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)

Treatment of NIH 3T3 cells with adenylate cyclase activator adrenaline (10(-6) M) or cAMP phosphodiesterase inhibitor theophylline (10(-3) M) was shown to lead to intracellular cAMP elevation followed by a 2.0-to 2.5-fold increase in the 2',5'-oligoadenylate synthetase activity. This process was blocked by actinomycin D. The rise in the intracellular cAMP level was also followed by a 3-4-fold decrease in the activity of 2'-phosphodiesterase. Propranolol prevented this inhibition but actinomycin D produced only a negligible effect on the process. Incubation of the cell homogenate with purified catalytic subunit of cAMP-dependent protein kinase and ATP also resulted in a decrease of 2'-phosphodiesterase activity. These results indicate that cAMP is involved in the regulation of enzymes of the 2',5'-oligoadenylate system. The possibility that certain biological functions of cAMP are implemented via 2',5'-oligoadenylate-dependent processes is discussed.
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PMID:Cyclic AMP-dependent regulation of activities of synthetase and phosphodiesterase of 2',5'-oligoadenylate in NIH 3T3 cells. 632 57

Right atria from rats were analyzed for chronotropic responses to phenylephrine in face of various drugs and procedures. Propranolol, 10(-8) M, produced a competitive antagonism against the agonist which concentration-effect curve was closely similar to that obtained from reserpinized animals. Prazosin, but not phentolamine (both 10(-6) M) showed inhibition of the phenylephrine-induced changes in heart rate, as judged by their -log EC50. Either of the alpha-adrenoceptor antagonists exhibited a greater steepness in the curve slope with respect to control. The simultaneous exposure of tissues to phentolamine and propranolol proved to effectively antagonize the chronotropic effect of the agonist. This held true for phentolamine assayed in atria from reserpine-pretreated rats. Previous incubation of tissues with papaverine, 10(-5) M, brought about supersensitivity to phenylephrine which was thoroughly inhibited by either phentolamine or propranolol. These results strongly suggest that beta-adrenoceptor stimulation of heart rate by phenylephrine takes place indirectly via norepinephrine release. There is also alpha 1-adrenoceptor stimulation (blocked by prazosin). Finally, it is hypothesized that supersensitivity develops by papaverine-enhanced Ca2+ influx, since numerous evidences are against a phosphodiesterase inhibition-dependent cAMP accumulation mechanism triggered by papaverine in the presence of phenylephrine.
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PMID:Antagonism and supersensitivity to phenylephrine-induced chronotropic responses. 667 6

The effect of vesnarinone (OPC-8212), an orally active positive inotropic agent was studied in tracheal muscle isolated from guinea pigs, and the mechanism of its action was analyzed. Vesnarinone (10(-6)-10(-4) M) caused a concentration-dependent relaxation of tracheal muscle pre-contracted by 10(-4) M histamine. The potency of the relaxing effect of vesnarinone was greater than that of theophylline; the pD2 values for vesnarinone and theophylline were 4.9 and 4.5, respectively. Vesnarinone reduced the high-K(+)-induced contracture of depolarized tracheal muscle non-competitively (pD'2 = 3.7). Vesnarinone at the low concentration of 3 x 10(-6) M shifted the concentration-response curve for isoproterenol in a parallel fashion to the left. Vesnarinone additively acted on the relaxing effect of isobutyl methyl xanthine. Propranolol (10(-5) M) and reserpine pre-treatment (5 mg/kg, i.p., 24 hr) had no effect on the relaxing effect of vesnarinone. These results suggested that vesnarinone elevated the intracellular cyclic AMP level via phosphodiesterase inhibition, resulting in the tracheal muscle relaxation.
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PMID:Relaxing effect of vesnarinone (OPC-8212) on the tracheal muscle strips isolated from guinea pigs. 769 Apr 33

