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)

Within the spectrum of the characteristic pharmacological activities (oxytocic (O), milk-ejecting (ME), antidiuretic (A), pressor (P) associated with the known natural and synthetic analogs of oxytocin and vasopressin it is possible to discern patterns of selectivity of these types: 1) interpeptide-like (a) O/A, (b) O/P; 2) intraoxytocin-like (a) O/ME; (b) ME/O; 3) intravasopressinlike (a) A/P, (b) P/A. Consideration of structural modifications of oxytocin or vasopressin, which individually or in combination give rise to peptides possessing enhanced selectivity of a given type, can in some cases provide a rational basis for the design of peptides with even greater selectivity. [1-Deamino-4-valine-8-D-arginine]vasopressin, the most highly specific antidiuretic peptide known to date, was designed in this fashion. By contrast, intraoxytocin-like selectivity, is manifested to only a minor degree in all peptides studied to date. Enhanced interpeptide-like selectivity of the type 1a (O/A; O/P) is readily attainable by specific single substitutions at positions 4 or 7 in oxtocin. Substitution of threonine in the 4 position of the oxytocic antagonist [1-deaminopenicillamine]oxytocin brought about a threefold enhancement in oxytocic inhibitory activity. Thus [1-deaminopenicillamine-4-threonine]oxytocin (dPTOT) is the most potent antagonist of the in vitro oxytocic response to oxytocin known to date. Thus analysis of the pharmacological data from over 300 analogs of oxytocin and vasopressin allows the delineation of those structural modifications that can optimize selectivities. The potential and limitations of this approach for the design of peptides possessing desired agonistic or antagonistic selectivity for potential clinical use and for studies on oxytocin and vasopressin receptors is discussed.
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PMID:Design of neurohypophyseal peptides that exhibit selective agonistic and antagonistic properties. 32 64

As part of a program in which we are attempting the design and synthesis of an antagonist of the antidiuretic response to arginine-vasopressin (AVP) [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),4-valine,8-D-arginine]vasopressin [d(CH2)5VDAVP] was synthesized and assayed for antidiuretic, vasopressor, and oxytocic activities. The required protected intermediate was synthesized by a combination of solid-phase synthesis and an [8 + 1] coupling in solution. d(CH2)5VDAVP has an antidiuretic potency of 0.10 +/- 0.02 unit/mg, less than 1/10000 that of its parent [deamino,4-valine,8-D-arginine]vasopressin (dVDAVP). d(CH2)5VDAVP is a specific antagonist of the vasopressor responses to AVP. It has an antivasopressor pA2 value of 7.68 +/- 0.05 when tested against AVP. It is also an antagonist of the in vitro oxytocic response to oxytocin (pA2 value = 6.62 +/- 0.07). With its negligible antidiuretic activity, absence of oxytocic activity, and its potent and specific ability to antagonize the vasopressor effects of AVP, d(CH2)5VDAVP is one of the most potent and selective vasopressor antagonists reported to date. It should thus be a useful tool with which to probe the possible role(s) that AVP may play in cardiovascular regulation under normal and pathological conditions.
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PMID:[1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),4-valine,-8-D-arginine]vasopressin, a potent and selective inhibitor of the vasopressor response to arginine-vasopressin. 62 9

In attempting to design an antagonist of the antidiuretic response to arginine-vasopressin (AVP) [1-deaminopenicillamine,4-valine,8-D-arginine]vasopressin (dPVDAVP) was synthesized by the solid-phase method and assayed for antidiuretic, vasopressor, and oxytocic activities. dPVDAVP has an antidiuretic potency of 123 +/- 22 units/mg, one-tenth that of its parent [deamino,4-valine,8-D-arginine]vasopressin (dVDAVP). Like dVDAVP its antidiuretic effect in conscious diabetes insipidus rats is greatly prolonged when compared to AVP. dPVDAVP causes a prolonged inhibition of vasopressor responses to AVP but not to norepinephrine or angiotensin II. It has an antivasopressor pA2 value of 7.82 +/- 0.05 when tested against AVP. Thus the penicillamine substitution at position 1 in dVDAVP increased its antivasopressor activity sixfold (dVDAVP has a pA2 value of 7.03 +/- 0.11). dPVDAVP is thus the most potent vasopressor antagonist yet reported. dPVDAVP was also found to be a potent inhibitor of the in vitro oxytocic response to oxytocin (pA2 value = 7.23 +/- 0.04). dPVDAVP with its potent and specific ability to antagonize the vasopressor effects of AVP should be a useful pharmacological tool with which to explore the possible participation of AVP's potent vasoconstrictor properties in cardiovascular regulation in physiological and pathological states.
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PMID:[1-deaminopenicillamine,4-valine]-8-D-arginine-vasopressin, a highly potent inhibitor of the vasopressor response to arginine-vasopressin. 92 26

