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 relaxant effect of vasoactive intestinal peptide (VIP) was investigated in isolated guinea-pig trachea in the presence of the phosphodiesterase (PDE) inhibitors, papaverine and 3-isobutyl-1-methylxanthine (IBMX), and the results were compared to those obtained with the cyclic AMP-dependent bronchodilators, isoproterenol and prostaglandin E2 (PGE2). The relaxant effect of VIP was greater when the magnitude of the leukotriene D4 (LTD4)-induced contraction was smaller. A similar effect was also observed for the relaxation induced by isoproterenol but not by PGE2. In the presence of papaverine (1 microM) and IBMX (3 microM), which reduced the 30 nM LTD4-induced contraction to the same extent, the relaxant effect of VIP was not changed, whereas the relaxant effects of isoproterenol and PGE2 were significantly potentiated. The potentiating effect of PDE inhibitors was also observed for the relaxation induced by the adenylate cyclase activator, forskolin, but not for the relaxation induced by the guanylate cyclase activator, sodium nitroprusside. These results suggest that the relaxation induced by VIP is different from that induced by cyclic AMP-dependent bronchodilator in the guinea-pig trachea.
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PMID:Effects of phosphodiesterase inhibitors on vasoactive intestinal peptide-induced relaxation of isolated guinea-pig trachea. 171 96

Adenylate cyclase activity in rabbit retinal homogenates can be stimulated directly by forskolin or through a receptor-mediated mechanism by vasoactive intestinal peptide (VIP). In contrast the alpha 2-adrenoceptor agonists clonidine and UK-14,304 reduce the basal cAMP level slightly. This was more evident following application of forskolin and VIP where the decrease of cAMP caused by clonidine and UK-14,304 is dose-dependent. The alpha 2-adrenoceptor agonist response is blocked by pertussis toxin and is insensitive to the phosphodiesterase inhibitor, isobutylmethylxanthine, suggesting the involvement of a Gi-protein. Clonidine and UK-14,304 attenuation of elevated cAMP levels can be inhibited by the alpha 2-receptor antagonist yohimbine and phentolamine but not by the specific alpha 1-receptor antagonist, prazosin. Serotonergic, cholinergic and beta-adrenergic receptor antagonists were without effect. The results demonstrate that alpha 2-adrenergic receptors in the retina exert inhibitory effects on adenylate cyclase activity mediated by an inhibitory guanine nucleotide regulating protein.
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PMID:Inhibition of cAMP production by alpha 2-adrenoceptor stimulation in rabbit retina. 171 42

We have studied the effect of phosphodiesterase inhibitors on relaxation of guinea pig tracheal smooth muscle in an attempt to elucidate the role of cyclic nucleotides in relaxation to stimulation of inhibitory nonadrenergic noncholinergic (i-NANC) nerves. SK&F 94120 (1-10 microM) potentiated relaxation induced by isoproterenol, vasoactive intestinal peptide (VIP) and electrical field stimulation (EFS) in the presence of atropine and propranolol but had no effect on relaxation induced by sodium nitroprusside. Zaprinast (3-30 microM) potentiated relaxation induced by sodium nitroprusside but not by isoproterenol or VIP. A small potentiation of relaxation to EFS was induced by 30 microM zaprinast but not by lower concentrations. Tetrodotoxin attenuated relaxations induced by EFS suggesting that they are at least partly neurogenic in origin. SK&F 94120 and zaprinast had no effect of tetrodotoxin-resistant relaxation to EFS. The guanylate cyclase inhibitor had no effect on EFS-induced relaxation. These findings suggest that cyclic AMP may mediate relaxation of guinea pig tracheal smooth muscle in response to stimulation of i-NANC nerves, and are in agreement with the view that VIP may be the neurotransmitter released by i-NANC nerves in this tissue.
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PMID:Potentiation of nonadrenergic neural relaxation in guinea pig airways by a cyclic cAMP phosphodiesterase inhibitor. 215 9

