UNIPROT:P01178 - FACTA Search

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

The activation of placental AC by either Mg2+ or Mn2+, in the presence and absence of NaF, followed sigmoidal saturation kinetics. Mn2+ enhanced maximally the NaF-stimulated Mg2+-dependent AC activity. The apparent Km of Mg2+-dependent AC for ATP was 0.4 mM, with and without NaF addition. GTP and GMP-P(NH)P stimulated the Mg2+-dependent AC in a dose-dependent manner with half-maximal stimulation taking place at concentrations of approximately 2 microM. In the presence of GMP-P(NH)P (10 microM) the kinetics of the AC dependence on Mg2+ ion concentration changed from sigmoidal to hyperbolic. Most of the AC activity (greater than 83 per cent) was associated with the particulate fractions of placental homogenate. For better reproducibility, the AC assay was performed using sonicated particulate fraction preparations; sonication did not alter the response of AC to stimuli to a variety of agents used in these experiments; freezing and thawing, however, obliterated the stimulation by beta-adrenergic agonists. Placental AC activity was inhibited by p-hydroxymercuriphenyl sodium sulphonate in a dose-dependent fashion, and the inhibition was reversed by dithiothreitol. Mg2+-dependent AC was inhibited by 0.5 mM phenylhydrazine (95 per cent). Mg2+-dependent AC activity was responsive to stimulation by epinephrine, without and with GTP addition, with half-maximal stimulation taking place at a concentration of 2 microM. The stimulatory effect of epinephrine was blocked by propranolol in a dose-dependent manner but was not blocked by phentolamine. Oestrone, oestradiol-17 beta, 2-hydroxyoestreone, 2-hydroxyoestradiol-17 beta, dehydroepiandrosterone sulphate, and progesterone, as well as oxytocin, did not alter either the basal or GMP-P(NH)P-stimulated Mg2+-dependent AC activities. Preincubation of 20 000 g particulate fraction with either NaF or GMP-P(NH)P, followed by washing, resulted in preparations that remained stimulated without the requirement of any further additions.
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PMID:Adenylate cyclase from term human placenta and its regulation. 712 27

In a continued effort to determine the importance of the hydrogen bonds for stabilization of the biologically active conformation of oxytocin, deamino-[9-glycolicamide] oxytocin was synthesized in order to study, in this respect, the hydrogen bond between the peptide N--H of Gly9 and the C=0 of Cys6. In this analog the amide linkage between residues at positions 8 and 9 is replaced by an ester. Thus the residue at position 9 cannot be involved in hydrogen bond formation with the C=O of Cys6. Deamino-[9-glycolicamide] oxytocin exhibited 134 +/- 13 U/mg and 355 +/- 48 U/mg of uterotonic activity in absence and in presence, respectively, of Mg2+, 108 +/- 8 U/mg of milk-ejecting activity, 0.35 +/- 0.03 U/mg of pressor activity and 2.5 +/- 0.1 U/mg of antidiuretic activity. It is concluded that the hydrogen bond under question is not critical for the conformation required for biofunctional interaction of oxytocin with its receptors in the uterus, mammary gland and other target organs.
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PMID:Biofunctional evaluation of a hydrogen bond stabilizing the beta-turn in the acyclic part of oxytocin. 719 72

We have previously shown that the substitution of 8-ornithine and 2-O-methyltyrosine alone and in combination in [1-deaminopenicillamine] oxytocin (dPOT) brought about enhancements in antagonistic potencies to responses to oxytocin in vivo. To explore the effects of these substitutions in analogs of dPOT containing larger alkyl substitutents on the beta carbon at position 1 and on the tyrosine residue at position two, the following six analogs were synthesized: [1-(beta-mercapto-beta, beta-diethylpropionic acid), 8-ornithine] vasotocin (1, dEt2OVT); (1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 8-ornithine] vasotocin (2, d(CH2)5OVT): [1-beta-mercapto-beta, beta-diethylpropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [3, dEt2 Tyr(Me)OVT]; [1-(beta-mercapto-beta, beta-diethylpropionic acid), 2-O-ethyltyrosine, 8-ornithine]vasotocin [4, dEt2 Tyr(Et)OVT]; [1-beta-mercapto-beta', beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [5, d(CH2)5 Tyr(me)OVT]: [1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [6,d(CH2)5 Tyr(Et)OVT]. The required protected intermediates were synthesized by a combination of solid-phase synthesis and by individual 8 + 1 couplings in solution. All six analogs antagonize the actions of oxytocin on the rat uterus in the absence of Mg2+, in the presence of 0.5 mM Mg2+ and in situ. They also antagonize milk ejection responses to oxytocin, and the vasopressor responses to arginine vasopressin, and all have very low antidiuretic activities. With pA2 values of 7.35 +/- 0.08 and 7.37 +/- 0.17, respectively, compounds 3 and 5 are the two most potent in vivo antagonists of oxytocin reported to date.
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PMID:Design and synthesis of potent in vivo antagonists of oxytocin. 721 14

