F 101926) and [1-(beta-mercapto-beta-beta-cyclopentamethylene propionic acid),2-D-phenylalanine,4-valine,8-arginine] vasopressin (SK&F 101071) antagonized arginine vasopressin-stimulated water flux and displaced the agonist dose-response relationship to the right in a parallel fashion. The most potent antagonists were those having the (O-ethyl)-D-tyrosine substitution at position 2. None of the antagonists tested had any effect on 8Br-cAMP-stimulated water flux at concentrations up to 10(-6)M.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of action and structural requirements of vasopressin analog inhibition of transepithelial water flux in toad urinary bladder. 309 Feb 34

The relationship between natriuretic activity of neurohypophysial peptides and renal prostaglandins (PGs) was investigated in anesthetized rats under water diuresis and on kidney homogenates. Over the course of water diuresis, urinary sodium excretion increased steadily, reaching a 3.5-fold increase in 90 min, but there was no significant change in PGE2 and PGF2 alpha excretion. Inhibition of PG synthesis by naproxen sodium abolished the increase in sodium excretion. Oxytocin (OT) and vasopressin, in submaximal antidiuretic doses, produced marked natriuresis to 2139% and 345% of the control rate, respectively, without a concomitant increase in PG excretion. [Leu4]OT, which is devoid of antidiuretic activity, produced natriuresis and diuresis also without a significant effect on PG excretion. Inhibition of PG synthesis by naproxen attenuated the natriuretic response but enhanced the antidiuretic response to OT. Both the natriuretic and diuretic responses to [Leu4]OT were attenuated. Although the possibility that naproxen may have antinatriuretic activity independent of its PG synthesis inhibitory action cannot be excluded, the data obtained are consistent with our postulate that the natriuretic effect of OT-peptides may be mediated in part via a renal PG mechanism. This postulate is strengthened further by our findings that natriuretic peptides, OT, vasopressin and [Leu4]OT stimulated PG synthesis in kidney homogenates in a dose-dependent manner. Their order of potency is in the same order of their relative natriuretic potencies. [Penicillamine1,Phe(Methyl)2,Thr4,Orn8]OT, an OT antagonist and non-natriuretic, had no significant PG synthesis stimulating activity in the kidney homogenates.
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PMID:Renal prostaglandins and natriuretic action of oxytocin and vasopressin in rats. 316 43

The distribution of FMRFamidelike peptides was studied in the nervous system of the lobster Homarus americanus by using immunocytochemical and radioimmunological techniques. By radioimmunoassay FMRFamidelike immunoreactivity (FLI) was found in low levels (ca. 1 pmol/mg protein) throughout the ventral nerve cord and in much higher amounts (60-100 pmol/mg protein) in the neurosecretory pericardial organs. Immunocytochemical studies showed FLI in approximately 300-350 cell bodies, and in distinct neuropil regions, neuronal fiber tracts, and varicose endings. Specificity of the immunostaining was tested by preabsorbing the antiserum with FMRFamide, with peptides having similar carboxyl termini to FMRFamide (Met-enkephalin-Arg-Phe, Phe-Met-Arg-Tyr-amide), with several amidated peptides (alpha-melanocyte-stimulating hormone, substance P, oxytocin), and with proctolin, a peptide found widely distributed in the lobster nervous system. Of these substances, only FMRFamide blocked the staining. In addition to the pericardial organs, significant levels of FLI were found in neurosecretory regions associated with thoracic second roots and in the connective tissue sheath that surrounds the ventral nerve cord. In all three regions, immunocytochemical studies showed the FLI to be localized to fine fibers and associated terminal varicosities lying close to the surface of the tissue, with no obvious target in their immediate vicinity. When examined at the ultrastructural level, the immunoreactive varicosities of the thoracic second roots and of the ventral nerve cord sheaths were found a few microns from the surface of the tissue and contained electron-dense granules. In the immunoreactive nerve cord sheath endings, in addition to the large, dense granules, small, clear vesicles were found. The appearance and location of these terminals suggest a neurohormonal role for FMRFamidelike peptides in lobsters. The observation that low levels of FLI are found in the hemolymph supports this suggestion. In addition, the localization of FLI to particular neuronal somata, fiber tracts, and neuropil regions suggests possible functional roles for these peptides in (1) integration of visual and olfactory information, (2) function of the anterior and posterior gut, and (3) the control of exoskeletal muscles.
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PMID:FMRFamidelike peptides of Homarus americanus: distribution, immunocytochemical mapping, and ultrastructural localization in terminal varicosities. 332 67