The effect of vasopressin analogues on plasma adenosine 3',5'-cyclic monophosphate (cAMP) concentration was examined in a group of five conscious dogs instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter). These dogs were infused for 20 min with a selective antidiuretic (V2) agonist, desamino-8-D-arginine vasopressin (DDAVP, 10 ng.kg-1 x min-1). This infusion was repeated on another day in the presence of the combined V1-V2 antagonist d(CH2)5-D-Tyr(Et)-4-valine,8-arginine vasopressin. The dogs also received an infusion of the selective V1 agonist 2-phenylalanine,8-ornithine oxytocin (Phe-OrnOT) at a rate of 10 ng.kg-1 x min-1. The effect of these infusions was compared with those of an isotonic saline infusion. Plasma cAMP measured in the aorta remained unchanged during all infusions but that of the selective V2 agonist DDAVP alone, during which it increased significantly from 22.4 +/- 0.8 to 32.6 +/- 4.6 and 37.0 +/- 4.1 pmol/ml after 10 and 20 min, respectively. In the plasma sampled from the inferior vena cava caudal to the renal veins, cAMP increased during DDAVP infusion from 22.2 +/- 2.5 to 39.2 +/- 3.8 and 36.0 +/- 4.0 pmol/ml after 10 and 20 min, respectively. The infusion of DDAVP was later given to the same dogs under anesthesia after bilateral nephrectomy, which did not modify the effect of DDAVP on arterial plasma cAMP. In another group of four conscious dogs, infusion of DDAVP at the same rate did not induce significant changes in plasma catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:cAMP and extrarenal vasopressin V2 receptors in dogs. 133 16

Familial neurohypophyseal diabetes insipidus in humans is a rare disease transmitted as an autosomal dominant trait. Affected individuals have very low or undetectable levels of circulating vasopressin and suffer from polydipsia and polyuria. An obvious candidate gene for the disease is the vasopressin-neurophysin (AVP-NP) precursor gene on human chromosome 20. The 2 kb gene with three exons encodes a composite precursor protein consisting of the neuropeptide vasopressin and two associated proteins, neurophysin and a glycopeptide. Cloning and nucleotide sequence analysis of both alleles of the AVP-NP gene present in a Dutch ADNDI family reveals a point mutation in one allele of the affected family members. Comparison of the nucleotide sequences shows a G----T transversion within the neurophysin-encoding exon B. This missense mutation converts a highly conserved glycine (Gly17 of neurophysin) to a valine residue. RFLP analysis of six related family members indicates cosegregation of the mutant allele with the DI phenotype. The mutation is not present in 96 chromosomes of an unrelated control group. These data suggest that a single amino acid exchange within a highly conserved domain of the human vasopressin-associated neurophysin is the primary cause of one form of ADNDI.
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PMID:A missense mutation in the vasopressin-neurophysin precursor gene cosegregates with human autosomal dominant neurohypophyseal diabetes insipidus. 174 Jan 4

Voltage-dependent Ca2+ channels of the aortic cell line A7r5 were studied using 45Ca2+ flux experiments. Ca2+ channels which have been studied belong to the L-type and are very sensitive to inhibitors and activators in the 1,4-dihydropyridine series as well as to (-)desmethoxyverapamil and d-cis-diltiazem. L-type Ca2+ channels in these smooth muscle cells are not affected by cyclic 8-bromo-AMP and dibutyryl cyclic AMP. However, the activity of these channels is strongly depressed after treatment with diacylglycerols (1-oleyl 2-acetylglycerol and 1,2-dioctanoylglycerol). Phorbol esters, which like diacylglycerols are well-known activators of protein kinase C (the Ca2+- and phospholipid-dependent enzyme), inhibit 70% of Ca2+ channel activity (K0.5 = 25 nM for phorbol 12-myristate 13-acetate and K0.5 = 200 nM for phorbol 12,13-dibutyrate). Phorbol esters that are inactive on kinase C are without effect on Ca2+ channel activity. [Arg8]Vasopressin and bombesin, two peptides that are well known for their action on polyphosphoinositide metabolism, inhibit Ca2+ channel activity to the same extent as active phorbol esters (65-70%). Oxytocin has the same type of effect presumably by acting at the V1-receptor. Both effects of [Arg8]vasopressin and oxytocin are suppressed by [1-(beta-mercapto-beta,beta-diethylpropionic acid)4-valine]arginine vasopressin, a specific vasopressin antagonist at the V1-receptor.
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PMID:Regulation of calcium channels in aortic muscle cells by protein kinase C activators (diacylglycerol and phorbol esters) and by peptides (vasopressin and bombesin) that stimulate phosphoinositide breakdown. 243 72

