Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the diuretics, 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) and its 4'-hydroxy derivative [DS-511(4'-OH)] on the ADH-cyclic AMP system was studied in slices of rat renal medulla. These compounds alone did not affect the basal level of cyclic AMP in the slices. Preincubation with 10(-6) mol DS-511 or 10(-7) to 10(-5) mol DS-511-(4'-OH) in the presence of theophylline, inhibited arginine vasopressin stimulated formation of cyclic AMP, but after washing the slices the formation was restored. Etacrynic acid required higher concentrations such as 10(-5) and 10(4-) mol to cause inhibition. No effect was observed with furosemide and hydrochlorothiazide in concentrations up to 10(-4) mol. DS-511(4'-OH) at concentrations higher than 10(-6) mol inhibited the activity of cyclic AMP-phosphodiesterase in the medullary homogenate. These results suggest the water diuretic action of DS-511 is partly mediated by its inhibition of the ADH-cyclic AMP system.
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PMID:Effect of the diuretic, 1,4-dimorpholino-7-phenylpyrido[3,4-d]-pyridazine (DS-511) and its derivatives on ADH-cyclic AMP system in rat renal medullary slices. 22 1

In mice with hereditary nephrogenic diabetes insipidus (NDI), the inability of vasopressin to increase hydraulic water permeability is reflected in a lack of intramembranous particle (IMP) clusters in apical membranes of inner medullary collecting ducts. The lack arises from anomalously high activity of one or two isozymes of adenosine 3',5'-cyclic monophosphate-phosphodiesterase (cAMP-PDE). We asked whether inhibition of these isozymes with rolipram and cilostamide would raise not only the tissue content of cAMP but also and simultaneously restore IMP clusters. Inner medullary collecting ducts from NDI mice were incubated in vitro. Tissue content of cAMP (fmol of cAMP per bundle) and number of IMP clusters (per 100 microns 2 of principal cell apical membrane) were, respectively: control, 44.8 +/- 13.0 and 4.16 +/- 1.49; arginine vasopressin (AVP), 31.7 +/- 8.0 and 3.98 +/- 1.56; rolipram and cilostamide, 109.7 +/- 21.0 and 58.09 +/- 15.74; and AVP plus rolipram and cilostamide, 305.7 +/- 75 and 48.63 +/- 11.03 (with the last four values showing significant difference from control and AVP only, respectively). In addition, treating NDI mice with rolipram and cilostamide in vivo reduced their high fluid turnover. We conclude that failure by AVP to increase cAMP in cells of collecting ducts, which results from anomalously high activity of one or two specific isozymes of cAMP-PDE, is the major or sole cause for the excretion of hypotonic urine in NDI mice (DI +/+ Severe strain).
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PMID:Induction of intramembranous particle clusters in mice with nephrogenic diabetes insipidus. 165 82

We investigated the tubular action of endothelin in rat nephron segments. The effects of endothelin on arginine vasopressin (AVP)-, parathyroid hormone-, glucagon-, calcitonin-, and isoproterenol-dependent cAMP accumulation were studied. The following nephron segments were microdissected: glomerulus (Gl), proximal convoluted tubule (PCT), cortical and medullary thick ascending limbs of Henle's loop (cTAL and mTAL, respectively), cortical collecting duct (CCD), outer medullary collecting duct (OMCD), and inner medullary collecting duct (IMCD). Endothelin dose dependently (10(-8)-10(-10)M) inhibited AVP-dependent cAMP accumulation in CCD, OMCD, and IMCD. This effect was independent of the presence or absence of phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, Ca channel blocker nicardipine, or indomethacin, but was abolished in the presence of protein kinase C inhibitor H-7. Protein kinase C stimulator dioctanoyl glycerol mimicked the effect of endothelin. On the other hand, endothelin had no inhibitory effect on AVP-dependent cAMP accumulation in cTAL or mTAL, parathyroid hormone-dependent cAMP accumulation in Gl and PCT, or glucagon-, calcitonin-, and isoprotereol-dependent cAMP accumulation in OMCD. We conclude that endothelin specifically inhibits AVP-dependent cAMP accumulation in CCD, OMCD, and IMCD through activating protein kinase C. This effect possibly has a role in maintaining urine volume to counteract the decrease in GFR caused by endothelin itself.
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PMID:Effects of endothelin on peptide-dependent cyclic adenosine monophosphate accumulation along the nephron segments of the rat. 169 79

