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)

Stimulation of quiescent human fibroblasts with the peptide mitogen bradykinin (BK) led to a biphasic elevation in cellular 1,2-diacylglycerol (DAG), as estimated by either measurement of total DAG mass or [3H]arachidonate incorporation. A rapid initial transient that peaked 15 s after BK addition was followed by a decline to near basal levels then a second rise to a plateau phase during which DAG levels remained elevated for less than or equal to 45 min. The source of the initial DAG transient appeared to be primarily polyphosphoinositides as these phospholipids were rapidly hydrolyzed after BK addition. This transient correlates well temporally with previous observations of the kinetics of inositol trisphosphate accumulation and intracellular free [Ca2+] observed in the same cells. Cultures preincubated with [3H]myristic acid incorporated label predominantly into the phosphatidylcholine (PC) pool. Subsequent addition of BK under these conditions caused only a relatively slow accumulation of [3H]DAG to a plateau level, without an initial transient. Together with the observation that PC was found to decrease upon BK stimulation, these observations suggest that the late phase of DAG accumulation may involve breakdown of other phospholipids including PC. To investigate the consequences of DAG elevation we examined the phosphorylation of an acidic 80 kDa protein, whose phosphorylation is solely dependent on the activation of protein kinase C (PK-C). The 80 kDa fibroblast protein could be immunoprecipitated by an antibody to bovine brain "myristoylated and alanine-rich C-kinase substrate" (MARCKS) and phosphopeptide maps of brain and fibroblast MARCKS were similar. Stimulation of [32P]-prelabeled fibroblasts with serum, BK, vasopressin, or 12-O-tetradecanoyl phorbol acetate, but not epidermal growth factor or calcium ionophores, resulted in the rapid phosphorylation of MARCKS. With BK or serum this phosphorylation showed an initial transient peak at less than 1 min then rose again to a plateau level that was sustained for less than or equal to 45 min. Removal of BK resulted in a rapid decline in MARCKS phosphorylation. These studies show that the biphasic DAG signal in BK-stimulated human fibroblasts correlates well with the state of activation of PK-C. However, the persistent activation of PK-C does not appear to require continued high levels of Ca2+.
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PMID:Transduction of the bradykinin response in human fibroblasts: prolonged elevation of diacylglycerol level and its correlation with protein kinase C activation. 190 4

In A7r5 vascular smooth muscle cultures basal Ca2+ influx was higher in growing versus quiescent cells (P less than 0.05), due primarily to a five-fold increase in dihydropyridine-inhibitable Ca2+ influx (P less than 0.005). Verapamil decreased [3H]thymidine incorporation in a concentration dependent fashion with a significant 6 +/- 2% inhibition at 0.1 microM and a maximal inhibition of 67 +/- 2% at 100 microM. Similarly, nitrendipine inhibited fetal calf serum-stimulated [3H]thymidine incorporation with a threshold concentration of 1 nM and a maximal inhibition of 79 +/- 12% at 10 microM. In quiescent cells, verapamil (10 microM) inhibited the increases in [3H]thymidine incorporation stimulated by fetal calf serum, serotonin, vasopressin or 12-0-tetradecanoyl phorbol-13-acetate by 37-43% (P less than 0.001 vs. control for all). Finally, verapamil (100 microM) and nitrendipine (10 microM) inhibited proliferation by 39 +/- 10 and 20 +/- 6%, respectively (P less than 0.01 and 0.02 vs. control, respectively). Thus in A7r5 cells, proliferation is associated with increased Ca2+ influx via dihydropyridine-sensitive Ca2+ channels and organic Ca2+ channel antagonists inhibit DNA synthesis and cell proliferation.
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PMID:Calcium influx modulates DNA synthesis and proliferation in A7r5 vascular smooth muscle cells. 191 88

Some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), were characterized to be very weak but selective nonpeptide angiotensin II (Ang II) receptor antagonists with a competitive mode of action. Chemical modifications of these led to EXP6155 and EXP6803, which showed approximately 10- and 100-fold higher affinity, respectively, but were orally ineffective. Oral activity was obtained for the biphenyl carboxylic acid derivatives EXP7711 and especially EXP9654. A further advance in the design of nonpeptide Ang II receptor antagonists was provided by DuP 753, an analogue of EXP7711 in which the carboxylic acid function is replaced by its tetrazol-5-yl equivalent. DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bi phe nyl-4- yl)methyl]imidazole, potassium salt) displaces radiolabeled Ang II from its specific binding sites in various tissues, affording IC50 values of approximately 20 nM. DuP 753 competitively antagonizes Ang II-induced responses in various in vitro and in vivo preparations but does not influence those to KCl, norepinephrine, vasopressin, and others, nor does it affect converting enzyme and renin. In high renin animal models of elevated arterial blood pressure, intravenous and oral administrations of DuP 753 produce a sustained decrease in pressure without influencing heart rate. Marked antihypertensive effects are observed in spontaneously hypertensive rats, but no efficacy is noticed in deoxycorticosterone acetate hypertensive animals. DuP 753 showed no agonistic properties in any of the above test systems and has been chosen to undergo clinical trials for the treatment of hypertension. In rats, the 5-carboxylic acid (EXP3174) represents a major metabolite of DuP 753.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II receptor antagonists. From discovery to antihypertensive drugs. 193 77

