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)

Topically administered salbutamol was extremely effective in suppressing immediate allergic conjunctivitis in the guinea pig; a dose as low as 0.1% elicited 98% inhibition. Topical pretreatment with 1% propranolol completely blocked the suppressant action of 0.1% salbutamol. This was also the case after systemic propranolol (1 mg/kg SC); the beta-adrenoceptor antagonist itself has no effect on antigen-induced inflammation. The effect of 0.1% salbutamol was unaltered by pretreatment with the specific beta 1-adrenoceptor antagonist betaxolol (1 mg/kg SC). In marked contrast, the suppressant action of 0.1% salbutamol was profoundly inhibited by pretreatment with the selective beta 2-adrenoceptor antagonist ICI-118,551 (0.5 mg/kg SC). The experiments employing beta-adrenoceptor antagonists unequivocally demonstrate that the salbutamol suppression of immediate allergic conjunctivitis in the guinea pig is mediated via the activation of beta 2-adrenoceptors. The methylxanthine phosphodiesterase inhibitor theophylline was active after oral administration, 50 mg/kg eliciting an 80% inhibition. Theophylline was inactive topically at 1% and 5%, but this could be due to the fact that the compound was insoluble at these concentrations. Thus, procedures that elevate cyclic-AMP levels suppress immediate hypersensitivity reactions in the guinea pig conjunctiva. Whether or nor this offers an alternative approach to treat allergic conjunctivitis in humans remains to be determined.
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PMID:The ability of salbutamol and theophylline to suppress immediate allergic conjunctivitis in the guinea pig. 366 75

1. Cyclic AMP and cyclic GMP levels were determined in bovine splenic nerve segments in the absence and presence of (+/-)-isoprenaline, (-)-phenylephrine, clonidine and ICI 63 197 (a phosphodiesterase inhibitor). The chosen concentrations of adrenoceptor agonists were those which are known to affect stimulation-induced overflow of noradrenaline from nerve terminals. 2. The mean levels of cyclic AMP ranged from 229 to 555 pmol/g of microwave irradiated tissue. Mean cyclic GMP levels ranged from 27.9 to 42.2 pmol/g. 3. Isoprenaline enhanced cyclic AMP levels but did not affect cyclic GMP levels. The effect was blocked with (+/-)-propranolol. ICI 63 197 increased cyclic AMP levels but did not change cyclic GMP. Phenylephrine and clonidine caused no consistent changes in cyclic AMP or cyclic GMP levels or in the concentration ratio between these two nucleotides. 4. The results support the involvement of cyclic AMP in the enhancing effect of beta-adrenoceptor agonists and phosphodiesterase inhibitors on stimulation-induced release of noradrenaline from sympathetic nerves.
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PMID:Effects of alpha- and beta-adrenoceptor agonists and a phosphodiesterase inhibitor (ICI 63 197) on cyclic AMP and GMP levels in bovine splenic nerve. 613 92

Primary culture of bovine adrenal subcapsular cells was used to investigate direct effects of catecholamines on aldosterone secretion. Cells dispersed with collagenase and DNAse and cultured at high density (1.5-2 million/ml) for 3 days displayed high sensitivity to angiotensin II and ACTH, with an ED50 of 1.4 and 1.5 nM, respectively. Adrenergic agonists elicited a 4- to 6-fold stimulation of aldosterone secretion with potency order (-)isoproterenol greater than (-)epinephrine equals (-)norepinephrine greater than (+)isoproterenol, and corresponding ED50 5, 240, 213, and 3000 nM, respectively. No reproducible inhibition by dopamine of basal or stimulated levels of aldosterone secretion could be detected, but a weak stimulatory effect was sometimes observed at high concentration greater than 10 microM. (-)Isoproterenol stimulation of aldosterone production was potently inhibited by the beta-adrenergic antagonists (-)alprenolol and (+)alprenolol with potencies of 1.8 and 110 nM, respectively. The alpha-adrenergic antagonists prazosin, yohimbine, and phentolamine only weakly inhibited (-)isoproterenol stimulation with potencies of 5, 13, and 140 microM, respectively. The potent beta 2-adrenergic antagonist ICI 118.551 and the weaker beta 1-adrenergic antagonist atenolol were roughly equipotent with potencies of 0.27 and 0.44 microM, respectively. Addition of the phosphodiesterase inhibitor Ro 20-1724 at 10 microM doubled the maximum stimulation effect of (-)isoproterenol without changing the potency of the catecholamine or the basal level of aldosterone secretion, suggesting a potential role of cAMP as a mediator of isoproterenol stimulation. These results indicate the presence of a beta 1-adrenergic receptor stimulating aldosterone secretion in bovine zona glomerulosa cells. The physiological significance of direct beta-adrenergic stimulation of aldosterone production is currently being assessed.
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PMID:Direct beta-adrenergic stimulation of aldosterone secretion in cultured bovine adrenal subcapsular cells. 614 9