The synthesis of N-acetyl-[2-(O-methyl)tyrosine]arginine-vasopressin [Ac-Tyr(Me)AVP] was undertaken utilizing a combination of the stepwise active ester and fragment condensation methods. Ac-Tyr(Me)AVP is an antagonist of the vasopressor response to vasopressin (pA2 = 7.18 +/- 0.08), devoid of vasopressor agonist activity, and has an antidiuretic potency of 0.026 +/- 0.002 unit/mg, a 15 000-fold decrease over the antidiuretic activity of [2-(O-methyl)tyrosine]arginine-vasopressin. The analogue is also an antagonist of the in vitro uterotonic activity of oxytocin with pA2 values of 7.29 +/- 0.08 in the absence of Mg2+ and 6.73 +/- 0.14 in 0.5 mM Mg2+. This result of Nalpha-acetylation of Tyr(Me)AVP parallels similar results in the oxytocin series and suggests that this substitution should be considered in the design of potential antagonists of the antidiuretic response to vasopressin.
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PMID:N-Acetyl-[2-(O-methyl)tyrosine]arginine-vasopressin, an interesting antagonist of the vasopressor response to vasopressin. 739 38

The apical membrane of frog skin contains two types of pathways which allow the passage of several monovalent cations in the absence of external Ca2+. Differences between the two pathways concern their open-close kinetics, selectivity, and the affinity for several blocking agents. Type S channels open and close relatively slowly, whereas type F channels display fast open-close kinetics. Both channel types allow the passage of Na+, K+, and Rb+ currents which are blocked by divalent cations and La3+ added to the extracellular side. Type F channels are permeable for Cs+ which is, however, excluded from type S channels. Shifts in open-close kinetics induced by Mg2+ occur at concentrations below 5 microM for type F channels, whereas more than a tenfold higher dose is required for the type S pathway. UO2(2+) concentrations up to 100 microM only occlude type S channels while 100 microM tetracaine selectively blocks type F channels. Apical membranes of toad urinary bladder, cultured amphibian renal epithelia (A6), and toad colon contain only type F channels. In toad bladder and A6 cells volume expansion strongly activates this pathway. Macroscopic currents carried by Ba2+ and Ca2+ could be recorded after activation of toad bladders with oxytocin and treatment of the apical surface with nanomolar concentrations of Ag+, which seems to interact with a site located at the channel interior.
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PMID:Poorly selective cation channels in apical membranes of epithelia. 750 54

We report the solid-phase synthesis of the D-Cys6 analogues of arginine-vasopressin (AVP), peptide 1, of the selective AVP vasopressor (V1a receptor) antagonist [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O-methyltyrosine]arginine-vasopressin (d(CH2)5[Tyr(Me)2]-AVP, (A)), peptide 2, of the three nonselective antidiuretic/vasopressor (V2/V1a receptor) AVP antagonists d(CH2)5[Tyr(Et)2]VAVP (B), d(CH2)5[D-Tyr(Et)2]VAVP (C), and d(CH2)5[D-Phe2]VAVP (D) (where V = Val4), peptides 3-5, of the nonselective oxytocin (OT) antagonists d(CH2)5-[Tyr(Me)2]OVT (E) and d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT (F) (where OVT = ornithine-vasotocin), peptides 6 and 7, and of the selective OT antagonists desGly-NH2,d(CH2)5[Tyr(Me)2,Thr4]OVT (G) and d(CH2)5]D-Trp2,Thr4]OVT (H), peptides 8 and 9. We also present the repeat syntheses of the previously reported d(CH2)5[D-Trp2]AVT (peptide 10) and its D-Cys6 analogue (peptide 11) (where AVT = arginine-vasotocin). Peptides 1-11 were assayed for agonistic and antagonistic activities in in vivo V1a, V2, and oxytocic assays and in in vitro oxytocic assays without and with 0.5 mM Mg2+. With V2 and V1a agonistic potencies of 0.82 and 0.41 units/mg, [D-Cys6]AVP has retained less than 0.3% of the V2 and V1a potencies of AVP. It exhibits no oxytocic activity and is an in vitro OT antagonist. pA2 = 6.67 (no Mg2+); pA2 = 5.24 (0.5 mM Mg2+). By contrast, with one or two exceptions, a D-Cys6/L-Cys6 interchange in antagonists 2-9, although resulting in reductions of antagonistic potencies in all assays for virtually all peptides 2-9 relative to A-H, has been well tolerated. For peptides 2-5, the anti-V2 and anti-V1a pA2 values range from approximately 5.54 to 7.33 and from 7.19 to 8.06, respectively; the range of in vitro anti-OT pA2 values (no Mg2+) is 7.35-7.87; with 0.5 mM Mg2+, the range is 7.24-8.21. Peptides 2 and 4 have in vivo anti-OT pA2s = 6.60 and 7.16, respectively. For peptides 6-9, the range of in vitro anti-OT pA2 values (no Mg2+) is 7.65-7.96; with 0.5 mM Mg2+, the range is 7.41-7.65, and the in vivo anti-OT pA2 values range from 6.85 to 7.33. With an in vivo anti-OT pA2 = 7.33, peptide 6 is equipotent with its parent E. The in vivo anti-OT potencies of peptides 7-9 are significantly reduced relative to those of F-H. The in vitro anti-OT (0.5 mM Mg2+) pA2 values of 10 and 11 are 7.54 and 7.50, both significantly lower than those previously reported.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of a D-Cys6/L-Cys6 interchange in nonselective and selective vasopressin and oxytocin antagonists. 775 99