Intracellular cyclic AMP (cAMP) regulates many critical differentiated functions of tracheal epithelial cells. An in vitro model system for reliable study of cAMP metabolism in these cells has been developed. Viable tracheal epithelial cells could be recovered from greater than 50% of necropsy specimens. Culture success rate was not significantly affected by age of subject, endotracheal intubation, or time between death and autopsy, although most specimens were obtained within 24 h of death. Human tracheal epithelial cells grown in primary culture displayed a typical histologic epithelial appearance, and the ultrastructure showed microvilli, junctional complexes, and tonofilaments. The cells uniformly stained with fluorescent antibody to cytokeratin, and expressed receptors for isoproterenol and vasoactive intestinal peptide. Human tracheal epithelial cells grown serum-free in an equal volume mix of Ham's F12 medium and Dulbecco's minimal essential medium containing growth supplements (Medium A) and cholera toxin (CT) had higher basal cAMP levels and greater increase in intracellular cAMP in response to phosphodiesterase inhibition than cells grown in Medium A without CT. Cells grown in Medium A without CT had similar morphology and grew at a comparable rate but attached to the culture substratum less readily than cells grown in Medium A with CT. Cells grown in Medium A without CT had less cAMP response to phosphodiesterase inhibition, less rapid accumulation of cAMP, and greater proportional response to receptor-mediated stimulation of cAMP production compared to cells grown with CT, though the final cAMP levels achieved were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine 3:5' cyclic monophosphate synthesis by human tracheal epithelial cells. 215 12

Secretin receptors in membranes from the neuroblastoma-glioma hybrid cell line NG108-15 were investigated by 125I-secretin binding and adenylate cyclase activation. On both parameters the corresponding relative potencies of parent peptides were, respectively: secretin greater than helodermin greater than peptide histidine isoleucinamide = vasoactive intestinal peptide. With secretin analogs and secretin fragments, the order of potency for binding was: secretin = [Val5]secretin greater than [Ala2]secretin = [Ala11]secretin greater than [Ala4, Val5] secretin greater than [Ala4]secretin greater than [D-Phe4] secretin greater than [D-Phe2]secretin = secretin (2-27) greater than secretin (3-27) greater than secretin (7-27). Also, on adenylate cyclase, [D-Phe4]secretin, [D-Phe2]secretin, secretin (2-27) and secretin (3-27) were partial agonists while secretin (7-27) was ineffective. The differentiating agent N6,2'-O-dibutyryladenosine 3',5'-monophosphate (1 mM) increased the density of secretin receptors and secretin-stimulated adenylate cyclase activity after a lag period of 4 h. After incubation for 24 h, receptor number and enzyme activity were increased 4- and 3-fold, respectively. These effects were inhibited totally by 1 microgram/ml cycloheximide and halved by 5 micrograms/ml actinomycin D. They were mimicked by 1 mM sodium butyrate but were not reproduced by either 8-bromoadenosine 3',5'-monophosphate or the phosphodiesterase inhibitor rac-4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone.
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PMID:Secretin receptors in the neuroglioma hybrid cell line NG108-15. Characterization and regulation of their expression. 217 30

The turtle urinary bladder possesses an active transport mechanism for the electrogenic secretion of alkali. This process is independent of exogenous Cl and Na, induced by cyclic AMP (cAMP), and potentiated in bladders from NaHCO3-loaded (alkalotic) turtles. In the present study, it is shown that the serosal addition of vasoactive intestinal peptide (VIP) induces rapidly developing parallel increases in alkali secretion and in the short-circuiting current carried by this secretion. The VIP-induced increment in alkali secretion is greater in the presence than in the absence of an exogenously added phosphodiesterase inhibitor. Additions of a cAMP analog subsequent to the VIP-induced alkali secretion fail to induce any further increase in alkalinization. These results provide evidence for the action of VIP as a hormonal up regulator of alkali excretion in the turtle urinary bladder.
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PMID:Vasoactive intestinal peptide stimulates alkali excretion in turtle urinary bladder. 243 84

Previous work has shown that incubation of hippocampal slices in medium without added calcium markedly attenuates the capacity of vasoactive intestinal peptide (VIP) to elevate cyclic AMP levels. The present studies examined the mechanism that confers calcium dependence on VIP stimulation of cyclic AMP accumulation in hippocampal slices. Calcium dependence was apparent immediately on slice preparation and was reversible only if calcium ions were added back very early during slice incubation (within 5 min). The cyclic AMP response to VIP was not abolished by preincubating slices in 100 microM adenosine, suggesting that calcium-dependent, VIP-induced release of adenosine does not mediate VIP elevation of cyclic AMP. VIP-stimulated cyclic AMP accumulation was not decreased by agents that block calcium influx (verapamil, nifedipine, magnesium ions), or by calmodulin antagonists (trifluoperazine, calmidozolium). In fact both verapamil (100 microM) and magnesium (14 mM) augmented VIP stimulation of cyclic AMP generation. Incubation of slices with the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine (MIX) did not affect VIP activation of cyclic AMP accumulation if slices were incubated without added calcium, but MIX did enhance VIP elevation of cyclic AMP content in slices incubated with calcium. Thus calcium dependence of the cyclic AMP response to VIP in hippocampal slices is unlikely to result from VIP-dependent calcium influx, from interactions with calmodulin, or from calcium-inhibited phosphodiesterase(s).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium dependence of vasoactive intestinal peptide-stimulated cyclic AMP accumulation in rat hippocampal slices. 243 83