The effect of different phosphodiesterase (PDE) inhibitors on the antigen or 48/80 induced histamine release from isolated Hooded Lister rat mast cells was tested. The unselective PDE inhibitors theophylline (2.5 mM) and IBMX (0.2 mM) and the selective cyclic GMP PDE inhibitor M & B 22948 (0.1 mM) inhibited the antigen induced histamine release by 50% while 48/80 induced release was inhibited by about 25%. The cyclic AMP selective PDE inhibitors ICI 63197 (0.5 mM) or Ro 20-1724 (0.2 mM) had no effect on 48/80 induced histamine release but tended to enhance antigen induced release. There was no correlation between the measured levels of cyclic AMP and the effect on histamine release by the investigated PDE inhibitors. Cyclic AMP or cyclic GMP up to 10(-3) M did not affect the anaphylactic histamine release. Dibutyryl-cAMP and dibutyryl-cGMP (10(-4) M) both inhibited the release about 20% but this effect could be explained by the effect of butyric acid as sodium butyrate (2 X 10(-4) M) also inhibited the release by 20%. The presence results suggest that cyclic nucleotides are not important regulators of histamine release from isolated mast cells.
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PMID:Evidence against a role of cyclic nucleotides in the regulation of anaphylactic histamine release in isolated rat mast cells. 616 52

The significance of a characteristic symptomatology (hypothermia, hypoactivity, forepaw shaking, grooming, head twitches) as a potential in vivo correlate of enhanced availability of brain adenosine cyclic 3',5'-monophosphate (cAMP) was examined in rats following systemic administration of various doses of dibutyryladenosine cAMP (dBcAMP) or of the phosphodiesterase (PDE) inhibitors rolipram, Ro 20-1724, ICI 63-197, isobutylmethylxanthine (IBMX) theophylline, cartazolate, and papaverine. The various PDE inhibitors could be assigned to three groups according to the pattern of behavioral alterations they induced. Rolipram, Ro 20-1724, and ICI 63-197 (group 1) caused hypothermia, hypoactivity, forepaw shaking, grooming, and head twitches. All behavioral effects were mimicked by dBcAMP but not dBcGMP. The order of potency and effective dosage range to induce the behavioral alterations were, in descending order, rolipram (0.09-1453 mumol/kg IP), ICI 63-197 (0.48-119 mumol/kg IP), Ro 20-1724 (5.6-1438 mumol/kg IP), corresponding with the recently reported efficacy of the drugs to elevate rat brain cAMP in vivo. Comparatively high doses of the alkylxanthine PDE inhibitors IBMX and theophylline (group 2) caused hypothermia, forepaw shaking, grooming, and head twitches concomitantly with a decline of the motor stimulatory effect, suggesting enhanced availability of brain cAMP. The order of potency and the effective dosage range to induce the behavioral alterations were, in descending order, IBMX (28.1-113 mumol/kg IP) and theophylline (139-555 mumol/kg IP). The third group, papaverine (295-1179 mumol/kg IP) and cartazolate (21.5-345 mumol/kg IP), caused only hypothermia and hypoactivity. The differences in the behavioral pattern of the two latter groups of compounds in comparison with dBcAMP and the selective cAMP PDE inhibitors are discussed with regard to their additional interference with adenosine actions besides their nonselective PDE inhibitory action.
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PMID:Characteristic behavioural alterations in rats induced by rolipram and other selective adenosine cyclic 3', 5'-monophosphate phosphodiesterase inhibitors. 618 75