The effect of exogenous prostaglandin E2 (PGE2) on hormone-dependent adenosine 3',5'-cyclic monophosphate (cAMP) accumulation was investigated by microradioimmunoassay in collecting tubules microdissected from the cortex (CCT) or outer medulla (MCT) of the rat kidney. Two phosphodiesterase inhibitors were used: either a xanthine derivative (isobutyl-methylxanthine (IBMX, 1 mM] active on all forms of phosphodiesterase or Ro 20-1724 (50 microM) active on the phosphodiesterase type III. A prostaglandin synthesis inhibitor was added to all media. In the presence of IBMX, 0.3 microM PGE2 inhibited by 39.1% the response induced in the CCT by the beta-adrenergic agonist isoproterenol (1 microM). Under the same experimental conditions, arginine vasopressin (AVP)-stimulated cAMP accumulation in CCT or MCT was not affected by PGE2. In the presence of Ro 20-1724, 0.3 microM PGE2 did not modify the response to 1 nM AVP in CCT but inhibited this response in MCT samples (mean inhibition: 52.7%). The inhibition by PGE2 was dose dependent with a maximum at 0.3 microM, observed for all concentrations of AVP tested (from 50 pM to 1 nM) and did not affect the concentration of AVP inducing half-maximal cAMP accumulation. In a second experimental series performed in the presence of adenosine deaminase, an A1-adenosine agonist [theta)-N6-(R-phenylisopropyl)adenosine (PIA, 0.1 microM] also decreased the response to 1 nM AVP in the MCT. The addition of an A1-adenosine antagonist relieved the effect of PIA but did not modify the inhibition observed with PGE2. Thus PGE2 decreased the synthesis of cAMP in beta-adrenergic sensitive cells in rat CCT and might affect the catabolism of AVP-dependent cAMP level rather than its synthesis in rat MCT.
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PMID:Two mechanisms of inhibition by prostaglandin E2 of hormone-dependent cell cAMP in the rat collecting tubule. 170 42

Administration of adenosine (Ado) into rat renal artery induces dose-dependent diuresis that is independent of changes in glomerular filtration rate or renal blood flow, suggesting a direct effect on tubule H2O reabsorption. To test the hypothesis that Ado modulates cellular action of arginine vasopressin (AVP) as a tubular mechanism for the diuretic effect of Ado, interaction of Ado with AVP was studied in primary cell culture of rat inner medullary collecting duct (IMCD) epithelium. Stimulation of cells with 10(-6) M AVP in presence of 0.1 mM Ro 20-1724, a nonmethylxanthine phosphodiesterase inhibitor that has no effect on Ado receptors, increased adenosine 3',5'-cyclic monophosphate (cAMP) levels twofold or more above baseline. Stimulation of cells with the A1 Ado-receptor agonist N6-cyclohexyladenosine (CHA), the A2-receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA), or with the P-site agonist 2',5'-dideoxyadenosine (DDA) significantly inhibited the AVP-stimulated cAMP response. Preincubation with pertussis toxin abolished the inhibitory effects of CHA and NECA, but not of DDA. The data suggest that, in the rat IMCD, Ado modulates AVP action by interfering with its ability to stimulate formation of its second messenger, cAMP. This effect is mediated by the extracellular Ado receptors A1 and A2 and by the intracellular P-site. It occurs by at least two pathways, one sensitive and the other insensitive to pertussis toxin.
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PMID:Interaction of adenosine with vasopressin in the inner medullary collecting duct. 217 61

The involvement of tissue cAMP in the vasodilating action of parathyroid hormone (PTH) was investigated. The bovine active fragment bPTH-(1-34) was used in all studies. In anesthetized dogs, theophylline, a phosphodiesterase inhibitor, potentiated the hypotensive action of bPTH-(1-34) at the dose of 1 microgram/kg. The potentiation was related to the dose of theophylline infused. In an in vitro rat tail artery helical strip assay, dibutyryl cAMP produced dose-related relaxation in arginine vasopressin (AVP) constricted blood vessels. bPTH-(1-34) also produced dose-related relaxation in the tail artery constricted by AVP. In the presence of isobutylmethylxanthine, another phosphodiesterase inhibitor, the bPTH-(1-34) dose--response curve was shifted to the left, indicating potentiation. Imidazole, which has phosphodiesterase stimulating activity, significantly decreased the in vitro vasorelaxing effect of bPTH-(1-34). In addition, bPTH-(1-34) increased significantly the rat tail artery cAMP content. b-PTH-(1-34) oxidized with hydrogen peroxide lost its vasorelaxing activity and was also ineffective in increasing the tail artery cAMP content. All these data strongly suggest that cAMP may be involved in eliciting the vasorelaxing action of bPTH-(1-34).
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PMID:Cyclic AMP and the vascular action of parathyroid hormone. 243 93

