Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

1. The ouabain-insensitive Na efflux in barnacle muscle fibres is promptly stimulated by injection of cyclic GMP. The minimal effective injected concentration is found to be about 10(-7) M. This effect of cyclic GMP could not be mimicked by injecting 5'-GMP. 2. External application of ouabain (10(-4) M) to fibres not pretreated with ouabain during the stimulatory response to cyclic GMP causes some inhibition of the Na efflux indicating that cyclic GMP does not cause appreciable inhibition of the Na:K pump. 3. The magnitude of the stimulatory response to injected cyclic GMP depends on the external Ca2+ concentration, as well as pHe but not on the Na+, K+ or Mg2+ concentration. It also depends on pHi, since acidification of HCO3-containing ASW leads to a greater enhancement of the response to cyclic GMP than is observed with acidified HERPES-ASW. 4. Stabilization of myoplasmic pCa by injecting 100 mM-EGTA before or after cyclic GMP fails to alter the magnitude of the response to the nucleotide. Enrichment of the fibre with Mg2+ at the time of injection of cyclic GMP leads to a reduced response. No change in response, however, is seen when the internal free Mg concentration is suddenly reduced by injecting 0.05 M-pyrophosphate with cyclic GMP. 5. Injection of cyclic GMP-dependent protein kinase stimulatory modulator before cyclic GMP fails to enhance the response to the nucleotide. The same is true of the phosphodiesterase inhibitor protein. However pre-injection of 10(-2) M-papaverine enhances the response to a subsequent injection of 10(-3) M-cyclic GMP. 6. Injection of pure protein kinase inhibitor (1.6 x 10(-4) M) before 10(-3) M-cyclic GMP reduces the response to the nucleotide. 7. The argument is put forward that injected cyclic GMP stimulates the ouabain-insensitive Na efflux mainly by activating cyclic AMP-protein kinase rather than cyclic GMP-proton kinase.
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PMID:Stimulation by cyclic GMP of sodium efflux in barnacle muscle fibres. 4 Oct 90

The addition of caffeine caused the accumulation of a new nucleotide compound simultaneously with the rigid inhibition of ribofalvin production in non-growing cells of Eremothecium ashbyii. In the present study we tried to identify the structure of the nucleotide compound using non-growing cells of the mold. 1) It became possible to obtain a large amount of mycelia by masscultivation in a reagent tank. 2) A new nucleotide compound, referred to as compound A in the paper, was extracted with perchloric acid solution and purified by the following subsequent procedures: 1) Dowex 1 x 2 (HCOO-) column, 2) charcoal treatment, 3) DEAE-Sephadex A25 (CI-) column, 4) Dowex 1 x 2 (C1-) column, and 5) DEAE-Sephadex A25 (HCO3-) column. 3) The structure of the new nucleotide compound was proved to be guanine ribonucleotidyl-(3'-5')-adenosine (GpA) from the results of the following analyses: 1) alkaline degradation, 2) UV-spectra, IR-spectra and NMR-spectra, and 3) enzymatic treatments with RNase T2 and phosphodiesterase. 4) The roles of caffeine and guanine ribonucleotidyl-(3'-5')-adenosine in connection with flavinogenesis of this mold were discussed.
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PMID:Formation of guanine ribonucleotidyl-(3'-5')-adenosine in a flavinogenic strain of Eremothecium ashbyii. 18 40

Enhanced cellular cAMP levels have been shown to increase apical membrane Cl- and HCO3- conductances in epithelia. We found that the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX) increases cAMP levels in Necturus gallbladder. We used conventional open-tip and double-barreled Cl- -selective microelectrodes to study the effects of IBMX on membrane conductances and intracellular Cl- activities in gallbladders mounted in a divided chamber and bathed with Ringer's solutions at 23 degrees C and pH 7.4. In HCO3- -free media, 0.1 mM IBMX added to the mucosal medium depolarized the apical membrane potential Va, decreased the fractional resistance FR, and significantly reduced intracellular Cl- activity (aCli). Under control conditions, aCli was above the value corresponding to passive distribution across the apical cell membrane. In media containing 25 mM HCO3-, IBMX caused a small transient hyperpolarization of Va followed by a depolarization not significantly different from that observed in HCO3- -free Ringer's. Removal of mucosal Cl-, Na+ or Ca2+ did not affect the IBMX-induced depolarization in Va. The basolateral membrane of Necturus gallbladder is highly K+ permeable. Increasing serosal K+ from 2.5 to 80 mM, depolarized Va. Mucosal IBMX significantly reduced this depolarization. Addition of 10 mM Ba2+, a K+ channel blocker, to the serosal medium depolarized Va and, essentially, blocked the depolarization induced by IBMX. These results indicate that mucosal IBMX increases apical HCO3- conductance and decreases basolateral K+ conductance in gallbladder epithelial cells via a cAMP-dependent mechanism. The latter effect, not previously reported in epithelial tissues, appears to be the major determinant of the IBMX-induced depolarization of Va.
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PMID:Cyclic AMP-induced changes in membrane conductance of Necturus gallbladder epithelial cells. 241 28

