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)

The adrenergic regulation of the low-Km pineal cAMP phosphodiesterase (PDE) activity was studied in adult female rats. PDE activity showed a transient enhancement (up to 42%) during the process of degeneration of pineal sympathetic nerve terminals that followed superior cervical ganglionectomy (SCGx), thus confirming the neural modulation of the enzyme. Treatment with isoproterenol (0.3-5.0 mg/Kg) increased significantly PDE activity within 2 hours. Phenylephrine induced a significant increase of pineal PDE only at a 10 mg/Kg dose, while at a lower dose (1 mg/Kg) it potentiated the stimulatory effect of isoproterenol. Treatment of pineal organ cultures with 100 microM propranolol inhibited norepinephrine (NE)-induced PDE activity while 100 microM phentolamine had no significant effect. Propranolol at doses unable to alter the in vitro NE-induced stimulation of pineal PDE activity (1 microM), antagonized such NE effect when used in combination with 1 microM phentolamine. At equimolecular concentrations (1 microM) the mixed alpha-beta-adrenergic agonist NE was more effective than the beta-adrenergic agonist isoproterenol to increase pineal PDE in vitro. These results suggest an alpha-beta-adrenergic interaction in the sympathetic modulation of low-Km PDE activity of rat pineal gland.
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PMID:Interaction between alpha- and beta-adrenoceptors in rat pineal adenosine cyclic 3',5'-monophosphate phosphodiesterase activation. 299 8

Incubation of purified bovine photoreceptor rod outer segments with [gamma-32P]ATP resulted in the labeling of phosphatidylinositol 4-phosphate (PIP) and phosphatidic acid (PA) with little labeling of phosphatidylinositol 4,5-bisphosphate (PIP2). Propranolol inhibited in a dose-dependent manner the labeling of PA and enhanced that of PIP. Various cationic amphiphilic drugs also were tested for these effects. Propranolol had the same effects on high-speed rat brain particulate material. While this particular preparation displayed more labeling of PIP2, propranolol was ineffective, as it was on retinal PIP-kinase. Ca2+-activated polyphosphoinositide phosphodiesterase activity in nerve-ending membranes also was inhibited by propranolol. It is concluded that cationic amphiphilic drugs can inhibit diacylglycerol kinase and the polyphosphoinositide phosphodiesterase and stimulate the phosphatidylinositol-kinase (but not PIP-kinase).
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PMID:Cationic amphiphilic drugs perturb the metabolism of inosititides and phosphatidic acid in photoreceptor membranes. 300 40

In vitro studies have demonstrated that AR-L 115BS (AR-L), a new orally active nonglycosidic inotropic agent with vasodilator properties, does not act via adrenergic receptors. However, because AR-L is a phosphodiesterase inhibitor and interaction with the adrenergic nervous system may exist in vivo, we compared the actions of intravenous AR-L, isoproterenol, and propranolol, alone and in combination, in normal dogs. In seven awake morphine-sedated dogs, AR-L (4 mg/kg i.v.) did not alter circulating catecholamines despite increasing maximum rate of change of left ventricular pressure (dP/dt) by 76%. In anesthetized dogs, peak inotropic effect of AR-L occurred at 6 mg/kg (dP/dt from 5,450 +/- 1,280 to 12,000 +/- 3,050 mm Hg/s). Propranolol (1 mg/kg) depressed dP/dt from 5,725 +/- 2,032 to 2,530 +/- 631 mm Hg/s, and this was completely reversed by increasing doses of AR-L (2-30 mg/kg) but the maximum dP/dt attained in these dogs (6,050 +/- 221 mm Hg/s) remained below the level achieved by AR-L in the absence of propranolol. To determine if that difference was due to an interaction of AR-L with the adrenergic nervous system, the effect of AR-L on isoproterenol activity was studied in groups of beta-blocked and unblocked animals. In either group, the dose-response curve of dP/dt to isoproterenol was shifted upward by AR-L, but the actions of the two drugs were additive without real synergism (e.g., after propranolol:isoproterenol 10 micrograms/min 73%; AR-L 6 mg/kg 81%; both 160%. In unblocked dogs, the results were: isoproterenol 2 micrograms/min 96%; AR-L 1 mg/min 39%; both 138%). Similarly, isoproterenol and AR-L were only additive in their effects on heart rate and systemic vascular resistance. Thus, although AR-L is a phosphodiesterase inhibitor, its predominant mechanism of action appears to be independent of the adrenergic nervous system.
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PMID:In vivo interaction of AR-L 115BS (Vardax) with the adrenergic nervous system. 608 57

