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 effects of secretin and vasointestinal peptide (VIP) on the production of cyclic AMP have been studied in gastric glands isolated by means of EDTA from rat fundic and antral mucosa. (1) In gastric fundus, secretin and VIP caused a time- and temperature-dependent stimulation of cyclic AMP production that was maximal when the test agents were incubated for 60 min at 20 degrees C in the presence of 0.5 mM 3-isobutyl-1-methylxanthine as a phosphodiesterase inhibitor. The dose-response curve was monophasic for both peptides, the production of cyclic AMP being sensitive to 10(-10) M secretin and to 5 . 10(-8) M VIP. Half-maximal stimulation was obtained with 2.9 10(-9) M secretin or 2 . 10(-7) M VIP and the maximal stimulation represented a 21-fold and a 19-fold increase above control for secretin and VIP, respectively. Histamine also stimulated cyclic AMP production, with a Km of about 5 . 10(-4) M. No additive effect on cyclic AMP production was oberved when secretin and VIP were simultaneously added at maximally active concentrations, while an additive effect was observed when secretin and histamine were added together. (2) In gastric antrum, the characteristics of the secretin- and VIP-stimulated cyclic AMP production were similar to those observed in gastric fundus. Histamine nevertheless failed to stimulate the formation of cyclic AMP in antral mucosa. (3) These data demonstrate the existence of a cyclic AMP system highly sensitive to secretin in gastric glands isolated from the rat fundus and antrum and suggest that VIP operates through this system. (4) It is proposed that the pepsinogen- and/or mucous-secreting cells are implicated in the regulation of cyclic AMP production by secretin in gastric glands of the rat.
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PMID:Evidence for a cyclic AMP system highly sensitive to secretin in gastric glands isolated from the rat fundus and antrum. 624 85

An EDTA procedure was used to prepare isolated epithelial cells of human gallbladder devoid of endogenous vasoactive intestinal peptide (VIP) as measured by radioimmunoassay. Specific binding sites for VIP were characterized in these cells. At 37 degrees C, the binding of (125)I-labeled VIP reached a peak within 20 min and then declined rapidly. At 15 degrees C, binding was stable between 90 and 180 min of incubation. Binding of the labeled peptide was inhibited by concentrations of native VIP of 30 pM-0.1 muM. Half-maximal inhibition was observed at 2 nM. Scatchard analysis indicated two functionally independent classes of receptor sites: 62,000 high affinity sites/cell with a dissociation constant (K(d)) of 1.3 nM, and 510,000 low affinity sites/cell with a K(d) of 16.2 nM. Secretin inhibited tracer binding but with a 1,000 times lower potency than native VIP. VIP strongly stimulated adenosine 3':5' monophosphate (cyclic AMP) production in human gallbladder epithelial cells. At 37 degrees C, 0.1 nM and 10 nM VIP raised cyclic AMP levels 44 and 100 times above the basal level, respectively. Maximal values remained constant between 60 and 90 min at 15 degrees C. The importance of the VIP-induced cyclic AMP rise was related, at least in part, to a low phosphodiesterase activity in human gallbladder epithelial cells. At equilibrium, during a 60-min incubation at 15 degrees C, cyclic AMP production was noted at concentrations of VIP as low as 3 pM. Maximal and half-maximal stimulations were observed at 10 nM and 0.2 nM VIP, respectively. Secretin also stimulated cyclic AMP production but with a 10,000 lower potency than VIP. In the guinea pig, VIP and secretin were equipotent stimulators of cyclic AMP in gallbladder epithelial cells. This particular feature was shown to be due to receptors specific for each peptide that were present in these cells.
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PMID:Importance of the vasoactive intestinal peptide receptor in the stimulation of cyclic adenosine 3',5'-monophosphate in gallbladder epithelial cells of man. Comparison with the guinea pig. 625 9

