Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The thromboxane A2 (TP)-receptor blocking activity and specificity of action of GR32191 ([1R-[1 alpha(Z),2 beta,3 beta,5 alpha]]-(+)-7-[5-([1,1'-biphenyl] -4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptoni c acid has been evaluated in human platelets and various smooth muscle preparations, both vascular and non-vascular, from a range of species including man. 2. Utilising a platelet counting method to assess aggregation the drug was found to antagonise, in a surmountable manner, human platelet aggregation produced by the TP-receptor agonists, U-46619, EP171 and SQ26655, in whole blood and physiological buffer, with pA2 values of approximately 8.3 and 8.7 in the two media respectively. In the presence of GR32191 the rate of aggregation induced by U-46619 was slowed. 3. The effect of GR32191 upon U-46619-induced platelet shape change and aggregation in platelet-rich plasma was evaluated utilising a turbidometric technique. Both shape change and aggregation were antagonised by GR32191. At relatively high concentrations of the drug a slowing of aggregation and shape change to U-44619 was seen and an unsurmountable antagonism became apparent. 4. The action of GR32191 upon human platelets was specific with platelet aggregation induced by adenosine 5'-diphosphate, platelet activating factor, vasopressin and adrenaline and the inhibitory effects of prostacylin (PGI2), prostaglandin D2 (PGD2) and N-ethylcarboxamide-adenosine (NECA) being unaffected by concentrations of the drug as high as 10 microM. Furthermore, at concentrations of up to 100 microM, the drug itself produced no shape change or aggregation, of human platelets. 5. GR32191 also specifically and potently antagonised in a competitive, surmountable manner the contractile actions of U-46619 upon human vascular smooth muscle and antagonised U-46619-induced contractions of vascular and airways smooth muscle preparations from rat, dog, guinea-pig and rabbit with varying potency. This is discussed in terms of possible heterogeneity of TP-receptors. 6. GR32191 therefore represents a highly potent and specific TP-receptor blocking drug. This profile of action, coupled to its long duration of effect in man described elsewhere, make it an ideal drug tool for elucidating the physiological and pathophysiological role of thromboxane A2.
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PMID:GR32191, a highly potent and specific thromboxane A2 receptor blocking drug on platelets and vascular and airways smooth muscle in vitro. 252 74

The present study investigates the effect of angiotensin II and LR-B/081 (-methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetra-zol-5-yl) [1,1'-biphenyl]-4-yl] methyl]-1(6H)-pyrimidinyl] methyl]-3-thiophenecarboxylate), a novel non-peptide angiotensin II receptor antagonist, on both early and late responses in rat vascular smooth muscle cells. Angiotensin II induced a rapid and transient elevation of inositol trisphosphate intracellular levels, triggered the release of both prostaglandin E2 and prostaglandin I2 (EC50 = 21 +/- 3 and 16 +/- 2 nM, respectively), and, in long-term studies, increased leucine and thymidine incorporation. All angiotensin II effects were antagonized by LR-B/081 and losartan, the reference non-peptide angiotensin AT1-selective receptor antagonist, whereas they were unaffected by PD123177 (1-(4-amino-3-methylphenyl)methyl-5-diphenylacetyl-4,5,6,7-tetr ahy dro-1H- imidazo[4,5-c]pyridine carboxylic acid), a non-peptide angiotensin AT2-selective receptor antagonist. LR-B/081 displayed a much higher potency than losartan in inhibiting angiotensin II-induced prostaglandin E2 (IC50 = 0.15 +/- 0.02 and 39 +/- 9 nM, respectively) and prostaglandin I2 release (IC50 = 0.18 +/- 0.04 and 134 +/- 40 nM, respectively) and was also more potent in blocking the increase in protein synthesis (IC50 = 242 +/- 119 nM and 1221 +/- 687 nM, respectively). Moreover, LR-B/081 and losartan blocked the response to angiotensin III but failed to inhibit the prostaglandin release stimulated by vasopressin or the mitogenic effect of serum. LR-B/081 and losartan were devoid of intrinsic properties in the experimental conditions employed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II-induced responses in vascular smooth muscle cells: inhibition by non-peptide receptor antagonists. 856 96