The model of "chemical hypoxia" with KCN plus iodoacetic acid mimics the ATP depletion and reductive stress of hypoxia. Here, we examined the effects of chemical hypoxia on cytosolic free Na+ and Ca2+ in single cultured rat hepatocytes by multiparameter digitized video microscopy and ratio imaging of sodium-binding furan indicator (SBFI) and Fura-2. Intracellular Na+ increased from about 10 mM to more than 100 mM after 20 min of chemical hypoxia, whereas cytosolic free Ca2+ remained virtually unchanged. In normoxic hepatocytes, phenylephrine (50 microM) and Arg-vasopressin (20-40 nM) induced Ca2+ oscillations in 70 and 40% of cells, respectively. These Ca2+ oscillations were suppressed after one spike following the onset of chemical hypoxia. Phenylephrine and vasopressin also increased inositol phosphate formation by 22 and 147%, respectively. This effect was suppressed by KCN plus iodoacetate. Intracellular acidosis is characteristic of chemical hypoxia. Intracellular acidosis induced by 40 mM Na-acetate suppressed Ca2+ oscillations but did not inhibit hormone-induced inositol phosphate formation. Cytosolic alkalinization also suppressed Ca2+ oscillations. However, prevention of intracellular acidosis with monensin (10 microM) did not prevent suppression of Ca2+ oscillations during chemical hypoxia. Mitochondrial depolarization with uncoupler did not change free Ca2+ levels during chemical hypoxia, indicating that mitochondria do not regulate free Ca2+ during chemical hypoxia. From these results, we conclude: 1) chemical hypoxia does not block Na+ influx across the plasma membrane; 2) Chemical hypoxia inhibits hormone-stimulated Ca2+ flux pathways across cellular membranes by two different mechanisms: (a) by ATP depletion, which disrupts hormone-myo-inositol 1,4,5-triphosphate coupling, and (b) by intracellular acidosis, which inhibits myo-inositol 1,4,5-triphosphate-stimulated Ca2+ release from intracellular stores; 3) during ATP depletion by chemical hypoxia, mitochondria do not take up Ca2+ to maintain cytosolic free Ca2+ at low concentrations.
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PMID:Suppression of Ca2+ oscillations in cultured rat hepatocytes by chemical hypoxia. 193 69

To gain insight into the mechanisms that could account for the augmentation of cellular reactivity in primary hypertension, we have examined some of the biochemical events which are implicated in the transmission of mitogenic signal as well as in cell reactivity. This study focussed on phospholipase C, protein kinase C and GTP-binding proteins (G-proteins), in response to thrombin or arginin-vasopressin (AVP). Cultured fibroblasts prepared from the adventitia of thoracic aorta of spontaneously hypertensive rat (SHR) were used as cell models and were compared with fibroblasts prepared from controls Wistar-Kyoto (WKY) rats. The mitogenicity of each agonist was estimated by measuring the incorporation of 3H-thymidine into the newly synthesized DNA. The agonist-induced phospholipase C activity was evaluated by measuring the production of 3H-inositol phosphates in cells prelabeled with 3H-inositol. The influence of protein kinase C and that of G proteins on the mitogenesis in cells stimulated by thrombin or AVP was determined by pretreating cells with phorbol 12-myristate, 13-acetate (TPA) and pertussis toxin, respectively. Kinetics and dose response studies have demonstrated that in response to thrombin and AVP, the phospholipase C activity and the incorporation of 3H-thymidine were significantly higher in the fibroblasts derived from SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Activation mechanisms by thrombin and vasopressin of fibroblasts in spontaneously hypertensive rats]. 195 75