Vasoactive intestinal peptide (VIP), secretin, catecholamines and prostaglandin E1 (PGE1) in the presence of a cyclic nucleotide phosphodiesterase inhibitor stimulate the accumulation of cyclic AMP in two colorectal carcinoma cell lines (HT 29 and HRT 18) with subsequent activation of the cyclic AMP-dependent protein kinases. In HT 29 cells incubated without phosphodiesterase inhibitor, 10(-9) M VIP promotes a rapid and specific activation of the lower Km cyclic AMP phosphodiesterase (1.7-fold); at 25 degrees C the effect is maintained for more than 15 min, while at 37 degrees C the activity returns to basal value within 15 min. As shown by dose-response studies, VIP is by far the most effective inducer (Ka equals 4 x 10(-10) M) of the cyclic AMP phosphodiesterase activity; partial activation of the enzyme is obtained by 3 x 10(-7) M secretin, 10(-5) M isoproterenol and 10(-5) M PGE1; PGE2 and epinephrine are without effect. In HRT 18 cells VIP is less active (Ka equals 2 x 10(-9) M) whereas 10(-6) M PGE1, 10(-6) M PGE2 and 10(-5) M epinephrine are potent inducers of th phosphodiesterase activity. The positive cell response to dibutyryl-cyclic AMP further indicates that cyclic AMP is a mediator in the phosphodiesterase activation process. The incubation kinetics and dose response effects of the various agonists on the cyclic AMP-dependent protein kinase activity determined for both cell types in the same conditions show a striking similarity to those of phosphodiesterase. Thus coordinate regulation of both enzymes by cyclic AMP was observed in all incubation conditions.
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PMID:Parallel activation of cyclic AMP phosphodiesterase and cyclic AMP-dependent protein kinase in two human gut adenocarcinoma cells (HT 29 and HRT 18) in culture, by vasoactive intestinal peptide (VIP) and other effectors activating the cyclic AMP system. 626 79

In animals, exogenous secretin produces dose--related increases in pancreatic tissue levels of cyclic AMP which are closely correlated with both bicarbonate and cyclic AMP outputs in pancreatic juice. These effects can be augmented by additional administration of phosphodiesterase inhibitors such as methylxanthines. Vasoactive intestinal peptide (VIP) produces similar though less pronounced effects than secretin. Following secretion or VIP the changes in pancreatic tissue cyclic AMP concentrations precede the physiological response, i.e. enhance water and electrolyte secretion. In man, bicarbonate and cyclic AMP concentrations of pure pancreatic juice obtained by endoscopic cannulation of Vater's papilla are significantly correlated in response to both secretin and VIP. VIP however, has a lower efficacy and potency relative to secretin. There is no significant correlation between pancreatic juice cyclic GMP and bicarbonate concentrations or outputs. These observations suggest that cyclic AMP plays an important role in mediating the stimulatory effects of secretin and VIP on hydrokinetic pancreatic exocrine function. However, it still remains to be elucidated in which specific way cyclic AMP initiates the secretory process. In principle, the action of cyclic nucleotides on cell function is thought to occur from their ability to activate cyclic nucleotide--dependent protein kinases which in turn are capable of activating enzymes of protein synthesis by phosphorylation (19). With respect to pancreatic secretion, studies of this kind are currently under way.
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PMID:[Role of "secondary transmitters" in the exocrine function of the pancreas]. 626 94

The binding of vasoactive intestinal peptide (VIP) and its effect on cyclic AMP production were assessed in HeLa cells. The binding of [125I]VIP is a moderately rapid process, reversible, saturable, specific and dependent on temperature. Virtually no inactivation of the peptide is observed after 2 h of exposure to the cells. At 15 degrees C, the binding data obtained at steady state are compatible with the existence of two classes of binding sites: a first class with a Kd of 2.4 nM and low binding capacity (1.5 X 10(5) sites/cell) and a second class with a Kd of 100 nM and a high binding capacity (4.9 X 10(6) sites/cell). Secretin is eight times less potent than VIP in competing with 125I VIP but glucagon, insulin and somatostatin are inactive. VIP-induced stimulation of cyclic AMP production depends on time and temperature and is potentiated by a phosphodiesterase inhibitor. A concentration of VIP as low as 10(-10) M is able to stimulate adenylate cyclase. Half-maximal stimulation is observed at 10(-9) M and maximal stimulation (4 times above basal levels) at 10(-8) M VIP. Secretin is an agonist of VIP but exhibits a 1000 times lower potency with respect to adenylate cyclase activation. Glucagon, insulin and somatostatin do not show any effect. The presence of high-affinity binding sites and high sensitivity and specificity of adenylate cyclase for VIP in HeLa cells provide a good model to study the role of this peptide on cell proliferation and differentiation.
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PMID:Interaction of vasoactive intestinal peptide with a cell line (HeLa) derived from human carcinoma of the cervix: binding to specific sites and stimulation of adenylate cyclase. 626 63