The uterotonic effects of arginine8-vasopressin (AVP) have been studied on uterine strips from non-pregnant women. Concentration-dependent contractions could be recorded over a 10 min period in the presence of AVP (5.5.10(-10)-3.10(-7) M); the most reproducible recordings were obtained with tissue from the inner part of the myometrium. Analogues of AVP and oxytocin (OT), modified at positions 1 (2-hydroxy-3-mercaptopropionic acid, deamino-3-mercaptopropionic acid), 2 (Phe), 4 (Arg, Val), 7 (Sar) or 8 (Orn) were synthesized and tested for uterotonic activity on human and rat uterine strips, and for vasopressor and antidiuretic activity in the rat in vivo. There was a positive correlation between the activity of these analogues on non-pregnant human myometrial tissue with that in the rat vasopressor assay (r = 0.86, P less than 0.01) but none with their activity in the antidiuretic assay. For example, [Mpa1,D-Arg8]vasopressin had more than twice the antidiuretic activity of AVP but less than 0.2% of its pressor or human uterotonic potency (Mpa = 3-mercaptopropionic acid). Correspondingly, the specific pressor analogue [Hmp1,Phe2,Orn8]OT was as potent as AVP on the human uterus, but had less than 3% of its antidiuretic activity (Hmp = 2-hydroxy-3-mercaptopropionic acid). There was no correlation between the uterotonic activities of AVP or its analogues when non-pregnant human and rat tissues were compared, indicating that rat uterine tissue is a poor guide when testing analogues intended for clinical use in non-pregnant women.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of vasopressin on the human non-pregnant uterus: studies with analogues of different vasopressor potencies. 338 99

NMR was used to monitor the binding to neurophysin of oxytocin and 8-arginine-vasopressin, 15N labeling being used to identify specific backbone 15N and 1H signals. The most significant effects of binding were large downfield shifts in the amino nitrogen resonance of Phe-3 of vasopressin and in its associated proton, providing evidence that the peptide bond between residues 2 and 3 of the hormones is hydrogen-bonded to the protein within hormone-neurophysin complexes. Suggestive evidence of hydrogen bonding of the amino nitrogen of Tyr-2 was also obtained in the form of decreased proton exchange rates on binding; however, the chemical shift changes of this nitrogen and its associated proton indicated that such hydrogen bonding, if present, is probably weak. Shifts in the amino nitrogen of Asn-5 and in the -NH protons of both Asn-5 and Cys-6 demonstrated that these residues are significantly perturbed by binding, suggesting conformational changes of the ring on binding and/or the presence of binding sites on the hormone outside the 1-3 region. No support was obtained for the thesis that there is a significant second binding site for vasopressin on each neurophysin chain. The behavior of both oxytocin and vasopressin on binding was consistent with formation of 1:1 complexes in slow exchange with the free state under most pH conditions. At low pH there was evidence of an increased exchange rate. Additionally, broadening of 15N resonances in the bound state at low pH occurred without a corresponding change in the resonances of equilibrating free hormone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Binding of oxytocin and 8-arginine-vasopressin to neurophysin studied by 15N NMR using magnetization transfer and indirect detection via protons. 342 16

Using implanted minipumps it was shown over a period of 7 days that the vasopressin antagonist, 1-deamino-pentamethylene-2-D-Phe-4-Ile-arginine vasopressin, caused increased diuresis in normal rats and reversed vasopressin- or oxytocin-induced antidiuresis in Brattleboro rats. When the antagonist was infused alone in Brattleboro rats it induced a marked antidiuretic response, indicating that the analogue also possessed agonistic properties. The agonist action could not be demonstrated in anaesthetized, hydrated normal rats. In these animals the analogue behaved as a pure antagonist. It is concluded that analogues which behave as antagonists in one test model may display agonistic properties under different experimental conditions.
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PMID:Antidiuretic antagonism and agonism of 1-deamino-pentamethylene-2-D-phenylalanine-4-isoleucine-arginine vasopressin in rats with diabetes insipidus. 355 52

Photoaffinity labeling of the single neurophysin tyrosine, Tyr-49, with Met-Tyr-azido-Phe amide has been reported to inhibit both neurophysin self-association and peptide binding. Accordingly, we investigated the functional consequences of modification, principally by tetranitromethane, of Tyr-49. Tetranitromethane-mediated tyrosine-tyrosine cross-linking permitted synthesis of covalent neurophysin "dimers" and of peptide-protein conjugates, the latter potentially analogous to the photoaffinity-labeled product. The self-association and binding properties of the covalent dimers were found to be similar or enhanced relative to those of the native protein. In contrast to the photoaffinity-labeled product, covalent conjugates of Tyr-49 with the ligand peptides Met-Phe-Tyr amide, Phe-Tyr amide, and Tyr-Phe amide also generally exhibited normal or increased binding affinity for exogenous peptide; a subfraction of the Phe-Tyr amide adducts showed evidence of reduced affinity. Diiodination of Tyr-49 had no significant effect on binding. However, among the products of tetranitromethane treatment in the absence of peptide was a novel inactive non-cross-linked product, representing modification only of Tyr-49 but containing no demonstrable nitrophenol. As evidenced by circular dichroism and nuclear magnetic resonance (NMR), this product was not significantly unfolded and retained the ability to self-associate. These latter results provide the strongest evidence thus far of a role for Tyr-49 in peptide-hormone binding. The disparate effects of different Tyr-49 modifications are collectively interpreted and reconciled with NMR data and the properties of the photoaffinity-labeled protein to suggest potential mechanisms of Tyr-49 participation in binding and the probable orientation of Tyr-49 relative to peptide residue 3 in neurophysin complexes.
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PMID:Chemical modification and cross-linking of neurophysin tyrosine-49. 356 65