Osmotic water permeability (Pf) in toad bladder is regulated by the vasopressin (VP)-dependent movement of vesicles containing water channels between the cytoplasm and apical membrane of granular cells. Apical endosomes formed in the presence of serosal VP have the highest Pf of any biological or artificial membrane (Shi and Verkman. 1989. J. Gen. Physiol. 94:1101-1115). We examine here: (a) the influence of protein kinase A and C effectors on transepithelial Pf (Pfte) in intact bladders and on the number and Pf of labeled endosomes, and (b) whether endosome Pf can be modified physically or biochemically. In paired hemibladder studies, Pfte induced by maximal serosal VP (50 mU/ml, 0.03 cm/s) was not different than that induced by 8-Br-cAMP (1 mM), forskolin (50 microM), VP + 8-Br-cAMP, or VP + forskolin. Pf was measured in endosomes labeled in intact bladders with carboxyfluorescein by a stopped-flow, fluorescence-quenching assay using an isolated microsomal suspension; the number and Pf (0.08-0.11 cm/s, 18 degrees C) of labeled endosomes was not different in bladders treated with VP, forskolin, and 8-Br-cAMP. Protein kinase C activation by 1 microM mucosal phorbol myristate acetate (PMA) induced submaximal bladder Pfte (0.015 cm/s) and endosome Pf (0.022 cm/s) in the absence of VP, but had little effect on maximal Pfte and endosome Pf induced by VP. However, PMA increased by threefold the number of apical endosomes with high Pf formed in response to serosal VP. Pf of endosomes containing the VP-sensitive water channel decreased fourfold by increasing membrane fluidity with hexanol or chloroform (0-75 mM); Pf of phosphatidylcholine liposomes (0.002 cm/s) increased 2.5-fold under the same conditions. Endosome Pf was mildly pH dependent, strongly inhibited by HgCl2, but not significantly altered by GTP gamma S, Ca, ATP + protein kinase A, and phosphatase action. We conclude that: (a) water channels cycled in endocytic vesicles are functional and not subject to physiological regulation, (b) VP and forskolin do not have cAMP-independent cellular actions, (c) activation of protein kinase C stimulates trafficking of water channels, but does not increase the number of apical membrane water channels induced by maximal VP, and (d) water channel function is sensitive to membrane fluidity. By using VP and PMA together, large quantities of endosomes containing the VP-sensitive water channel are labeled with fluid-phase endocytic markers.
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PMID:Regulation of the formation and water permeability of endosomes from toad bladder granular cells. 197 9

Phorbol ester-induced translocation of the calcium/phospholipid-dependent protein kinase, protein kinase C (PKC), from soluble to particulate cell fractions was inhibited in primary cultures of hepatocytes isolated from rats chronically exposed to the liver tumor promoter phenobarbital (PB). Inhibition of translocation (34%) was significant after a 15-min treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA, 500 nM); an 85% inhibition was observed after 60 min. In contrast, the translocation responses to two non-phorbol ester activators of PKC, ATP (1 mM) and arginine-vasopressin (0.1 microM), were not significantly impaired. Assessment of total PKC specific activity revealed that translocation induced by TPA and the two nonphorbol activators was not associated with PKC degradation in hepatocytes from either control or PB-exposed rats. The defect in TPA-induced translocation was correlated with an impaired down-regulation of the hepatocyte surface receptor for epidermal growth factor in hepatocytes from PB-exposed rats. Chronic exposure to PB did not affect the total content or specific activity of PKC in whole liver, nor did it affect the distribution of PKC activity between soluble and particulate fractions in unstimulated liver or hepatocytes. However, both the diminished epidermal growth factor receptor response and the inhibition of TPA-induced PKC translocation were reversed by withdrawal of PB for 2 to 4 weeks. Hepatocytes isolated from female rats were found to contain a 3- to 4-fold greater PKC specific activity and content than hepatocytes from male rats. However, no sex-related differences were observed in PKC distribution or in the modulation of translocation by chronic PB exposure and withdrawal. Immunoblotting of partially purified liver extracts revealed that the defect in phorbol ester-induced translocation was not caused by altered expression of PKC isozymes. PKC isozymes II and III, but not I, were detected, and their amounts were unaffected by PB exposure, although higher levels were detected in female relative to male livers. These data demonstrate reversible inhibition of phorbol ester-induced PKC activation by the liver tumor promoter, PB, and suggest that PB alters a component of the PKC-signaling pathway other than the expression of PKC isozymes.
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PMID:Reversible and phorbol ester-specific defect of protein kinase C translocation in hepatocytes isolated from phenobarbital-treated rats. 198 78