Vasoactive intestinal peptide (VIP) has been shown to increase cyclic AMP content in isolated epithelial cells of rat ventral prostate. The stimulatory effect of VIP was dependent on time and temperature and was potentiated by a phosphodiesterase inhibitor. At 15 degrees C, the response occurred in the 1 X 10(-10)-10(-7)M range of VIP concentrations. Half-maximal stimulation of cellular cyclic AMP was obtained at 1.4 nM and maximal stimulation (3-fold basal level) at about 100 nM VIP. Chicken VIP and porcine secretin were agonists of porcine VIP but exhibited a 2-times higher and a 170-times lower potency, respectively. A high concentration (1 X 10(-6)M) of glucagon, somatostatin, neurotensin, substance P, Met-enkephalin or Leu-enkephalin did not modify cAMP levels. The finding of a VIP-stimulated cAMP system in rat prostatic epithelial cells together with the previous characterization of high-affinity receptors for VIP in the same cell preparation, as well as the presence of VIP-containing neurones innervating the male genitourinary tract, strongly suggest that VIP may be involved in prostatic growth regulation and function.
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PMID:Cyclic AMP-stimulating effect of vasoactive intestinal peptide in isolated epithelial cells of rat ventral prostate. 631 52

Luminal application of acid was recently shown to stimulate surface epithelial HCO3(-) transport in stomach and duodenum. Effects of some potential transmitters of this response were therefore studied in amphibian gastric fundic and proximal duodenal mucosa in vitro. Duodenal HCO3- transport, which could be titrated directly, was stimulated by dibutyryl cAMP (DBcAMP, 10(-6) M), the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-6) M), noradrenaline (10(-6) M), pancreatic glucagon (10(-8) M), and gastric inhibitory peptide (GIP, 10(-10) M). Stimulation by glucagon, but not by prostaglandin E2 (PGE2, 10(-6) M), required Cl- in the luminal solution and was prevented by furosemide (10(-3) M). This suggests that glucagon may affect HCO3(-)-Cl- exchange at the luminal membrane while transport stimulated by prostaglandins may be electrogenic. Stimulatory effects of glucagon and PGE2 were also additive. Gastric HCO3- transport, studied in tissues after inhibition of H+ secretion by histamine H2-antagonists, clearly differed from duodenum in that noradrenaline and GIP were inhibitory and DBcAMP was without effect. Stimulation of gastric HCO3- transport was observed with glucagon (10(-8) M), natural cholecystokinin (CCK, 10(-8) M), and CCK octapeptide (10(-7) M), CCK preparations had no effect in the duodenum. Although tested over a wide range of concentrations, no effect on either duodenal or gastric HCO3- transport was observed with histamine, pentagastrin, tetragastrin, urogastrone, ACTH, bombesin, motilin, secretin, serotonin, somatostatin, substance P, or vasoactive intestinal peptide.
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PMID:Gastric and duodenal HCO3- transport in vitro: effects of hormones and local transmitters. 697 77

1. The effects of nicardipine on the secretion of pancreatic juice were investigated in dog isolated, blood-perfused pancreas, and compared with those of papaverine, aminophylline and secretin. 2. Intra-arterial administration of nicardipine (1-10 micrograms) elicited a dose-dependent increase in pancreatic secretion. Papaverine (0.1-1 mg), aminophylline (0.3-3 mg) and secretin (0.03-0.1 units) also elicited increased secretion. The secretory activity of nicardipine (10 micrograms) was approximately equal to that of 0.5 mg of papaverine, 1.5 mg of aminophylline and 0.03 units of secretin. 3. The concentration of bicarbonate in the pancreatic juice induced by nicardipine was increased, but the protein concentration was only increased slightly. These effects are analogous to those of secretin. 4. Nicardipine-induced secretion was not modified by pretreatment with relatively large doses of phentolamine, propranolol, atropine, guanethidine, haloperidol or metiamide. 5. Secretin-induced secretion was significantly potentiated by infusion of papaverine, but not by infusion of nicardipine or aminophylline. 6. These results suggest that nicardipine acts on the exocrine cells in the dog pancreas, at least in part, through the increase of intracellular cyclic AMP concentration by inhibiting phosphodiesterase activity.
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PMID:Effects of nicardipine on pancreatic exocrine secretion in the dog. 716 2