1 To test the possibility that adenosine receptors exist within the trachea of the guinea-pig, an attempt has been made to identify a compound with adenosine antagonist activity in this tissue.2 Quinidine, phentolamine, phenoxybenzamine, 2-2'-pyridylisatogen tosylate (PIT) and caffeine were tested for antagonism of spasmolytic responses to adenosine, adenosine 5'-triphosphate (ATP) and adenine on the guinea-pig isolated trachea.3 Quinidine (10 and 25 mug/ml), phentolamine (10 and 30 mug/ml) and phenoxybenzamine (10 mug/ml) had little or no effect on response to adenosine, ATP and adenine. PIT (21 mug/ml) potentiated responses to adenosine, ATP and adenine by an unexplained mechanism.4 Caffeine (25 mug/ml) partially relaxed the trachea and inhibited spasmolytic responses to both adenosine and ATP, but not to adenine, isoprenaline, aminophylline or prostaglandin E(2) (PGE(2)).5 A number of compounds related to caffeine (xanthine, hypoxanthine, theophylline and theobromine) were tested for adenosine antagonist activity. Xanthine (300 mug/ml) and hypoxanthine (300 mug/ml) did not relax the trachea or antagonize spasmolytic responses to adenosine. Both theophylline (10 mug/ml) and theobromine (30 mug/ml) partially relaxed the trachea; theophylline, but not theobromine, antagonized spasmolytic responses to adenosine.6 pA(2) values for caffeine and theophylline as antagonists of adenosine were 4.3 and 4.7 respectively. However, the slopes of the Schild plot regressions were significantly less than 1.0 for both compounds.7 Four compounds, adenine, AH 8883, M30966 and ICI 63197, which like caffeine and theophylline, have phosphodiesterase inhibitory activity were tested for adenosine antagonist activity in the trachea. Adenine and AH 8883 had no effect and M30966 and ICI 63197 caused significant potentiation.8 The effects of caffeine and theophylline were also investigated on the non-adrenergic inhibitory response to nerve stimulation (NAIR). Both caffeine (100 mug/ml, n = 4) and theophylline (30 mug/ml, n = 4) enhanced the NAIR (20 Hz) while virtually abolishing matched responses to exogenous adenosine.9 The results support the existence of adenosine receptors in the guinea-pig trachea.
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PMID:Purine antagonists in the identification of adenosine-receptors in guinea-pig trachea and the role of purines in non-adrenergic inhibitory neurotransmission. 624 33

1. Cyclic AMP levels have been determined in the soleus muscles of anaesthetized cats in the absence of drugs, and during depression of incomplete tetanic contractions produced by (-)-isoprenaline, ICI 63,197 (a phosphodiesterase inhibitor) or levodopa. 2. Cyclic AMP levels were elevated at the peak of tension depression produced by isoprenaline. Effects of isoprenaline on cyclic AMP and on contractions were dose dependent and statistically significantly related one to the other. Both effects were blocked by propranolol. 3. ICI 63,197 and levodopa produced isoprenaline-like effects on contractions but times to peak effect and recovery were longer. Cyclic AMP levels estimated during the depressant action were elevated. 4. The results support the involvement of cyclic AMP in the depressant effect of beta-adrenoreceptor agonists on slow-contracting mammalian skeletal muscle.
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PMID:Effects of isoprenaline, levodopa and a phosphodiesterase inhibitor (ICI 63,197) on cyclic AMP levels and contractions of soleus muscles in anesthetized cats. 625 31

