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)

Systematic analysis of the hydrolysis of benzyloxycarbonyl (Cbz)-dipeptides by cathepsin A [EC 3.4.12.1] purified from rat liver lysosomes showed that multiple forms of cathepsin A preferentially cleave peptide bonds with leucine, methionine, and phenylalanine. Cbz-Met-Met, -Met-Phe, -Phe-Met, and -Phe-Ala were hydrolyzed 6 to 8 times faster than the standard substrates, Cbz-Glu-Phe and Cbz-Glu-Tyr. The pH optima of the hydrolyses were 4.6 to 5.8. Hydrolysis of peptide bonds with glycine, isoleucine, and proline was very slow, but the rate depended on the nature of the adjacent amino acids. Proteins such as albumin, cytochrome c, gamma-globulin, hemoglobin, histone, myoglobin, and myosin were scarecely degraded. Peptide hormones, such as glucagon and adrenocorticotropic hormone (ACTH) were hydrolyzed markedly with optimum pH's of 4.5 and 4.6, respectively. Angiotensin I, II, bradykinin, Lys- and Met-Lysbradykinin (kallidin and Met-kallidin), and substance P were also hydrolyzed at appreciable rates. pH optima for these peptide hormones were 5.2 to 5.6. On the other hand, insulin and its A chain, luteinizing hormone-releasing hormone (LH-RH), oxytocin and vasopressin were cleaved slowly. In the hydrolyses of glucagon and other peptides, multiple forms of rat liver lysosomal cathepsin A again showed a carboxypeptidase nature, cleaving peptide bonds sequentially from the carboxyl terminal. Almost all of the amino acids were cleaved on prolonged incubation. Vaso-activites of angiotensin II and bradykinin were rapidly lost on hydrolysis by cathepsin A. Lysosomal cathepsin C [dipeptidylaminopeptidase I, EC 3.4.14.1] also activated angiotensin II, but did not inactive bradykinin. Cathepsin A, therefore, can be regarded as one of the lysosomal angiotensinases and kinases. No distinct differences were observed between the multiple forms of cathepsin A in these hydrolyses and inactivations of peptides.
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PMID:Studies on cathepsins of rat liver lysosomes. III. Hydrolysis of peptides, and inactivation of angiotensin and bradykinin by cathepsin A. 1 61

Replacement of the aliphatic isoleucine residue in position 3 of oxytocin (the first corner position of the beta-turn in the 20-membered ring of the solution conformation of the hormone) by phenylalanine has been shown to result in analogues with reduced affinity and intrinsic activity when tested by the individual dose-response procedure on the isolated rat uterus. Studies of effects of structural modifications have been extended to include two additional beta-turn corner positions. First, the dose-response behavior of [Leu4]oxytocin and [Phe4]oxytocin, two analogues in which the Glu4 side chain in the second corner position of the beta-turn in the 20-membered ring has been substituted by hydrophobic and bulky groups, was compared with that of oxytocin. Second, the solid-phase synthesis and biological properties of [Phe3,Leu4,Met8]oxytocin and [Phe3,4,Met8]oxytocin are described. The presence of leucine or phenylalanine in position 4 evokes a drastic reduction in both the affinity and intrinsic uterotonic activity of the resulting analogues, with phenylalanine significantly more effective in reducing intrinsic activity than leucine (p less than 0.001).
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PMID:Conformation-activity studies of oxytocin. Effects of structural modifications at corner positions of the beta-turns on the uterotonic activity. 91 5

Synthesis and biological properties are reported for some analogs of oxytocin with replacements of the isoleucine residue in position 3, i.e., (3-proline)oxytocin and(3-D-alanine)oxytocin, and the glutamine residue in position 4, i.e., (4-D-alanine)-oxytocin and (4-D-leucin)oxytocin. (3-Proline)oxytocin exhibited smaller than0.02 U/MG oxytocic activity, 0.005 plus or minus smaller than 0.001 U/mg rat pressor activity and 0.003 plus or minus 0.0001 U/mg antidiuretic activity. (3-D-Alanine)oxytocin had no agonistic activity in the bioassays tested except for the rat antidiuretic assay (smaller than 0.0005 U/mg). The 4-D-alanine analog showed 0.05 plus or minus 0.003 U/mg oxytocic activity, 0.07 plus or minus 0.01 U/mg avian vasodepressor activity, and smaller than 0.001 U/mg rat antidiuretic activity. (4-D-Leucine)oxytocin possessed 0.001 plus or minus U/mg rat pressor activity, and showed slight inhibitory properties in the oxytocic and avian vasodepressor assays, inhibiting the oxytocin response in the latter assay by about 60% at a girnibe-to-analog ratio of 1:5000. The activity profiles of the analogs are compared to that of oxytocin and are discussed on the basis of the proposed solution conformation of oxytocin.
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PMID:Oxytocin analogs with substitutions in postions 3 and 4. 114 Aug 89