Basophil-rich rabbit leucocytes sensitized by anti-horseradish peroxidase antibodies released platelet-activating factor (PAF) and histamine upon exposure to the specific antigen. This release was preceded and accompanied by a sharp decrease in the intracellular concentration of cyclic AMP. Isoproterenol, a beta-adrenergic agent, and theophylline, a phosphodiesterase inhibitor, used individually or in combination, increased the intracellular concentration of cyclic AMP and inhibited the release of both PAF and histamine. Propranolol, a beta-adrenergic blocking agent, suppressed the effect of isoproterenol on cyclic AMP level and mediator release. Dibutyryl cyclic AMP, an alkylated derivative of cyclic AMP, inhibited PAF and histamine release. These results indicate that cyclic AMP, which is known to control the release of other mediators of immediate hypersensitivity, also regulates the release of PAF. Histamine and PAF followed one another closely in all of our release or inhibition experiments, bringing more evidence for the basophil origin of PAF.
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PMID:Pharmacological modulation of platelet-activating factor (PAF) release from rabbit leucocytes. I. Role of cAMP. 615 8

The effects of the beta-adrenergic hormone agonist, isoproterenol, on testosterone and cyclic AMP production in mouse Leydig cells in culture have been investigated. It was found that isoproterenol increased testosterone production on days 1, 2 and 3 of culture but not in freshly cultured cells. Cyclic AMP production was however increased on all days of culture. In subsequent studies carried out on day 2 of culture the amounts of testosterone formed during incubation with isoproterenol were 20-90% of those obtained with maximum stimulating levels of luteinizing hormone. The amounts of cyclic AMP formed were extremely low compared with those obtained with luteinizing hormone (22 +/- 5.3 and 2320 +/- 100 pmoles/10(6) cells/2 h respectively). Isoproterenol (10(-8) -10(-7) M) gave a significant increase in testosterone production and reached a maximum with 10(-6) M. Similar dose-response curves for cyclic AMP production were obtained. The stimulation of cyclic AMP and testosterone by isoproterenol was highly dependent on the presence of the phosphodiesterase inhibitor, methylisobutylxanthine. Propranolol blocked, in a dose-dependent manner, both isoproterenol-stimulated cyclic AMP and testosterone production. In the presence of excess luteinizing hormone no additional effects of isoproterenol were detected. Epinephrine also stimulated testosterone production. It is concluded that catecholamines stimulate testosterone production in mouse Leydig cells in monolayer culture and that this effect if mediated by cyclic AMP.
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PMID:Catecholamine stimulation of testosterone production via cyclic AMP in mouse Leydig cells in monolayer culture. 618 Sep 42

Fenoterol, a beta 2-adrenergic agonist recently introduced to treat asthmatic disorders, inhibits antigen-induced histamine release from human basophil leukocytes and lung mast cells in a dose-dependent fashion. The dose-response inhibition curve is paralleled by a fenoterol-induced increase in the cAMP levels of human leukocyte preparations. The relationship between the effect of fenoterol and cAMP level is supported by the finding that the beta 2-adrenergic agonist only inhibits the first stage of antigen-induced histamine release and not the release caused by the Ca2+ ionophore, A23187. Propranolol, a competitive antagonist of beta 2-adrenergic receptor, blocks the inhibition of release and the cAMP accumulation caused by fenoterol. Finally, theophylline, a cAMP phosphodiesterase inhibitor, synergistically potentiates the inhibitory effect of fenoterol on histamine release and the accumulation of cAMP. These data suggest that fenoterol may modulate the in vivo release of the mediators of immediate hypersensitivity reactions via the activation of beta 2-adrenergic receptor linked to adenylate cyclase on human basophils and mast cells.
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PMID:Inhibition of IgE-mediated histamine release from human basophils and mast cells by fenoterol. 620 44