Following intraperitoneal administration, the selective cAMP phosphodiesterase (PDE) inhibitors rolipram, ICI 63 197 and Ro 20-1724 were investigated in mice in comparison with imipramine for their effectiveness in two classical test models for prediction of clinical antidepressant activity: antagonism of reserpine-induced hypothermia or hypokinesia and potentiation of yohimbine lethality. Rolipram was approximately 15 times more potent than imipramine or Ro 20-1724 and approximately as potent as ICI 63 197 in antagonizing reserpine-induced hypothermia. The antihypothermic effect of the phosphodiesterase inhibitors occurred at a smaller dose than that of imipramine. In contrast to imipramine, the phosphodiesterase inhibitors reversed reserpine-induced hypokinesia. Rolipram was approximately as potent as ICI 63 197 and about 15 times more potent than Ro 20-1724. Rolipram was approx. 5 times more potent than Ro 20-1724 and approx. as potent as imipramine or ICI 63 197 in potentiating the lethality of yohimbine. In both test models the (-)-isomer of rolipram was approx. 10-15 times more potent than the (+)-isomer, indicating a stereospecific mechanism of action. The present data suggest an antidepressant action of selective cAMP phosphodiesterase inhibitors due to enhancement of central noradrenergic transmission. The hypothesis is put forward that the increase of noradrenaline turnover induced by phosphodiesterase inhibitors in conjunction with the inhibitory action of the compounds on cAMP metabolism enables more efficient adaptative changes to occur at central synapses resulting in a rapid onset of the antidepressant activity. Preliminary results with rolipram in patients with endogenous depression seem to support this assumption.
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PMID:Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors. 630 50

A luteinizing hormone-releasing hormone (LHRH) agonist (ICI 118630) potentiated the effects of luteinizing hormone (LH) and dibutyryl cyclic AMP on steroidogenesis during 4 h incubations with rat Leydig cells. LH-stimulated cyclic AMP levels were decreased by the addition of the LHRH agonist. The potentiation of the LH-increased steroidogenesis was dependent on Ca2+; maximum effects required at least 2.5 mM Ca2+ in the incubation medium. The calcium ionophore A23187 negated the potentiation in a dose-dependent manner (ED50 = 0.2-0.3 microM), but had no effect on LH-induced steroidogenesis, despite a 90% decrease in cyclic AMP production. The latter decrease was found to be dependent on the Ca2+ concentration. In the presence of the phosphodiesterase inhibitor methylisobutylxanthine (MIX), the ionophore A23187 induced a dose-dependent decrease in both LH and LH plus LHRH agonist-stimulated steroidogenesis and cyclic AMP production. The results obtained indicate that calcium, rather than cyclic AMP, is the mediator of the potentiating effects of LHRH agonist on LH-increased steroidogenesis in rat Leydig cells. The marked inhibition of the synergism in the presence of calcium ionophore A23187 suggests that Leydig cell calcium homeostasis must be intact for LHRH agonist action to occur. LHRH agonist causes a Ca2+-dependent decrease in LH-stimulated cyclic AMP production.
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PMID:The effect of calcium on the potentiation of LH-stimulated steroidogenesis and inhibition of LH-stimulated cyclic AMP production by LHRH agonist (ICI 118630) in rat Leydig cells. 632 Dec 72

The possible involvement of cyclic AMP in the stimulation-evoked 3H-overflow from rabbit isolated ear artery preloaded with 3H-noradrenaline was studied. Cyclic AMP (10(-5)-3 x 10(-4)M), 8-bromo-cyclic AMP (3 x 10(-4)M) and adenosine (10(-5)-3 x 10(-4)M) enhanced stimulation-evoked 3H-overflow. Dibutyryl-cyclic AMP (10(-5)-3 x 10(-4)M) had no effect. Theophylline (3 x 10(-5)M) and the phosphodiesterase inhibitor AH 21-132 (3 x 10(-5)M) did not alter the enhancement of 3H-overflow caused by either cyclic AMP or adenosine. Forskolin (3 x 10(-6)M) and the phosphodiesterase inhibitors ICI 63 197 (10(-4)M) and AH 21-132 (3 x 10(-6)-3 x 10(-5)M) increased stimulation-evoked 3H-overflow. Forskolin (10(-6)M) enhanced the effect of ICI 63 197 (3 x 10(-5)M) but it did not alter the effect of AH 21-132. It is concluded that cyclic AMP is involved in the stimulation-evoked release of noradrenaline from postganglionic sympathetic nerves in the rabbit ear artery.
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PMID:Role of cyclic AMP in stimulation-evoked release of 3H-noradrenaline from rabbit isolated ear artery. 761 43


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