Indirect immunofluorescence histochemistry was used to investigate the distribution and extent of co-localization of chemical messengers in magnocellular neurons of the supraoptic and paraventricular nuclei. In order to increase the number of neurons immunoreactive to the antisera used, experimental manipulations were employed. The homozygous Brattleboro (diabetes insipidus) rat was also investigated. In untreated rats, only vasopressin- and oxytocin-like immunoreactivities could be observed. Colchicine treatment alone resulted in appearance of galanin-, dynorphin-, cholecystokinin-, [Leu]enkephalin- and thyrotropin-releasing hormone-positive cells. In hypophysectomized rats, all these markers, except tyrosine hydroxylase, showed substantial further increases. In addition, peptide histidine-isoleucine-immunoreactive cell bodies could now be seen. After salt-loading alone, tyrosine hydroxylase-like immunoreactivity was markedly increased, whereas vasopressin- and oxytocin-like immunoreactivity were very weak or undetectable. When salt-loaded rats received colchicine, corticotropin-releasing factor- and peptide histidine-isoleucine-like immunoreactivity in addition increased, whereas galanin- and dynorphin-like immunoreactivity markedly decreased. The Brattleboro rats resembled untreated rats, except their lack of vasopressin-like immunoreactivity, the marked increase in tyrosine hydroxylase-like immunoreactivity, and smaller increase in galanin- and dynorphin-like immunoreactivity. Addition of colchicine to Brattleboro rats resulted in some distinct further changes in that dynorphin-like immunoreactivity decreased in some neurons and that [Leu]enkephalin-, corticotropin-releasing factor- and peptide histidine-isoleucine-like immunoreactivity increased substantially. Several similarities could be observed between the salt-loaded and Brattleboro rats, with or without colchicine. However, a marked difference in immunoreactive [Leu]enkephalin levels was observed with no difference in dynorphin-like immunoreactivity, and opposite changes in galanin-like immunoreactivity. The results confirm the traditional view that hypothalamic magnocellular neurons in the supraoptic and paraventricular nuclei contain two separate cell populations, characterized by vasopressin and oxytocin, respectively, and that they contain additional messenger molecules in specific patterns. Vasopressin-containing neurons primarily express tyrosine hydroxylase, galanin, dynorphin, [Leu]enkephalin and peptide histidine-isoleucine, and to a minor extent cholecystokinin and thyrotropin-releasing hormone. Oxytocin-containing neurons mainly have cholecystokinin and corticotropin-releasing factor, and to a minor extent galanin, dynorphin, [Leu]enkephalin and thyrotropin-releasing hormone. Furthermore, our results detail individual co-existence situations among these putative messenger molecules. Thus, magnocellular neurons respond in a differential way to various stimuli and they store multiple bioactive substances in specific combinations.
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PMID:Localization of chemical messengers in magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei: an immunohistochemical study using experimental manipulations. 170 Oct 38

From a series of potent cyclic hexapeptide oxytocin (OT) antagonists, a compound that exhibited significant bradykinin (BK) agonist activity was identified. L-366,811 (cyclo[L-proline-D-tryptophan-L-isoleucine-D-pipecolic acid-L-piperazine-2-carboxylic acid-N-Me-D-phenylalanine]) stimulated phosphatidylinositol (PI) turnover in rat uterine slices in vitro (approximately EC50, 2 microM) with a maximal effect (15-fold increase over basal) greater than that obtained for either BK or OT. L-366,811 also elicited dose-related contractions of the isolated rat uterus, producing measurable effects at 100 nM. Several other equally potent OT antagonists from the cyclic hexapeptide structural class were either less potent or inactive as activators of uterine PI turnover or contractility. The stimulatory effects of L-366,811 on uterine PI turnover and contractions were blocked by BK antagonists but not by an arginine vasopressin (AVP)/OT antagonist. In radioligand binding studies, L-366,811 exhibited moderate affinity (IC50, 360 nM) for the [3H]BK binding site in rat uterus, consistent with its potency in the functional models. These results indicate that L-366,811 exhibits BK agonist activity in rat uterus in vitro.
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PMID:Bradykinin agonist activity of a novel, potent oxytocin antagonist. 189 11