Intracellular recordings were made from sympathetic preganglionic neurones (SPNs) in transverse slices of thoraco-lumbar spinal cord of young rats (12-20 days old). A small group of SPNs generally having higher membrane potentials (-70 mV) compared to a remaining group (-66 mV) showed spontaneous oscillations of their membrane potential. Oxytocin superfused in concentrations of 0.1-30 microM had four effects on SPNs, inducing slow depolarisation, EPSPs, IPSPs and brief rhythmic oscillations. The slow depolarisation was unaffected by TTX whereas this abolished the other changes. The oxytocin-induced depolarisation was associated with a slow inward current and was not reversed at membrane potentials negative to EK, it increased at more positive potentials and was still present in low Ca2+ and high Mg2+ solutions. These features of the oxytocin induced current are similar to those of the TTX resistant voltage dependent Na+ current described in brainstem autonomic neurones. Vasopressin superfused at concentrations of 0.1 microM to 30 microM had similar effects on SPNs to those of oxytocin. A comparison of the effects of oxytocin and vasopressin on the same neurones revealed that oxytocin was almost 10 times less potent than vasopressin. The effects of oxytocin were not mimicked by a selective oxytocin agonist but were mimicked by a selective vasopressin V1a agonist and blocked by a selective V1a antagonist. Therefore it is concluded that the effects of oxytocin on SPNs are mediated by the vasopressin V1a receptor. It is suggested that oxytocin and vasopressin terminals in the lateral horn are part of a descending system controlling oscillating networks of SPNs in the spinal cord.
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PMID:Oxytocin acts at V1 receptors to excite sympathetic preganglionic neurones in neonate rat spinal cord in vitro. 792 7

Effect of oxytocin on contractile activity, passive and Mg2+, ATP-dependent Ca2+ transport through myocyte plasmic membrane was studied in the experiments carried out on intact samples of the uterus smooth muscle and fraction of myometrium sarcolemma vesicules. It was shown that at short-term (30 s) application of oxytocin (2.10(-7) M) powerful prolonged contractile reaction of myometrium bands was observed. After the chelating of Ca2+ in the washing medium by means of EGTA (2mM) or while introducing into it blockers of electrically controlled calcium channels the bands responded to oxytocin application with a single physical contraction. High concentrations of peptide hormone (10(-6) M) introduced into the preincubation medium of the smooth muscle bands before the isolation of the membrane fraction or directly into the incubation medium produced no effect on passive liberation of Ca2+ vesicules from the sarcolemma vesicules. At the same time preincubation of the bands in the solution containing smaller concentration of octapeptide (10(-7) M) decreased the initial velocity of Mg2+, ATP-dependent Ca2+ transport in the vesicules by 30% on the average. Possible mechanisms of oxytocin effects on intracellular homeostasis of Ca2+ in the myometrium, on the contractile activity of the uterus are discussed.
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PMID:[Uterotonic effect of oxytocin and transport of Ca2+ through the myometrial sarcolemma]. 847 40