The calcium ionophore A23187 stimulates luminal alkalinization and inhibits Cl- absorption in short-circuited urinary bladders of postprandial or alkalotic turtles. The ionophore appears to mimic the action of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) by its similar effects on HCO3- secretion and Cl- absorption and by increasing cytosolic cAMP levels of isolated bladder epithelial cells. However, only A23187 (or ionomycin), but not IMBX or cAMP, elevated cytosolic Ca2+ of aequorin- or quin2-loaded cells. Since A23187, but not IBMX or cAMP inhibits luminal acidification, we postulate that cytosolic Ca2+ regulates the acidification process by a cAMP-independent mechanism and controls HCO3- secretion as well as Cl- absorption, at least in part, via cAMP-mediated pathways.
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PMID:Calcium ionophore-induced changes in HCO3- secretion and Cl- absorption in turtle bladder: relation to action of 3-isobutyl-1-methylxanthine. 243 20

Intracellular microelectrode techniques were employed to study the effect of cyclic AMP on apical membrane Cl-/HCO3- exchange and electrodiffusive HCO3- transport in Necturus gallbladder epithelium. Intracellular cAMP levels were raised by addition of either the phosphodiesterase inhibitor theophylline (3 X 10(-3) M) or the adenylate cyclase activator forskolin (10(-5) M) to the serosal bathing solution. Measurements of pH in a poorly buffered control mucosal solution upon stopping superfusion show acidification, owing to secretion of both H+ and HCO3-. When the same experiment is performed after addition of amiloride or removal of Na+ from the mucosal bathing medium, alkalinization is observed since H+ transport is either inhibited or reversed, whereas HCO3- secretion persists. The changes in pH in both amiloride or Na-free medium were significantly decreased in theophylline-treated tissues. Theophylline had no effect on the initial rates of fall of intracellular Cl- activity (aCli) upon reducing mucosal solution [Cl-] to either 10 or 0 mM, although membrane voltage and resistance measurements were consistent with stimulation of apical membrane electrodiffusive Cl- permeability. Estimates of the conductive flux, obtained by either reducing simultaneously mucosal [Cl-] and [HCO3-] or lowering [Cl-] alone in the presence of a blocker of anion exchange (diphenylamine-2-carboxylate), indicate that elevation of intracellular cAMP inhibited the anion exchanger by approximately 50%. Measurements of net Cl- uptake upon increasing mucosal Cl- from nominally zero to levels ranging from 2.5 to 100 mM suggest that the mechanism of inhibition is a decrease in Vmax. Consistent with these results, the rate of intracellular alkalinization upon reducing external Cl- was also inhibited significantly by theophylline. Reducing mucosal solution [HCO3-] from 10 to 1 mM under control conditions caused intracellular acidification and an increase in aCli. Theophylline inhibited both changes, by 62 and 32%, respectively. These data indicate that elevation of intracellular cAMP inhibits apical membrane anion (Cl-/HCO3-) exchange. Studies of the effects of rapid changes in mucosal [HCO3-] on membrane voltages and the apparent ratio of membrane resistances, both in the presence and in the absence of theophylline, with or without Cl- in the mucosal solution, do not support the hypothesis that cAMP produces a sizable increase in apical membrane electrodiffusive HCO3- permeability.
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PMID:Cyclic AMP inhibits Cl-/HCO3- exchange at the apical membrane of Necturus gallbladder epithelium. 282 Nov 59