Although guanosine 3',5'-cyclic monophosphate (cGMP) is present in renal nephron segments, there is no information on the role of cGMP as a mediator of renal tubular transport events. We found that an activator of guanylate cyclase (nitroprusside) and 8-bromocGMP (8-BrcGMP) significantly increased hydraulic conductivity in rabbit and rat cortical collecting tubules (CCT) perfused in vitro. The effect of 10(-4) M 8-BrcGMP to increase CCT hydraulic conductivity was reversible and comparable in magnitude and time course to that produced by maximal concentrations of arginine vasopressin. In rabbit CCT, cGMP increased hydraulic conductivity in the presence of phosphodiesterase inhibition with methylisobutylxanthine and in the presence of supramaximal concentrations of arginine vasopressin. Neither nitroprusside nor 8-BrcGMP stimulated adenylate cyclase activity in microdissected CCT. These data demonstrate that cGMP can act independently of either stimulation of adenylate cyclase activity or inhibition of phosphodiesterase activity to increase hydraulic conductivity in the mammalian CCT.
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PMID:Cyclic guanosine monophosphate increases hydraulic conductivity in rabbit and rat CCT. 246 Oct 96

Cysts, a common abnormality of kidneys, are collections of urine-like fluid enclosed by a continuous layer of epithelial cells. Renal cysts derive from nephrons and collecting ducts and progressively enlarge as a consequence of epithelial proliferation and transepithelial fluid secretion. The initiation of cyst formation and the factors that control cyst enlargement are unknown. We used an in vitro model of renal cysts to explore the role of the cAMP signal transduction system in the formation and expansion of cysts. MDCK cells, cultured in hydrated-collagen gel, produced polarized monolayered epithelial cysts when intracellular cAMP was increased by prostaglandin E1, arginine vasopressin, cholera toxin, forskolin, or 8-bromoadenosine 3',5'-cyclic monophosphate. All agonists were potentiated by 3-isobutyl-1-methylxanthine, a nucleotide phosphodiesterase inhibitor. The cell proliferation component of cyst enlargement was accelerated by cAMP agonists, as shown by the increased growth of MDCK cells in subconfluent monolayers. The fluid secretion component, reflected by the transepithelial movement of fluid across polarized monolayers of MDCK cells grown on permeable supports, was stimulated by cAMP agonists in the basolateral medium. Chloride levels were higher in the cyst fluid and the secreted fluid than in the bathing medium. We conclude that the development of MDCK cysts is dependent on cAMP. This signal transduction system may be an important modulator of epithelial cell proliferation and transepithelial fluid secretion in the kidney.
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PMID:Renal epithelial cyst formation and enlargement in vitro: dependence on cAMP. 247 25

The effect of somatostatin on the stimulation of adenosine-3',5'-cyclic monophosphate (cAMP) production by arginine vasopressin (AVP) was examined in rat renal papillary collecting tubule cells in culture. The presence of phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine AVP at a concentration of 1 X 10(-10) M or higher significantly increased cellular cAMP levels in a dose-dependent manner. The stimulation by AVP of cellular cAMP production was significantly attenuated by 1 X 10(-6) M somatostatin (1 X 10(-9) M AVP, 477.5 +/- 23.0 vs. 292.4 +/- 28.5 fmol/micrograms protein per 10 min, P less than 0.01). When the cells were pretreated with pertussis toxin, pertussis toxin completely abolished the inhibitory effect of somatostatin on cellular cAMP production in response to AVP. Such an effect was obtained with a concentration of 0.1 ng/ml or higher of pertussis toxin and an incubation time of longer than an hour. The exposure of cells to 100 ng/ml pertussis toxin for two hours recovered the cellular cAMP response to 1 X 10(-9) M AVP in the presence of 1 X 10(-6) M somatostatin, the value of which 527.1 +/- 32.6 fmol/micrograms protein per 10 minutes, was a comparable level to that in response to only 1 X 10(-9) M AVP. Also, somatostatin inhibited the cellular cAMP response to glucagon and cholera toxin, but did not inhibit basal and forskolin-stimulated cAMP levels. Pertussis toxin treatment of cells completely abolished these inhibitory effects of somatostatin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reversal of somatostatin inhibition of AVP-induced cAMP by pertussis toxin. 289 65

The involvement of calmodulin in the secretion of beta-endorphin from the mouse anterior pituitary tumor cell line, AtT-20, was investigated. The calmodulin inhibitor W7 potentiated secretion produced by 8-BrcAMP, and induced a secretory response to arginine vasopressin, which did not elevate beta-endorphin levels when added alone. Release of hormone in response to CRF was not affected. Calmodulin phosphodiesterase inhibitor 8-MeOMeMIX produced a dose-dependent increase in 8-BrcAMP stimulation, suggesting that inhibition of cAMP degradation is the mechanism of enhancement of 8-BrcAMP-induced secretion in the presence of W7.
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PMID:Modulation of beta-endorphin secretion from mouse pituitary tumor cells by calmodulin inhibitor W7. 296 20


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