In an attempt to identify a physiological prolactin-releasing factor in the sheep, ovariectomized ewes were given intracarotid injections (10(-8)-10(-7) mol/animal) of thyrotropin-releasing hormone (TRH), vasoactive intestinal polypeptide (VIP), peptide histidine-isoleucine amide (PHI), oxytocin (OT), arginine vasopressin (AVP), substance P (SP), bombesin (BB), neurotensin (NT) and neuropeptide Y (NPY). Administration of TRH, AVP, NT and OT resulted in immediate and significant increases in plasma prolactin concentrations, the greatest stimulatory effect being obtained after TRH; other peptides had no effect in ovariectomized hypothalamo-pituitary intact ewes. AVP, NT and OT failed to release prolactin in ovariectomized ewes. These results suggest that (1) AVP, NT and OT may act via the hypothalamus to regulate prolactin secretion in hypothalamo-pituitary intact ewes; (2) VIP, PHI, SP, BB and NPY appear to have no direct roles at the pituitary level to control prolactin secretion in sheep, and (3) TRH stimulates prolactin secretion in ovariectomized ewes by a direct pituitary action.
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PMID:Effect and site of action of hypothalamic neuropeptides on prolactin release in sheep. 246 Jul 94

[4-(0-methyl)-L-threonine]-oxytocin, a new analogue of neurohypophyseal hormone oxytocin, was synthesized. Its uretonic activity was found to be 150 I. U./mg. The comparison of the potency of [4-(0-methyl)-threonine]-oxytocin with a very active analogue [4-threonine]-oxytocin and low active analogue [4-isoleucine] -oxytocin supports the hypothesis of high uterotonic activity of 4-substituted analogue of oxytocin to be related to the presence of suitably located hydrophilic and lipophilic grouper in the side chain in position 4, and to the proton donor/proton acceptor properties of hydrophilic group.
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PMID:[4-(0-methyl)-L-threonine] -oxytocin. Synthesis and uterotonic activity. 285 67

Arginine vasopressin (AVP), a nine-amino acid neurohypophyseal hormone, is capable of replacing the helper cell requirement for IFN-gamma production by Lyt-2+ mouse splenic lymphocytes. We present data here showing that the AVP helper signal occurs via interaction with a novel R on splenic lymphocytes and involves primarily the N-terminal six-amino acid cyclic ring (pressinoic acid) with the C-terminal three-amino acid end of AVP playing a minor role. Pressinoic acid was capable of providing help at concentrations similar to those of AVP, whereas oxytocin and isoleucine pressinoic acid were 10- and 100-fold less effective, respectively. Isoleucine pressinoic acid has the same structure as pressinoic acid except for the substitution of isoleucine for phenylalanine in position 3 of the sequence. Consistent with the function data, R binding competitions with splenic lymphocyte membrane preparations showed that AVP and pressinoic acid competed similarly with [3H]AVP, whereas oxytocin and isoleucine pressinoic acid were much less effective competitors. Further characterization of the AVP lymphocyte R was performed using AVP analogues having well defined agonist and antagonist activities on either V1 (vasopressor) R or V2 (antidiuretic) R. The AVP helper signal was blocked by the V1 antagonist [d(CH2)1(5) Tyr(methyl)]AVP but not by another V1 antagonist, [d(CH2)1(5)D-Tyr(ethyl)2Val4]AVP. Both V1-R antagonists were able to block [3H]AVP binding to the V1-R on liver cells, whereas only the V1 antagonist that blocked AVP help was able to compete effectively for the spleen AVP-R. Neither a V2 agonist nor a V2 antagonist had any effect on AVP help in IFN-gamma production. These data strongly indicate the presence of a novel AVP-R on spleen lymphocytes, which is related to the classic V1-R on liver cell membranes.
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PMID:Arginine vasopressin (AVP) replacement of helper cell requirement in IFN-gamma production. Evidence for a novel AVP receptor on mouse lymphocytes. 296 81

In the nervous system of the obligatory endoparasite Diphyllobothrium dendriticum immunoreactivity (IR) to growth hormone-releasing factor (GRF), peptide histidine isoleucine (PHI), bovine pancreatic polypeptide (BPP), gastrin, gastrin-releasing peptide (GRP), oxytocin, FMRFamide (FMRF) and serotonin (5HT) was demonstrated by immunocytochemical methods. A very strong GRF-IR was observed in the CNS and PNS of larvae and of the constantly growing adult worms. GRF-IR axon terminals occur beneath the basal lamina of the tegument along the inside of the bothridia, the holdfast organ of the worm. GRF-IR fibres surround the yolk producing vitelline glands and occur in the wall of the vagina. PHI-IR was observed in the CNS and PNS of larvae and adult worms. PHI-IR terminals occur beneath the basal lamina of the tegument along the strobila, the nutrient absorbing surface of the worm. PHI-IR fibres seem to innervate the testicular follicles. FMRF-IR fibres and perikarya occur close to the vitelline glands and the uterine pore and in the male copulatory organ. Numerous large 5HT-IR perikarya with long varicose fibres were observed in the nervous system of the worm. 5HT-IR perikarya occur close to the genital atrium. D. dendriticum is the phylogenetically lowest organism in which IR to PHI has been demonstrated.
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PMID:Immunocytochemical evidence for the presence of "mammalian" neurohormonal peptides in neurones of the tapeworm Diphyllobothrium dendriticum. 308 Feb 46

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


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