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)

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

1. The contractile responses of helically cut vascular strips of chickens to vasoactive agents were studied.2. Large pulmonary arteries were contracted by neurohypophysial peptides, but not by angiotensin, acetylcholine, histamine, 5-hydroxytryptamine, bradykinin or eledoisin. The activity of oxytocin was greater than that of arginine vasopressin.3. Vasodilator effects of oxytocin upon small (200-500 mu diameter) mesenteric and muscular arteries were demonstrable, but inconsistent.4. Magnesium potentiated in a parallel fashion the vasoconstrictor effects of oxytocin and of arginine vasopressin.5. Deamino-oxytocin was potentiated by magnesium. This finding suggests a difference between the peptide-protein interactions of tissue receptors and those of neurophysin.
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PMID:Neurohypophysial peptide interaction with magnesium in avian vascular smooth muscle. 429 87

Preparations of rabbit small intestine smooth muscle cell sarcolemma are capable of hydrolyzing ATP in the presence of millimolar concentrations of Mg2+ and Ca2+ and possess the activity of Mg2+,Ca2+-ATPase having a high affinity for Ca2+ (Km = 5.8 X 10(-6) M). The optimal conditions for the Mg2+,Ca2+-ATPase reaction were established. It was demonstrated that sarcolemmal preparations hydrolyze ATP, GTP, ITP and UTP almost at the same rates. The enzyme contains SH-groups that are unequally exposed to the water phase and are inhibited by 50% by p-chloromercurybenzoate and by 90% by dithionitrobenzoate. The Mg2+,Ca2+-ATPase activity is highly sensitive to oxytocin: at the concentration of 10(-7) MU/ml, the hormone completely inhibits the enzyme without affecting its Mg2+-, Ca2+- and Na+,K+-ATPase activities.
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PMID:[Mg2,Ca2+-ATPase activity of sarcolemmas of intestinal smooth muscle cells in the rabbit]. 615 2

A crude membrane fraction prepared from bovine adrenal medulla bound tritium labeled arginine-vasopressin (3H-AVP) in a time and temperature dependent manner. Physiological concentrations of Mg2+ (1-3 mmol/l) were required for the binding reaction, while Ca2+ (5-80 mmol/l) had no effect. The reaction was saturable and reversible. Scatchard plots of the data suggested the presence of a single class of high affinity (Kd=0.41 nmol/l) and low capacity (Bmax=26 fmol/mg protein) binding sites. The specificity of the binding reaction was examined using various structural analogs of AVP which displaced 3H-AVP. Arginine-vasotocin proved to be equipotent with AVP, while oxytocin and 1-deamino,8-D-arginine-vasopressin were about 500-fold less effective. Two relatively selective V1-receptor antagonists, dPenTyrMeAVP and d(CH2)5-TyrMeAVP were 2- and 20-fold less potent than AVP, respectively These data strongly suggest that the bovine adrenal medulla contains V1-type receptors for vasopressin, which could be involved in the regulation of the function of chromaffin cells.
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PMID:Characterization of high affinity binding sites for vasopressin in bovine adrenal medulla. 623 39

The present study investigated whether specific [3H]oxytocin binding sites previously demonstrated in estrogen-dominated rabbit uterus have properties expected of physiologic receptors coupled to uterine contraction. Microsomal membranes from estrogen-dominated rabbit uterus were found to contain high-affinity specific oxytocin binding sites with Kd = 2-3 nM. These sites were predominantly myometrial in locus. Specific oxytocin binding exhibited a pH optimum between 7.5 and 8.0. Mg2+ or Mn2+ was necessary for maximal specific [3H]oxytocin binding; in contrast, Ca2+ at submillimolar concentrations inhibited specific binding. Oxytocin binding sites were not detectable in microsomal membranes isolated from progesterone-dominated rabbit uterus. Relative binding and uterotonic activities of 10 synthetic neurohypophyseal hormone analogues were determined in estrogen-dominated rabbit uterus. A qualitative correlation was observed between binding and uterotonic responses. Angiotensin II and insulin did not compete with [3H]oxytocin for uterine binding sites. It is concluded that the specific high affinity [3H]oxytocin binding sites demonstrated in estrogen-dominated rabbit uterus have the selectivity for neurohypophyseal hormone analogues expected for physiologic receptors coupled to uterine contraction.
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PMID:Oxytocin receptors coupled to uterine contraction in estrogen-dominated rabbits. 624 2

Contractile effects of oxytocin, prostaglandin F2 alpha, acetylcholine, KCl, RbCl, and BaCl2 in the presence of Mn2+ and La3+ ions and other cations were studied in the rat myometrium at 37 degrees C. The effects depended mainly on the kind of the blocking agents (oxytocin in the presence of Mn2+ significantly increased muscle tone whereas in the presence of La3+, Cd2+, Mg2+ the effect was absent). The tone increase in the presence of Ca permeability blocking agents seems to be due to the effect of the agents on the intracellular sources of Ca ions.
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PMID:[Effect of stimulator substances on the contractile activity of the isolated rat myometrium against a background of various calcium permeability blockaders]. 624 89