We report the solid-phase synthesis of eight 2-O-alkyltyrosine analogues of 1-deamino-arginine-vasopressin (dAVP) with enhanced antidiuretic agonistic specificity. These peptides are as follows: 1-deamino[2-O-methyltyrosine]-arginine-vasopressin (dTyr(Me)AVP), 1-deamino[2-O-ethyltyrosine]arginine-vasopressin (dTyr(Et)AVP), 1-deamino[2-O-methyltyrosine,8-D-arginine]vasopressin (dTyr(Me)DAVP), 1-deamino[2-O-ethyltyrosine,8-D-arginine]vasopressin (dTyr(Et)DAVP), 1-deamino[2-O-methyltyrosine,4-valine]arginine-vasopressin (dTyr(Me)VAVP), 1-deamino[2-O-ethyltyrosine,4-valine]arginine-vasopressin (dTyr(Et)VAVP), 1-deamino[2-O-methyltyrosine,4-valine,8-D-arginine]vasopressin (dTyr(Me)VDAVP), and 1-deamino[2-O-ethyltyrosine,4-valine,8-D-arginine]vasopressin (dTyr(Et)VDAVP). All analogues were tested for antidiuretic, antivasopressor, and antioxytocic activities. Deamination, as was expected, significantly enhanced the antidiuretic properties of these analogues relative to their parent N-amino-O-alkyltyrosine peptides. With the exception of dTyr(Me)AVP, all of these analogues are antagonists of the vasopressor responses to AVP and of the uterine response to oxytocin. Thus they all exhibit high antidiuretic agonistic specificity. Due to its remarkable properties, dTyr(Me)VDAVP is a unique compound in this series. It appears to be the most potent antidiuretic agonist (1740 units/mg) and also a vasopressor antagonist and a potent oxytocin antagonist. It is thus a highly specific antidiuretic agonist. In general, all of these new analogues are highly specific and thus are potentially useful as pharmacological tools and clinical agents.
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PMID:2-O-alkyltyrosine derivatives of 1-deamino-arginine-vasopressin: highly specific and potent antidiuretic agonists. 290 37

Neurohypophysial hormones stimulate the motility of tunica albuginea, epididymis, and vas deferens acting through oxytocin (OT) and V1 vasopressin receptors. To test the hypothesis that these hormones are involved also in the regulation of seminal vesicle physiology, we studied binding of [3H]OT and [3H] arginine vasopressin ([3H]AVP) to porcine seminal vesicle membranes. Neurohypophysial hormones bind to two different classes of sites. The first class shows low capacity (35 fmol per mg of protein) and a very high affinity (Kd less than 1 nM) for both the labeled ligands. The second class is characterized by a high capacity (2000 fmol per mg of protein) and a high affinity for AVP (Kd approximately equal to 2.5 nM), whereas OT has 160 times lower affinity. Lysine vasopressin and the V1 antagonist [1-deaminopenicillamine, 2-(O-methyl)tyrosine]Arg8-vasopressin compete with high affinity with [3H]AVP binding, whereas the V2 agonist [1-deamino,4-valine]D-Arg8-vasopressin (dVDAVP) is 110 times less potent than AVP. The OT agonist [Thr4,Gly7]OT and the OT antagonist [1(beta-mercapto-beta, beta-cyclopentamethylene propionic acid), 2-(O-ethyl)tyrosine, 8-ornithine]vasotocin failed to affect [3H]AVP binding. These findings seem to suggest that AVP interacts with the V1 vasopressin isoreceptor in porcine seminal vesicle membranes. However, AVP stimulates adenylate cyclase activity in a dose-dependent fashion with an EC50 of 14 nM, whereas OT or dVDAVP has no effect at 100 nM. Moreover, a well-characterized V1 vasopressin antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid),2-(O-methyl)tyrosine]Arg8-vasopressin [d(CH2)5Tyr(Me)AVP], competes with [3H]AVP binding with an IC50 of 0.17 microM. These pharmacological properties are distinct from the previously described V1 and V2 vasopressin receptors and indicate the presence of a new class of AVP receptors. Although this vasopressin isoreceptor shares some pharmacological characteristics with the V1 (pressor) isoreceptor, it has low affinity for the V1 antagonist d(CH2)5-Tyr(Me)AVP and is linked to the adenylate cyclase system. The extremely high density of AVP receptors in porcine seminal vesicles (2 pmol per mg of protein) is comparable to the density of V2 vasopressin receptors in porcine renal medulla, suggesting a physiological role for vasopressin in the seminal vesicle.
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PMID:Identification and characterization of a vasopressin isoreceptor in porcine seminal vesicles. 294 37