We have characterized a specific binding site for angiotensin IV on bovine aortic endothelial cell membranes. Pseudo-equilibrium studies at 37 degrees C for 2 h have shown that this binding site recognizes angiotensin IV with a high affinity (Kd = 0.71; average of two experiments that yielded values of 0.71 and 0.72 nM). The binding site is saturable and relatively abundant with a maximal binding capacity of 0.59 pmol/mg protein (average of two experiments that yielded values of 0.39 and 0.78 pmol/mg of protein). Non-equilibrium kinetic analyses at 37 degree C revealed a calculated Kd of 59 pM (average of two experiments that yielded values of 67 and 50 pM). The binding site displays a high affinity for angiotensin receptors AT1 or AT2. An analysis of specificity showed that the binding site displays a high affinity for angiotensin IV, low affinities for angiotensin II, [Sar1, Val5, Ala8]angiotensin II and does not recognize L-158,809 (5,7-dimethyl-2-ethyl-3-[(2'-(1 H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl)methyl]-3H-imidazo[4, 5-beta]pyridine H2O) and PD 123319 (1-[4-dimethylamino)3-methylphenyl]methyl-5-(diphenylacetyl) 4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridine-6-carboxylic acid). A few unrelated hormones (bradykinin, [Arg8] vasopressin, endothelin-1, atrial natriuretic factor, isoproterenol and adrenocorticotropic hormone) were unable to inhibit any 125I-angiotensin IV binding. The affinities of different structural analogues of angiotensin IV revealed that the N-terminal position is critical for receptor recognition and the C-terminal proline is also important. GTP gamma S and polyvinyl sulfate did not affect the binding, suggesting that the receptor is not coupled to a G-protein. The divalent cations Mg2+ and Ca2+ were shown to diminish the binding of 125I-angiotensin IV. Cross-linking of 125I-angiotensin IV to bovine aortic endothelial cell membranes in the presence of disuccinimidyl suberate, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a major band of 186 +/- 12 kDa. The presence in high concentration of this angiotensin binding site on aortic endothelial cells suggest the existence of a novel mechanism involved in the control of vascular tone or vascular permeability.
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PMID:Characterization of a binding site for angiotensin IV on bovine aortic endothelial cells. 856 70

The pharmacological profile of a novel selective vasopressin V2 receptor antagonist, VP-343(N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[ 1,2-a]quinoxalin-5(1H)-yl]carbonyl]phenyl]-4'-methyl[1,1'-biphenyl ]-2-carboxamide) was characterized in several in vitro and in vivo rat models. The IC50 values of VP-343 for vasopressin V1A and V2 receptors were 110 and 0.77 nM, respectively. VP-343 inhibited dose-dependently the pressor response to exogenous arginine vasopressin (AVP; 30 mU/kg, i.v.) in pithed rats, with an ID50 value of 0.57 mg/kg (i.v.). VP-343 induced strong aquaresis in normal saline-loaded conscious rats. Antidiuretic activities of VP-343 have not been detected in AVP deficient Brattleboro rats, showing its lack AVP V2 agonistic activity. During repeated administration for 21 d (3 mg/kg, p.o.) and after recovery, the aquaretic action of VP-343 still remained. In the aged (17 month) saline-loaded conscious rats study, VP-343 (3 mg/kg, p.o.) exhibited remarkable diuretic action. In a single dose oral toxicity study in mice, VP-343 did not produce any clinical signs and mortality at any of the tested doses. The results indicate that VP-343 is a potent, orally active, selective V2 receptor antagonist, suggesting that it can be expected to be useful as an aquaretic drug.
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PMID:Pharmacological profile of VP-343, a novel selective vasopressin V2 receptor antagonist, in rats. 1070 81