Receptors for oxytocin were identified in a particulate fraction from the myometrium of the pregnant ewe. Specific binding of [3H]-oxytocin was rapid, reversible, and saturable. It showed an absolute requirement for Mg2+ and the selectivity among oxytocin analogues expected for the receptor. On fractionation of the myometrium by differential and discontinuous gradient centrifugation, [3H]-oxytocin binding showed a fractionation pattern which was similar to that for plasma membrane markers, but different from those for endoplasmic reticulum or mitochondrial markers. It is concluded that oxytocin receptors are located in the plasma membrane of the ewe myometrium. This subcellular fraction is a useful preparation for the study of receptor mechanisms and the regulation of myometrial contractility.
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PMID:Identification and characterization of receptors for oxytocin in the myometrium of the pregnant ewe. 629 Mar 51

The magnocellular neurones of the supraoptic nucleus which synthesize and secrete vasopressin and oxytocin have been commonly regarded as simple "output" neurones in that they receive an input, generate an action potential and in turn release hormone from their terminals in the posterior pituitary. Three lines of evidence are presented which suggest that rat supraoptic nucleus neurons also have axon collaterals which terminate in the hypothalamus close to the nucleus. Small injections of horseradish peroxidase were made directly into the nucleus in hypothalamic slices, allowing visualization of the axons of supraoptic neurones. Collaterals of these axons could be observed in regions both dorsal and dorsolateral to the supraoptic nucleus. In a separate series of experiments, sections of perfusion-fixed hypothalamus were stained for vasopressin and oxytocin using specific antisera. Peptide-containing collaterals of both types were observed near the supraoptic nucleus, in a region similar to that seen after horseradish peroxidase injections. Finally, electrophysiological studies were carried out on hypothalamic slices containing the supraoptic nucleus. A small concentric bipolar stimulating electrode was placed directly into the nucleus and activity of lateral hypothalamic neurones within 0.1-1 mm of the nucleus was recorded. Of 68 neurones studied, 52 were excited by supraoptic stimulation via a synaptic pathway that could be blocked by Ca2+ -free solutions containing 18 mM Mg2+. These studies suggest that supraoptic neurones communicate via axon collaterals with other neurones in the lateral hypothalamus, in addition to their previously well characterised functional role in neurosecretion.
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PMID:Axon collaterals of supraoptic neurones: anatomical and electrophysiological evidence for their existence in the lateral hypothalamus. 632 27

Studies with sarcolemma from cattle myometrium containing inside-out cytoplasmic vesicles, using Ca2+-EGTA buffer, showed that the affinity of ionized Ca2+ for the Mg2+- or ATP-dependent transport is higher than that for the Na+-Ca2+ exchange system (Kd = 3,2 X 10(-6) and (4.3-5.3) X 10(-5) M), respectively. The Km values for MgATP are 2.15 mM. Oxytocin added to the homogenization medium containing rabbit and cattle myometrium cells, i.e. during the formation of closed sarcolemmal fragments, resulted in inhibition of Mg2+, ATP-dependent accumulation of 45Ca2+ by plasma membranes. However, an addition of oxytocin to the incubation medium did not affect the kinetics of active accumulation of Ca2+. It was assumed that the system of non-electrogenic Na+-Ca2+ exchange in the myometrium possessing a low affinity for Ca2+ provides for the maintenance of ionized Ca2+ concentration in the myocytes at 10(-5) M. Therefore, this system cannot induce relaxation of mechanical tension of the uterus. Further decrease of Ca2+ in the myoplasm from 10(-5) to 10(-7) M and, correspondingly, the relaxation of myometrium is provided for by the Mg2+, ATP-dependent efflux of Ca2+ from the myocytes having a high affinity for this cation. The decrease of the activity of ATP-dependent Ca2+-pump by oxytocin is the cause of Ca2+ elevation in the myoplasm and, consequently, of myometrium contraction.
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PMID:[Contribution of the Mg2+-, ATP- AND Na+-dependent Ca2+-transport systems to the regulation of Ca2+ concentration in myometrial cells]. 670 45

[5-beta-Malamidic acid]oxytocin was synthesized to study the importance of the hydrogen bond between the C=O of Tyr2 and the peptide N-H of Asn5 for the stabilization of a biologically functional conformation of oxytocin. This analog lacks the peptide N-H at residue 5 required for the formation of a hydrogen bond with the C-O of Tyr2. [5-beta-Malamidic acid] oxytocin exhibited 45.1 +/- 2.5 U/mg and 65.6 +/- 5.9 U/mg of uterotonic activity, in vitro, in the absence and in the presence, respectively, of Mg2+, 147 +/- 14 U/mg of uterotonic activity in vivo, 203 +/- 13 U/mg of milk-ejecting activity, 0.37 +/- 0.03 U/mg of pressor activity and 0.32 +/- 0.29 U/mg of antidiuretic activity. It is concluded that devoid of the hydrogen bond under question, an oxytocin-like peptide can still assume the conformation needed to interact with the oxytocin receptors.
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PMID:Biofunctional evaluation of a hydrogen bond stabilizing the conformation in the cyclic part of oxytocin. 711 27


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