The mechanism by which extracellular ATP stimulates insulin secretion was investigated in RINm5F cells. ATP depolarized the cells as demonstrated both by using the patch-clamp technique and a fluorescent probe. The depolarization is due to closure of ATP-sensitive K+ channels as shown directly in outside-out membrane patches. ATP also raised cytosolic Ca2+ [( Ca2+]i). At the single cell level the latency of the [Ca2+]i response was inversely related to ATP concentration. The [Ca2+]i rise is due both to inositol trisphosphate mediated Ca2+ mobilization and to Ca2+ influx. The former component, as well as inositol trisphosphate generation, were inhibited by phorbol myristate acetate which uncouples agonist receptors from phospholipase C. This manoeuvre did not block Ca2+ influx or membrane depolarization. Diazoxide, which opens ATP-sensitive K+ channels, attenuated membrane depolarization and part of the Ca2+ influx stimulated by ATP. However, the main Ca2+ influx component was unaffected by L-type channel blockers, suggesting the activation of other Ca2+ conductance pathways. ATP increased the rate of insulin secretion by more than 12-fold but the effect was transient. Prolonged exposure to EGTA dissociated the [Ca2+]i rise from ATP-induced insulin secretion, since the former was abolished and the latter only decreased by about 60%. In contrast, vasopressin-evoked insulin secretion was more sensitive to Ca2+ removal than the accompanying [Ca2+]i rise. Inhibition of phospholipase C stimulation by phorbol myristate acetate abrogated vasopressin but only reduced ATP-induced insulin secretion by 34%. These results suggest that ATP stimulates insulin release by both phospholipase C dependent and distinct mechanisms. The Ca2+)-independent component of insulin secretion points to a direct triggering of exocytosis by ATP.
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PMID:Extracellular ATP causes Ca2(+)-dependent and -independent insulin secretion in RINm5F cells. Phospholipase C mediates Ca2+ mobilization but not Ca2+ influx and membrane depolarization. 199 9

The stimulated hydrolysis of inositol lipids and phosphatidylcholine (PtdCho) by bombesin, [Arg8]vasopressin ([Arg8]Vp) and prostaglandin F2 alpha (PGF2 alpha) was analysed in Swiss 3T3 cells pre-labelled to isotopic equilibrium with either [methyl-3H]choline, myo-[2-3H]inositol or [9,10 (n)-3H]palmitic acid. All three agonists activated the phospholipase D-catalysed hydrolysis of PtdCho as determined by the release of [3H]choline (Cho) and the formation of [3H]phosphatidylbutanol (PtdBut). The release of [3H]choline by each agonist exhibited similar sensitivity to prolonged pre-exposure to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). The release of [3H]choline exhibited the same dose dependency as the production of total inositol phosphates for each mitogen suggesting that the two responses might be mediated through identical receptors. Acute pre-treatment with TPA allowed the dissociation of inositol lipid hydrolysis from PtdCho breakdown, since it inhibited inositol phosphate accumulation but stimulated choline generation. The loss of mitogen stimulated choline release in cells pre-treated with the phorbol ester for 48 h was not due to loss of stimulated inositol phosphate production which was reproducibly enhanced in these 'down-regulated' cells.
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PMID:Hydrolysis of phosphatidylcholine by phospholipase D is a common response to mitogens which stimulate inositol lipid hydrolysis in Swiss 3T3 fibroblasts. 201 90

We have examined the effect of bradykinin (BK) and other peptide mediators with related cellular actions on tyrosine phosphorylation in confluent Swiss 3T3 fibroblast cells using an anti-phosphotyrosine antibody. Immunoblots of extracts from cells stimulated with BK showed a major heterogeneous band centered at Mr 120,000. Three phosphorylated protein species were present within this band. The lower of these three phosphoproteins was occasionally present under basal conditions. The detection of this group of phosphoproteins by the antibody was prevented by coincubation with an excess of phosphotyrosine but not with an excess of phosphoserine or phosphothreonine. The BK-promoted increase in phosphorylation was rapid and transient with the peak response apparent following BK exposure for 1 min. The response was dose-dependent with half-maximal effect occurring at 10-30 nM BK. The antagonist Arg0, Hyp3, Thi5,8, D-Phe7-BK completely inhibited the response indicating that BK was acting via a B2 kinin receptor. Bombesin, at 0.1 microM, stimulated an increase in phosphorylation of the 120-kDa group of proteins with the same efficacy as 0.1 microM BK. On the other hand, 1 microM vasopressin was considerably less efficaceous than either of the former agonists. Short-term preexposure to 0.1 microM 12-O-tetradecanoyl-phorbol-13-acetate (1 min), a protein kinase C stimulator, or 30 microM H7 (15 min), a protein kinase C inhibitor, had no significant effect either on the basal or BK-promoted increase in tyrosine phosphorylation of these proteins. BK also stimulated inositol phosphate formation in these cells. Genistein, a tyrosine kinase inhibitor, inhibited BK stimulation of tyrosine phosphorylation. In addition, genistein partially inhibited BK stimulation of inositol phosphate formation. These results show that an increase in tyrosine phosphorylation of a 120-kDa group of proteins is an early protein kinase C-independent cellular signal elicited by both bradykinin and bombesin.
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PMID:Bradykinin and bombesin rapidly stimulate tyrosine phosphorylation of a 120-kDa group of proteins in Swiss 3T3 cells. 201 98


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