The effects of nutrient urea (240 mM) on H+ secretion, potential difference, and resistance were studied in isolated sheets of bullfrog fundic mucosa. H+ secretion was significantly reduced while transmucosal resistance was significantly increased and potential difference was significantly decreased. Measurement of CO2 utilization by, and distribution across, the mucosal sheets demonstrated that oxidative metabolism is increased (tCO2, 4.93 +/- 0.2 to 5.83 +/- 0.3 mumole/cm2 hr-1, P less than 0.05) and that generation of protons (H+) within the oxyntic cell is stimulated (delta CO2, 1.48 +/- 0.1 to 2.22 +/- 0.2 mumole/cm2 hr-1, P less than 0.05, and nutrient HCO-3 1.35 +/- 0.2 to 2.21 +/- 0.2 mueq/cm2 hr-1, P less than 0.05) in spite of paradoxically diminished H+ appearance on the secretory surface. Studies using 120 and 60 mM urea suggest that the effects may be dose dependent. Results with 240 mM sucrose on the nutrient surface would indicate that those seen with urea cannot be attributed entirely to the hyperosmolality. Pretreatment of the mucosal sheets with metiamide (10(-3) M) resulted in the expected decrease in titratable H+ (to 0) but had no effect on urea-stimulated oxidative metabolism (tCO2, 2.09 +/- 0.2 to 2.91 +/- 0.4 mumole/cm2 hr-1, P less than 0.02) or the generation of protons by the oxyntic cell (delta CO2, 0.68 +/- 0.1 to 1.35 +/- 0.3 mumole/cm2 hr-1, P less than 0.02, and nutrient HCO3- 0.83 +/- 0.1 to 1.65 +/- 0.3 mueq/cm2 hr-1, P less than 0.05). Both simultaneous or subsequent treatment with theophylline (5 X 10(-3) M) reversed the inhibitory effect of urea on H+ secretion. Transmission electron microscopy revealed involution of the secretory membrane following treatment with urea but maintenance of the microvillous secreting configuration of the membrane when theophylline was added to the nutrient solution. These results suggest that although nutrient urea stimulates the generation of H+ within the cell it simultaneously inhibits release of H+ by the secretory membrane. Failure to inhibit urea-stimulated generation of H+ within the cell by metiamide indicates that the increased oxidative metabolism and generation of protons stimulated by nutrient urea is probably not histamine-mediated. It is suggested that urea inhibits adenylyl cyclase and thus cAMP-mediated evolution of the secretory membrane with reduced H+ transport, an effect that can be reversed by inhibiting phosphodiesterase with theophylline.
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PMID:The effects of high-nutrient urea on in vitro bullfrog fundic mucosa. 309 89

The effects of synthesized phosphodiesterase inhibitors, DM 9278 and HWA 285, on pancreatic exocrine secretion were investigated in isolated and blood-perfused canine pancreas. Close-arterial injections of DM 9278 (10-300 micrograms) and HWA 285 (300-3000 micrograms) caused dose-dependent increases in the flow rate of pancreatic juice and perfusion blood flow. Bicarbonate concentration in the pancreatic juice stimulated by DM 9278 (300 micrograms) or HWA 285 (3000 micrograms) was significantly higher than that in the resting pancreatic juice, although neither of the compounds affected protein concentrations in the pancreatic juice. In the secretory volume, 100 micrograms of DM 9278 corresponded roughly to 1000 micrograms of HWA 285, 0.1 units of secretin or 0.3 units of pancreozymin. These secretory and vascular effects were not modified by pretreatment with atropine or sulpiride. This study suggests that both DM 9278 and HWA 285 act directly on ductular cells of the pancreas and induce secretion of water and electrolytes.
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PMID:Effects of synthesized phosphodiesterase inhibitors, DM 9278 and HWA 285, on pancreatic exocrine secretion of the dog. 384 75