The effects of dihydroxy bile acids on intestinal cyclic nucleotides, Na+-K+-ATPase, and net secretion, and of propranolol pretreatment on these actions were determined. Ileal and colonic loops were constructed in each of 12 rabbits, six of which were treated with propranolol preoperatively. In random order, normal saline, 6mM deoxycholic, chenodeoxycholic, or ursodeoxycholic acids were injected into the intestinal loops. Five hours after, net luminal secretion and mucosal adenylate cyclase, phosphodiesterase, cGMP, and Na+-K+-ATPase were determined. Deoxycholic and chenodeoxycholic acids each increased adenylate cyclase activity (< 0.01) and net secretion (p < 0.01), and decreased cGMP (p < 0.05). Ursodeoxycholic acid did not alter adenylate cyclase activity or secretion but increased cGMP (p < 0.05). Phosphodiesterase and Na+-K+-ATPase were unchanged. Propranolol reversed all of the bile acid effects. In conclusion, chenodeoxycholic and deoxycholic acid induce net intestinal secretion, probably via cAMP. Ursodeoxycholic acid does not affect cAMP but increases cGMP and does not promote net secretion.
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PMID:The effect of dihydroxy bile acids on intestinal secretion, cyclic nucleotides, and Na+-K+-ATPase. 625 79

The uptake of 14C-ring labelled histamine and histidine was studied in human and guinea-pig leucocytes, and in rat peritoneal mast cells. Histamine uptake by sensitized human leucocytes was partly released by antigen or anti-IgE challenge, suggesting that histamine is taken up by the same cells that synthesize and secrete that amine, i.e. basophils. Histamine antagonists, particularly of the H2-subclass, had an inhibitory effect, but histamine agonists had a relatively small and inconsistent effect. Adrenoceptor stimulants and phosphodiesterase inhibitors produced small effects, but dibutyryl cAMP at a concentration of 4-10 mM consistently increased histamine uptake by more than 100% during a 30 min incubation. By contrast, ATP exerted an inhibitory effect, starting at a concentration of 0.2 mM and reaching a maximum (90% inhibition) at 10 mM. Histidine uptake was inhibited by ATP and slightly stimulated by cAMP. Propranolol caused stimulation of histamine uptake and inhibition of histidine uptake at micromolar concentrations. These results suggest that the uptake of histamine is not due to simple diffusion. Although it does not contribute significantly to total cell histamine content or to the removal mechanism of extracellular histamine, it may contribute to the auto-regulatory processes modulating histamine release, synthesis and metabolism. It may also have a significant effect on the extracellular level of histamine, under the influence of drugs or in pathological states.
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PMID:Effect of purine nucleotides and other compounds on the uptake of histamine and histidine. 628 73