Recently we reported the discovery of a series of 2-O-alkyltyrosine- (or 2-p-alkylphenylalanine), 4-threonine-, and 8-ornithine-substituted analogs of [1-penicillamine]oxytocin [( Pen1]OT) which possess prolonged anti-OT activity. In this study, we attempt to improve the potency and the duration of action of this series of OT antagonists by exploring the effects of D-stereoisomer substitution in the 2 position. We compare the in vitro anti-OT potency, expressed in pA2 values, and the duration of in vivo inhibitory action, expressed in recovery t1/2, of [Pen1]OT, [Pen1,Orn8]OT, [Pen1,Thr4]OT, [Pen1,Tyr(OMe)2,Thr4, Orn8]OT, [Pen1, Tyr(OEt)2,Thr4,Orn8]OT, [Pen1,D-Tyr(OEt)2,Thr4,Orn8]OT, [Pen1,Phe2,Thr4]OT, [Pen1,Phe(Me)2,Thr4,Orn8]OT, [Pen1,D-Phe(Me)2,Thr4,Orn8]OT, [Pen1,Phe(Et)2,Thr4,Orn8]OT, and [Pen1,D-Phe(Et)2,Thr4,Orn8]OT. The results show that modifications of the amino acid in position 2 by alkylation of the aromatic ring and use of D-stereoisomerism produce nonparallel effects on the in vitro potency and duration of action of OT antagonists. Time-action curve determinations show that long-acting OT antagonists exhibit delayed peak inhibitory action. Long action is not coupled with high potency in all cases. This dissociation between potency and duration of action gives support to our hypothesis that the potency and duration of action of these peptides may each have different conformational structure requirements.
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PMID:Long-acting oxytocin antagonists: effects of 2-D-stereoisomer substitution on antagonistic potency and duration of action. 357 33

The interchange reaction of disulfides was caused by the copper(II)/ascorbic acid/O2 system. The incubation of two symmetric disulfides, L-cystinyl-bis-L-phenylalanine (PP) and L-cystinyl-bis-L-tyrosine (TT), with L-ascorbic acid and CuSO4 in potassium phosphate buffer (pH 7.2, 50 mM) resulted in the formation of an asymmetric disulfide, L-cystinyl-L-phenylalanine-L-tyrosine (PT), and the final ratio of PP:PT:TT was 1:2:1. As the reaction was inhibited by catalase and DMSO only at the initial time, hydroxyl radical generated by the copper(II)/ascorbic acid/O2 system seemed to be responsible for the initiation of the reaction. Oxytocin and insulin were denatured by this system, and catalase and DMSO similarly inhibited these denaturations. As the composition of amino acids was unchanged after the reaction, hydroxyl radical was thought to cause the cleavage and/or interchange reaction of disulfides to denature the peptides.
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PMID:Interchange reaction of disulfides and denaturation of oxytocin by copper(II)/ascorbic acid/O2 system. 359 55

Perdeuteriated peptides were synthesized that are capable of binding to the hormone binding site of neurophysin but that differ in the position of aromatic residues. The binding of these peptides to bovine neurophysin I and its des-1-8 derivative was studied by proton nuclear magnetic resonance spectroscopy in order to identify protein residues near the binding site through the observation of differential ring current effects on assignable protein resonances. Phenylalanine in position 3 of bound peptides was shown to induce significant ring current shifts in several resonances assignable to the 1-8 sequence, including those of Leu-3 and/or Leu-5, but was without effect on Tyr-49 ring protons. The magnitude of these shifts was dependent on the identity of peptide residue 1. By contrast, the sole demonstrable direct effect of an aromatic residue in position 1 was a downfield shift in Tyr-49 ring protons. Study of peptide binding to des-1-8-neurophysin demonstrated similar conformations of native and des-1-8 complexes except for the environment of Tyr-49, confirmed the peptide-induced ring current shift assignments in native neurophysin, and indicated an effect of binding on Thr-9. These observations are integrated with other results to provide a partial model of neurophysin-peptide complexes that places the ring of Tyr-49 at a distance 5-10 A from residue 1 of bound peptide and that places both the 1-8 sequence and the protein backbone region containing Tyr-49 proximal to each other and to peptide residue 3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Application of peptide-mediated ring current shifts to the study of neurophysin-peptide interactions: a partial model of the neurophysin-peptide complex. 359 76


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