Although secretin and vasoactive intestinal peptide (VIP) stimulate production of the second-messenger substance cyclic AMP and exert a positive inotropic action on rat ventricle in vitro, a direct action of these peptides on cardiomyocytes has not been established. In contrast to hearts of other mammalian species, which possess VIP-preferring receptors, rat heart is unique in that the existence of a "relatively nonselective receptor" at which both secretin and VIP may bind has been proposed. We wished to define the receptor(s) for secretin and VIP present on rat ventricular cardiomyocytes using a homogeneous suspension of viable cells. With adenosine deaminase 5 U/ml and the phosphodiesterase (PDE) inhibitor isobutyl methylxanthine (IBMX) 1 mM, both secretin and VIP increased intracellular levels of cyclic AMP maximally and concentration dependently after 5 min: EC50 values were 8 and 58 nM, respectively. At maximally effective concentrations, secretin 1 microM increased intracellular levels of cyclic AMP fourfold above basal levels, whereas a 1.6-fold increase was induced by VIP 10 microM. Maximum changes in cell length (dL) of isolated cardiomyocytes during electrically stimulated (0.5 Hz) contractions were determined in the presence of adenosine deaminase 2.5 U/ml. Under these conditions, both secretin and VIP produced a concentration-dependent positive contractile response that became maximal 5 min after addition of the peptide. Secretin 50 nM increased the amplitude of cellular contractions maximally to a value 37% greater than that obtained without peptide. VIP 20 nM increased the amplitude of cellular contractions maximally to a value 19% greater than that obtained without peptide. The EC50 values were 470 and 700 pM for VIP and secretin, respectively. The selective antagonist at VIP-preferring receptors, 4-Cl DPhe-6 Leu-17 VIP 10 microM did not antagonise the actions of VIP. In the presence of the selective antagonist at receptors for secretin, secretin 7-27 > or = 10 microM, the concentration dependence of the effect of secretin on accumulation of cellular cyclic AMP and contractile amplitude displayed a rightward parallel shift: the pA2 value for secretin 7-27 was 4.96. Secretin 7-27 also induced a rightward parallel shift of the concentration dependence of the actions of VIP. VIP 10 microM was additive with low concentrations of secretin (< 10 nM) in stimulating production of cyclic AMP but antagonised this response at higher concentrations of secretin (> 10 nM). Similarly, VIP 2 and 20 nM enhanced the contractile response to low concentrations of secretin (< 1 nM), but antagonised the response at higher concentrations of secretin (> 1 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Secretin and vasoactive intestinal peptide are potent stimulants of cellular contraction and accumulation of cyclic AMP in rat ventricular cardiomyocytes. 752 89

1. The effects of the cyclic nucleotide phosphodiesterase (PDE) inhibitors, Ro20,1724, 3-isobutyl-1-methylxanthine (IBMX), trifluoperazine (TFP) and amrinone on pancreatic exocrine secretion were investigated in anaesthetized dogs in comparison with those of secretion and cholecystokinin octapeptide (CCK-8). 2. Ro20,1724 (1-30 nmol/kg), IBMX (3-30 nmol/kg), secretin (0.01-0.1 pmol/kg) or CCK-8 (0.1-1 pmol/kg) injected i.a. elicited a dose-dependent increase in the secretion of pancreatic juice, but TFP and amrinone (up to 1 mumol/kg) did not. 3. The bicarbonate concentration in pancreatic juice was increased and the protein concentration was decreased by Ro20,1724, IBMX and secretin. Cholecystokinin octapeptide increased the protein concentration but did not alter the bicarbonate concentration. 4. Ro20,1724 and IBMX elicited more than the respective additive secretory response when added together with secretin, although the stimulatory effects of CCK-8 with Ro20,1724 and IBMX were additive. 5. Ro20,1724 and IBMX increased cyclic AMP concentration but did not affect cyclic GMP concentration. 6. These results suggest that Ro20,1724 and IBMX have secretory properties on pancreatic exocrine glands of the dog, which may be mediated through an increase in cyclic AMP subsequent to inhibition of PDE activity. Furthermore, pancreatic PDE enzymes in the dog may be mainly type IV.
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PMID:Effects of cyclic nucleotide phosphodiesterase IV inhibitor, Ro20,1724, on pancreatic exocrine secretion in dog. 752 65


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