Immediately after mounting in the Ussing chamber between choline bicarbonate Ringer solutions devoid of exogenous Na and Cl, the serosal fluid is electronegative to the luminal fluid in bladders from postabsorptive and acidotic turtles; and electropositive in bladders from alkalotic turtles. In bladders from postprandial turtles, the electrical orientation, initially serosal positive, reverses to serosal negative. Serosal additions of 3-isobutyl-1-methylxanthine (IBMX) and adenosine 3',5'-cyclic monophosphate (cAMP) produce no changes in the negative short-circuiting current (Isc) of acidotic turtles but induce large positively-directed increases of Isc in bladders from other turtle groups. With IBMX and cAMP in the (HCO3 + CO2)-rich serosal fluid at pH 7.2 and with luminal pH maintained at 4.0-5.0, the rate at which titratable alkali enters the luminal fluid is electrochemically equal to the positive Isc; and this increased positive Isc is the same as that in the absence of transepithelial gradients. The effects of acetazolamide and 4-acetamido-4-isothiocyanostilbene-2,2'-disulfonic acid on positive and negative Isc are presented. It is concluded that isolated bladders from alkalotic, postprandial or postabsorptive turtles, but not those from acidotic turtles, possess an active electrogenic mechanism for a Na-independent Cl-independent secretion of bicarbonate. This transport process is accelerated by phosphodiesterase inhibitors (IBMX) and cAMP or its eight substituted derivatives.
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PMID:Active electrogenic mechanisms for alkali and acid transport in turtle bladders. 618 18

The effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin were investigated using [125I]bovine serum albumin (125I-BSA). Forskolin, forskolin 7-ethyl carbonate and 7-desacetylforskolin, which are potent activators of adenylate cyclase, greatly potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E1-induced response. On the other hand, 14,15-dihydroforskolin and 1,9-dideoxyforskolin, which are weak or inactive as activators of adenylate cyclase, did not have any significant effect on bradykinin and prostaglandin E1-induced plasma exudations. The phosphodiesterase inhibitors, ZK 62711, dipyridamole, HL 725, and 3-isobutyl-1-methylxanthine potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E1-induced response. Papaverine had biphasic effects on the bradykinin-response and slight inhibitory effects on the prostaglandin E1-response. 8-Bromo cyclic AMP in the doses of 0.01 to 1 microgram potentiated the bradykinin-induced plasma exudation, but had no effect at doses of 10 and 100 micrograms. 8-Bromo cyclic AMP at all doses significantly inhibited the prostaglandin E1-induced response. The results suggest that the effects of forskolin and its analogs on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin derive from activation of cyclic AMP-generating systems.
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PMID:Effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin. 631 36

Our previous study of the choroid plexus showed that elevation of cellular cyclic AMP stimulated HCO3 secretion into the cerebrospinal fluid (c.s.f.). To explore the mechanism of this stimulation, we have used micro-electrodes to observe the effect of phosphodiesterase inhibitors on membrane potentials, resistances and electromotive forces (e.m.f.) in the bull-frog plexus. The potential profile under control conditions was -45 mV across the apical membrane (Vvc) and -9 mV across the epithelium (Vvs) with respect to the c.s.f. Two-dimensional cable analysis indicated that 70% of adjacent epithelial cells were electrically uncoupled, and that the coupling coefficient for the remaining cells was only 0.12. The results of circuit analysis gave values for membrane resistance and e.m.f. across the apical membrane of 200 omega cm2 and -135 mV, across the basolateral membrane of 386 omega cm2 and -138 mV, and across the paracellular shunt of 20 omega cm2 (the shunt e.m.f. was assumed to be negligible). Addition of phosphodiesterase inhibitors (10 mM-theophylline or 1 mM-3-isobutyl-1-methylxanthine (IBMX) ) depolarized Vvc by 18 mV and Vvs by 2 mV. Circuit analysis showed that the inhibitor reduced the apical membrane resistance by more than 60% and depolarized the apical e.m.f. by 70 mV without affecting the basolateral membrane or the shunt parameters. In Cl-free solutions IBMX depolarized Vvc and decreased the apical membrane resistance similar to that observed in regular buffer solution. However, in HCO3-free buffer solutions, the effects of IBMX on Vvc and membrane resistances were insignificant. In thirty-five cells in sixteen tissues a linear relationship was observed between the magnitude of the spontaneous membrane potential (Vvc) and the magnitude of IBMX-induced depolarization (delta VIBMXvc): delta VIBMXvc = -0.8 Vvc -15 (in mV). This suggests that HCO3 is accumulated within the epithelium above electrochemical equilibrium. We conclude that cyclic AMP increases HCO3 secretion across the choroid plexus by increasing the apical membrane HCO3 conductance.
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PMID:Regulation of bicarbonate transport across the brush border membrane of the bull-frog choroid plexus. 661 1


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