The aim of this work is to investigate the therapeutic efficacy of VP-343 ((N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a]qunoxalin-5(1H)-yl]phenyl]-4'-methyl[1,1'-biphenyl]-2-carboxamide), a selective vasopressin V2 receptor antagonist, using the experimental SIADH (syndrome of inappropriate secretion of antidiuretic hormone) rat model. In the model, which was accomplished by administering continuously 1-desamino-8-D-arginine vasopressin (DDAVP), serum sodium levels (S(Na)) and serum osmolarity levels (S(Osm)) significantly and remarkably decreased, which was accompanied with hyper-osmolarity of urine and oliguria. VP-343 increased rapidly and dose-dependently S(Na) and S(Osm). VP-343 exhibited marked diuretic action and decreased urine osmolarity dose-dependently. In the SIADH rat model, all serum levels of chloride, calcium, creatinine, total cholesterol, and uric acid decreased when compared with normal levels. VP-343 increased all serum levels of chloride, calcium, and total cholesterol. These results indicate that VP-343 has efficacy to normalize the abnormalities in DDAVP-induced SIADH.
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PMID:The therapeutic efficacy of VP-343, a selective vasopressin V2 receptor antagonist, in the experimental SIADH rat model. 1108 60

The aim of this work was to investigate histopathologically the relationship between the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and kidney abnormalities and the therapeutic efficacy of VP-343 ((N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-alqunoxalin-5(1H)-yl]phenyl]-4'-methyl[1,1'-biphenyl]-2-carboxamide], a selective vasopressin V2 receptor antagonist, in an experimental SIADH rat model. In the model, which was prepared by continuously administering 1-desamino-8-D-arginine vasopressin (DDAVP), histopathologic abnormalities, such as dilatation of tubules, basophilic changes in tubules, inflammatory cell infiltration, and mineralization were found in the kidney, accompanied by significant increases in the relative weight of the kidney, lung, liver, adrenal gland, and heart. VP-343 was shown to be effective in protecting the kidney from the histopathologic abnormalities and to normalize the relative weight of the kidney and several common pathophysiologic features, such as hyponatremia, hyposmolarity of plasma, hyperosmolarity of urea, and oligurea, as described previously. These results demonstrate the occurrence of histopathologic abnormalities in the kidney and the efficacy of VP-343 in improving abnormalities in the DDAVP-induced SIADH rat model.
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PMID:Histopathological study of kidney abnormalities in an experimental SIADH rat model and its application to the evaluation of the pharmacologic profile of VP-343, a selective vasopressin V2 receptor antagonist. 1151 Apr 81

We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1). We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Compound 1 competitively inhibits binding of [3H]oxytocin and the peptide antagonist 125I-ornithine vasotocin analog to human and rat oxytocin receptor expressed in human embryonic kidney 293-EBNA or Chinese hamster ovary cells with nanomolar potency. Selectivity against vasopressin receptor subtypes is >6-fold for V1a and >350-fold for V2 and V1b. Compound 1 inhibits oxytocin-evoked intracellular Ca2+ mobilization (IC50 = 8 nM). Compound 1 has no intrinsic agonist activity at the oxytocin receptor. Oxytocininduced contraction of isolated rat uterine strips is blocked by compound 1 (pA2 = 7.82). In anesthetized nonpregnant rats, single administration of compound 1 by i.v. or oral routes causes dose-dependent inhibition of contractions elicited by repeated injections of oxytocin with ED50 = 3.5 mg/kg i.v. and 89 mg/kg p.o., respectively. Compound 1 significantly inhibits spontaneous uterine contractions in pregnant rats near term when administered intravenously or orally. We conclude that compound 1 is a potent, selective, and orally active nonpeptide oxytocin receptor antagonist, which is a suitable candidate for evaluation as a potential tocolytic agent for the management of preterm labor.
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PMID:Pharmacology of (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a new potent and selective nonpeptide antagonist of the oxytocin receptor. 1266 Mar 15