Membrane currents were recorded from voltage-clamped Xenopus laevis oocytes, surrounded by their enveloping follicular and epithelial cells. Porcine vasoactive intestinal peptide (VIP) generated a membrane current due to an increase in membrane conductance to K+. The VIP current was mimicked by the adenylate cyclase activator forskolin and was potentiated by phosphodiesterase inhibitors, suggesting that adenosine 3',5'-cyclic monophosphate (cyclic AMP) plays a role in mediating the response. Though resembling the follicle's responses to catecholamines and adenosine in ionic basis and apparent mechanism, the response to VIP was not blocked by catecholaminergic or purinergic antagonists, indicating the presence of a specific VIP receptor in the follicle. Among the VIP related peptides, PHM-27 generated similar but smaller K+ currents and porcine secretin and glucagon neither elicited a response nor blocked that to VIP. After treating follicles with collagenase to remove the epithelial and follicular cells the responses to VIP were either substantially reduced or abolished, suggesting that the VIP receptors and K+ channels are both located in the follicular cells.
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PMID:Membrane currents elicited by porcine vasoactive intestinal peptide (VIP) in follicle-enclosed Xenopus oocytes. 244 88

Studies were conducted to evaluate the effects of vasoactive intestinal peptide (VIP) on steroidogenesis and plasminogen-activator (PA) activity in isolated granulosa cells of the largest preovulatory (F1) follicle of the hen. Vasoactive intestinal peptide, but not avian pancreatic polypeptide, the chicken VIP fragment (16-28) or the VIP congener, PHM-27, induced a dose-related increase in progesterone and androgen secretion, with an apparent median effective dose (ED50) of 5.9 X 10(-7) and 5.7 X 10(-7) M, respectively. The effects of VIP were, at least in part, mediated by the adenylyl cyclase system in that cotreatment of cells with VIP and the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), potentiated the steroidogenic effects. However, the time course of action for VIP on steroidogenesis was considerably slower than that for the gonadotropin, luteinizing hormone (LH), and this was attributed to a slower induction of cyclic adenosine 3',5'-monophosphate (cAMP) formation within granulosa cells. Finally, VIP was found to be a potent inhibitor of PA activity, and this inhibition was potentiated by coincubation of VIP with IBMX. We suggest that, in the hen, VIP has a direct and specific action on both steroidogenesis and PA activity, and that these actions are mediated, at least in part, by the adenylyl cyclase system. The comparatively slow induction of cAMP formation by VIP suggests that this peptide is involved in the control of cell differentiation and development rather than the ovulatory process.
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PMID:Effects of vasoactive intestinal peptide on steroid secretion and plasminogen activator activity in granulosa cells of the hen. 245 37

The interactions between dopamine and muscarinic receptor subtypes coupled to adenylate cyclase in superfused rat neostriatal slices were investigated using the efflux of cyclic AMP, in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, as a highly sensitive parameter of cyclic AMP production. Cyclic AMP efflux induced by simultaneous activation of (stimulatory) D-1 and (inhibitory) D-2 dopamine receptors by dopamine was reduced profoundly by the muscarinic receptor agonist oxotremorine and by inhibition of acetylcholinesterase with physostigmine, but not by the M-1 muscarinic receptor agonist McN-A-343. In contrast, upon blockade of D-2 receptors with (-)-sulpiride, dopamine-stimulated cyclic AMP efflux was inhibited by oxotremorine and physostigmine as well as by McN-A-343. Cyclic AMP efflux induced by isoprenaline, adenosine or vasoactive intestinal peptide was not affected by oxotremorine. The M-1 receptor-selective antagonist pirenzepine, unlike the nonselective antagonist atropine, was about 10 times less potent in antagonizing the inhibitory effects of (a near-maximally effective concentration of) oxotremorine upon simultaneous D-1 and D-2 receptor activation that upon selective D-1 receptor activation (i.e., upon blockade of D-2 receptors). In the latter case, pirenzepine was about 5 times more effective as an antagonist when muscarinic receptors were activated by McN-A-343 than upon exposure of the slices to oxotremorine or physostigmine, whereas the potency of atropine was independent of the agonist used.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:M-1 and M-2 muscarinic receptor-mediated inhibition of dopamine-sensitive adenylate cyclase in rat neostriatum: a permissive role for D-2 dopamine receptors. 245 77


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