We report the solid phase synthesis and some pharmacological properties of seven position two analogues (peptides 1-7) of one of our lead oxytocin antagonists, des-9-glycinamide[1-(beta-mercapto-beta,beta-pentamethylenepropionic+ ++ acid),2-O-methyltyrosine,4-threonine]ornithinevasotocin(desGly+ ++-NH2, d(CH2)5-[Tyr(Me)2,Thr4]OVT) (A). Peptides 1-7 have the following substituents at position two (1) D-Tyr(Me); (2) L-Tyr(Et); (3) D-Tyr(Et); (4) L-Tyr; (5) D-Tyr; (6) D-Phe and (7) D-Trp. These were evaluated for agonistic and antagonistic activities in in vitro and in vivo OT assays, in vivo vasopressor (V1a-receptor) assays and in vivo antidiuretic (V2-receptor) assays. None of the seven peptides exhibits oxytocic or vasopressor agonism. Peptides 1, 2, 4, 6 and 7 are extremely weak V2 agonists (V2 activities range from 0.001 to 0.02 U/mg). Peptides 3 and 5 exhibit weak V2 antagonism (pA2 < 6.0 and < 5.5, respectively). Peptides 1-7 exhibit potent in vitro (no Mg2+) OT antagonism (anti-OT pA2 values range from 7.66 to 8.03). Peptides 1 and 4-7 exhibit potent in vivo OT antagonism. Estimated in vivo anti-OT pA2 values range from 7.06 to 7.79 (peptides 2 and 3 were not tested). With anti-V1a pA2 values of 5.17-6.25 all seven peptides exhibit reduced anti-V1a potencies relative to the parent peptide (A) (anti-V1a pA2 = 6.46). Four of these peptides (4-7) exhibit striking gains in in vitro and in vivo anti-OT/anti-V1a selectivities compared to (A) which has an in vitro selectivity of 30 and an in vivo selectivity of 18. The D-Tyr2 (5), D-Trp2 (7), D-Phe2 (6) and L-Tyr2 (4) analogues of (A) exhibit anti-OT (in vitro)/anti-V1a selectivities = 240, 390, 404 and 540, respectively. The L-Tyr2 (4), D-Trp2 (7), D-Phe2 (6) and D-Tyr2 (5) analogues exhibited anti-OT (in vivo)/anti-V1a selectivities of 72, 80, 88 and 95, respectively. Peptides 4-7 appear to be the most selective peptide OT antagonists reported to date. In this regard it may be noted that they appear to be as or more potent and much more selective than the closely related OT antagonist 1-deamino[D-Tyr(Et)2,Thr4]OVT (Atosiban) which is currently undergoing clinical trial as a potential therapeutic agent for the prevention of premature labor. Atosiban (peptide 8) was resynthesized and pharmacologically evaluated in our laboratories. Atosiban exhibits the following antagonistic potencies. Anti-OT (in vitro, no Mg2+) pA2 = 7.71; anti-OT in vivo pA2 = 7.05; anti-V1a pA2 = 6.14 and anti-V2 pA2 approximately 5.9. Its anti-OT (in vivo)/anti-V1a selectivity is 8. Some of these antagonists may be suitable candidates for evaluation as potential tocolytic agents for use in the treatment of pre-term labor. They could also serve as useful new pharmacological tools for studies on the physiological roles of oxytocin. Finally, the findings presented here provide useful clues for the design of more potent and more selective OT antagonists.
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PMID:Design and synthesis of highly selective in vitro and in vivo uterine receptor antagonists of oxytocin: comparisons with Atosiban. 853 78

1. The ionic basis of the histamine-induced depolarization of immunohistochemically identified neurones in the supraoptic nucleus (SON) was investigated in the hypothalamo-neurohypophysial explant of male rats. Histamine (0.1-100 microM) caused an H1 receptor-mediated, dose-dependent depolarization of fifty of sixty-two vasopressin neurones in the SON. In contrast, twenty-three oxytocin neurones were either depolarized (n = 6), hyperpolarized (n = 4), or unaffected (n = 13) by histamine. Due to the low percentage of responding cells, oxytocin neurones were not further investigated. 2. Chelation of intracellular Ca2+ with 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid (BAPTA; 100-500 mM) blocked the depolarization, whereas blocking Ca2+ influx and synaptic transmission with equimolar Co2+ or elevated (5-20 mM) Mg2+ in nominally Ca(2+)-free solutions was without effect. 3. The amplitude of the histamine-induced depolarization was relatively independent of membrane potential. The input resistance was unaltered by histamine in nine neurones, but in nine other neurones it was decreased and in two neurones it was increased by more than 5%. Neither elevating extracellular K+ nor addition of the K+ channel blockers, apamin, d-tubocurarine, tetraethylammonium (TEA), or intracellular Cs+ decreased the histamine effect. Indeed, broadly blocking K+ currents with TEA and Cs+ significantly increased the depolarization to histamine. 4. Tetrodotoxin (2-3 microM) did not inhibit the histamine-induced depolarization. However, equimolar replacement of approximately 50% of extracellular Na+ with Tris+ or N-methyl-D-glucamine reduced or eliminated the response. 5. The depolarization of vasopressin neurones by histamine thus requires extracellular Na+ and intracellular Ca2+. Activation of a Ca(2+)-activated non-specific cation current or a Ca(2+)-Na+ pump are possible mechanisms for this effect.
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PMID:The ionic dependence of the histamine-induced depolarization of vasopressin neurones in the rat supraoptic nucleus. 888 57

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