Intracellular calcium regulates a number of membrane functions in the erythrocyte, including control of shape, membrane lipid composition and cation permeability. Measurement of total red cell calcium has yielded values between 5 and 15 nmol/ml cells, and these low values in part reflect the absence of Ca2+ -containing organelles. Most intracellular Ca2+ is bound and the low cell ionized Ca2+ concentration (approximately 0.2 microM) is maintained by a combination of low membrane permeability and a powerful Ca2+ -pump. This pump has been identified with a (Ca2+ + Mg2+)-stimulated ATPase, and both Ca2+ transport and ATP splitting are stimulated by calmodulin, a low molecular weight protein which binds Ca2+ avidly and activates many Ca2+ -dependent enzymes. Both high and low affinity kinetics for Ca2+ pumping have been demonstrated, depending on the extent of binding of calmodulin to the pump. A stoichiometry of either 1 or 2 Ca2+ ions pumped per ATP molecule split has been shown, and the value may vary with the level of intracellular Ca2+. Phenothiazines, such as chlorpromazine inhibit the Ca2+ -pump by antagonizing the increment in activity produced by calmodulin. The passive inward leak of Ca2+ into erythrocytes can be quantitated by 45Ca2+ uptake into red cells whose Ca2+ -pump has been inhibited. Estimates of the Ca2+ permeability, based on unidirectional influx, yield values many orders of magnitude lower than for nucleated cells. Influx of Ca2+ into human erythrocytes occurs by a facilitated diffusion process, which can be inhibited by phenothiazines and the cinchona alkaloids. Calcium affects many membrane functions including cation permeability, lipid composition and some cytoskeletal interactions which may determine cell shape. Any rise in intracellular Ca2+ activates a specific K+ channel which normally makes little contribution to K+ fluxes. Kinetic studies of this process demonstrate either high or low affinity Ca2+ -activation of K+ efflux, with low affinity of the channel to Ca2+ being the probable state in vivo. Propranolol is the best known activator of Ca2+ -stimulated K+ efflux, although the mechanism of stimulation is unclear. Like other tissues, red cells possess a Ca2+ -activated phosphoinositol phosphodiesterase. Although it has been suggested that the echinocytic shape change induced by Ca2+ is due to the hydrolysis of polyphosphoinositides, it seems more likely that this shape change results from an effect of Ca2+ on the macromolecular interactions of the cytoskeleton. Abnormal Ca2+ permeability may contribute to red cell destruction in a variety of diseases. For example, in sickle cell anemia a large Ca2+ influx occurs when cells are sickled under deoxy conditions, and moreover, the ability of the Ca2+ -pump to extrude the increment of cell Ca2+ is impaired. Thus, red cell Ca2+ is increased 3-7-fold above normal and this may contribute to the short survival of sickle red cells...
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PMID:Calcium ions, drug action and the red cell membrane. 629 89

In exorbital lacrimal glands, pentoxifylline (a methylxanthine) induces labeled protein secretion in a dose-related manner: the half-maximal and maximal stimulations are at 4 and 10 mM, respectively. In the presence of papaverine (10(-5) M), a phosphodiesterase inhibitor, labeled protein discharge is strongly stimulated by isoproterenol, via beta-adrenergic receptors: the maximal response is at 10(-6) M. l-Propranolol specifically inhibits the secretory stimulation to isoproterenol in a dose-related manner: for 5 X 10(-6) M isoproterenol in the presence of 10(-5) M papaverine, the half-maximal and maximal inhibitions are at 3 X 10(-7) and 10(-5) M, respectively. The beta-adrenergic response is mimicked by the adenosine 3',5'-cyclic monophosphate (cAMP) analogue dibutyryl cAMP (DBcAMP) at a 10(-3) M concentration. The time course of labeled protein secretion induced by pentoxifylline, DBcAMP, and isoproterenol shows a latency. In the presence or absence of extracellular calcium, pentoxifylline and isoproterenol immediately increase the cAMP intracellular level. Extracellular calcium omission increases the observed latency and also affects the maximal rate of protein secretion. As opposed to the cholinergic agonist, pentoxifylline has only a slight but sustained effect on 45Ca efflux, whereas isoproterenol has none. These data suggest that labeled protein secretion, such as that of peroxidase, can also be stimulated in rat exorbital lacrimal gland, through beta-adrenergic receptors; in the stimulation evoked by a beta-adrenergic agonist, DBcAMP, or methylxanthine, calcium could play a key role.
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PMID:Protein secretion induced by isoproterenol or pentoxifylline in lacrimal gland: Ca2+ effects. 632 Jun 58


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