Extracellular recordings were made from ninety-seven spontaneously firing cells in the paraventricular nucleus (p.v.n.) of the rat hypothalamic slice preparation. The spontaneously firing cells tested fired at 0.1-8 spikes/s but the majority showed a slow irregular firing pattern. The average firing rate of all ninety-seven cells was 2.2 +/- 0.2 spikes/s (mean +/- S.E. of mean). Six cells showed a phasic firing pattern. Following bath application of arginine-vasopressin (AVP) 10(-7) M, sixty-four (66%) of ninety-seven p.v.n. cells showed excitatory responses and three (3%) cells inhibitory responses. Bath application of oxytocin (OXT) 10(-7) M excited thirty-nine (57%) of sixty-eight p.v.n. cells and inhibited two (3%) cells. Individual p.v.n. cells responded to application of both AVP and OXT, but the magnitude and threshold of the responses varied from cell to cell. Of the sixty-six cells tested with both peptides at 10(-7) M, sixteen showed similar responses to both and fifteen showed no response to either: twenty cells showed a greater response to AVP and fifteen a greater response to OXT. Of six phasic firing cells, two showed excitatory responses to AVP and all four cells tested did not show any response to OXT. The dose-dependence of the response to AVP and OXT was tested in six p.v.n. cells. There was a direct relationship between peptide concentration and increased firing rate. The threshold concentration of the peptides ranged from 10(-8) to 10(-10) M. The cells responsive to the peptides were not located in particular areas of the p.v.n. but were diffusely distributed throughout the nucleus. After blocking synaptic transmission with a low Ca2+ and high Mg2+ medium, all tested cells (AVP, n = 15; OXT, n = 14) which had responded to applications of AVP or OXT in normal medium still showed responses to the peptides, although the effect was less marked in half the cells. However, in the absence of synaptic transmission two cells showed unimpaired responses to one of the peptides but greatly depressed responses to the other. The V1-receptor antagonist [1-(beta-mercapto-, beta-cyclopentamethylenepropionic acid)], 8-D-arginine-vasopressin (d(CH2)5DAVP) or V1/V2-receptor antagonist [1-(beta-mercapto-, beta-cyclopentamethylenepropionic acid), 2-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-TyrVAVP) completely or partly blocked the AVP-induced responses, while the V2-receptor agonist 1-deamino-8-D-arginine-vasopressin (dDAVP) did not influence the spontaneous discharges of the cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Excitation of neurones in the rat paraventricular nucleus in vitro by vasopressin and oxytocin. 300 46

The neurohypophysial hormones oxytocin (OT) and vasopressin (VP) are involved in the regulation of the contractility of the male genital tract in several animal species. We investigated the presence of specific binding sites for [3H]OT and [3H]arginine VP (AVP) in membranes prepared from tunica albuginea, epididymis, and vas deferens from prepubertal pigs 2-16 weeks of age. Membranes were incubated with [3H]OT and [3H]AVP in the presence or absence of the corresponding unlabeled peptides. Binding equilibrium was reached in 60 min at 22 C. Millimolar concentrations of Mg2+ increased the specific binding of both ligands. Analysis of families of self- and cross-displacement curves using the computer program LIGAND clearly demonstrated that two classes of binding sites were present in all tissues investigated. The first class of sites, designated the OT site, shows high affinity for OT, AVP, lysine vasopressin, arginine vasotocin, the selective OT agonists [Thr4,Gly7]OT and [Asu1,6]OT, and the OT antagonists derived from ornithine vasotocin (OVT), namely d(CH2)5Tyr(Et)OVT and dEt2OVT. The second class of sites, designated the VP site, shows high affinity for AVP, lysine vasopressin, arginine vasotocin, and the selective V1 antagonist d(CH2)5Tyr(Me)AVP. The V2 agonist [1-deamino,4-valine]8-D-AVP shows low affinity for both sites. Isotocin, desglycinamide [Arg-8]AVP and tocinoic acid were ineffective in displacing [3H]AVP or [3H]OT. The highest density of OT receptors was found in tunica albuginea and epididymis, whereas the highest density of AVP receptors was found in vas deferens. Adenylate cyclase was not activated in any of the tissues studied by concentrations of AVP or OT up to 100-fold greater than their Kd values. This is the first demonstration and pharmacological characterization of specific OT and V1 VP receptors in the tunica albuginea, epididymis, and vas deferens. The recent demonstration of high local concentration of neurohypophysial hormones in the gonads of several mammals support a physiological role of these OT and VP receptors in regulation of the motility of the male genital tract.
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PMID:Identification and characterization of two classes of receptors for oxytocin and vasopressin in porcine tunica albuginea, epididymis, and vas deferens. 302 94


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