1. SCA40 (1nM-10 microM), isoprenaline (1-300 nM) and levcromakalim (100 nM-10 microM) each produced concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachea. Propranolol (1 microM) markedly (approximately 150 fold) antagonized isoprenaline but did not antagonize SCA40. The tracheal relaxant action of SCA40 was unaffected by suramin (100 microM) or 8-(p)-sulphophenyltheophylline (8-SPT; 140 microM). 2. An isosmolar, K(+)-rich (80 mM) Krebs solution increased tracheal tone, antagonized SCA40 (approximately 60 fold), antagonized isoprenaline (approximately 20 fold) and very profoundly depressed the log concentration-effect curve for levcromakalim. Nifedipine (1 microM) did not itself modify the relaxant actions of SCA40, isoprenaline or levcromakalim. However, nifedipine prevented the rise in tissue tone and the antagonism of SCA40 and isoprenaline induced by the K(+)-rich medium. In contrast, nifedipine did not prevent the equivalent antagonism of levcromakalim. 3. Charybdotoxin (100 nM) increased tracheal tone, antagonized SCA40 (approximately 4 fold) and antagonized isoprenaline (approximately 3 fold). Nifedipine (1 microM) prevented the rise in tissue tone and the antagonism of SCA40 and isoprenaline induced by charybdotoxin. 4. Quinine (30 microM) caused little or no change in tissue tone and did not modify the relaxant action of isoprenaline. However, quinine antagonized SCA40 (approximately 2 fold). Nifedipine (1 microM) prevented the antagonism of SCA40 induced by quinine. 5. Tested on spontaneously-beating guinea-pig isolated atria SCA40 (1 nM-10 microM) increased the rate of beating in a concentration-dependent manner. Over the concentration-range 1 microM-10 microM, SCA40 also caused an increase in the force of atrial contraction. 6. Intracellular electrophysiological recording from guinea-pig isolated trachealis showed that the relaxant effects of SCA40 (1 micro M) were often accompanied by the suppression of spontaneous electrical slow waves but no change in resting membrane potential. When the concentration of SCA40 was raised to 10 micro M, its relaxant activity was accompanied both by slow wave suppression and by plasmalemmal hyperpolarization.7. SCA40 (10 nM- 100 micro M) more potently inhibited the activity of cyclic AMP phosphodiesterase (PDE)than that of cyclic GMP PDE derived from homogenates of guinea-pig trachealis. Theophylline(1 micro M- 1O mM) also inhibited these enzymes but was less potent than SCA40 in each case and did not exhibit selectivity for inhibition of cyclic AMP hydrolysis.8. Tested against the activity of the isoenzymes of cyclic nucleotide PDE derived from human blood cells and lung tissue, SCA40 proved highly potent against the type III isoenzyme. It was markedly less potent against the type IV and type V isoenzymes and even less potent against the isoenzymes types I and II.9. It is concluded that the tracheal relaxant action of SCA40 (1 nM- 1 micro M) does not involve the activation of beta-adrenoceptors or P1 or P2 purinoceptors. Furthermore, this action is unlikely to depend upon the opening of BKca channels with consequent cellular hyperpolarization and voltage-dependent inhibition of Ca2+ influx. The tracheal relaxant action of SCA40 (up to 1 micro M) is more likely to depend upon its selective inhibition of the type III isoenzyme of cyclic nucleotide PDE. At concentrations above 1 micro M, SCA40 exerts more general inhibition of the isoenzymes of cyclic nucleotide PDE and may then promote the opening of BKca channels.
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PMID:Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40. 771 10

The mitosis inhibitory pentapeptide, pGlu-Glu-Asp-Ser-GlyOH (EPP), which was isolated from mouse epidermis extracts, belongs to a group of growth inhibitory peptides that all have pyroglutamyl at the N-terminal end. Earlier experiments with crude or partially purified skin extracts have shown that the inhibitory effect could be enhanced by beta-receptor agonists and by dibutyryl cAMP, and that beta-receptor blockade could neutralise it. We now show that treatment with the beta receptor blocker propranolol before or after EPP treatment of hairless mice significantly modifies the effect of EPP on mouse epidermal cell proliferation, as estimated by using a metaphase-arrest technique (Colcemid) to estimate the G2-M cell flux. The interaction between propranolol and EPP is complex; only the EPP-induced inhibition of the G2-M cell flux was modified by beta-receptor blockade, while the late (18-21 h) inhibition of the mitotic rate was unaltered. Propranolol alone was followed by a dose-related and transient increase in the epidermal mitotic rate. The phosphodiesterase inhibitor caffeine had no effect on its own on epidermal cell proliferation but counter-acted the late (18-21 h) EPP-induced inhibition.
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PMID:Beta-receptor blockade by propranolol modifies the effect of the inhibitory, endogenous epidermal pentapeptide on epidermal cell flux at the G2-M transition but not at the G1-S transition. 819 66

The pharmacological activity of atherosperminine, isolated from Fissistigma glaucescens, was determined in isolated guinea-pig trachealis. Atherosperminine (25-100 microM) and theophylline (10-1000 microM) both inhibited the contractile response caused by carbachol, prostaglandin F2 alpha (PGF2 alpha), U46619 (thromboxane A2 analogue), leukotriene C4 (LTC4) and Ca2+ (in the presence of 120 mM KCl) in a concentration-dependent manner. The inhibition was characterized by a rightwards shift of the concentration-response curves with suppression of the maximal contraction. Propranolol (1 microM), glibenclamide (10 microM) and removal of tracheal epithelium did not modify the relaxant action of atherosperminine. Atherosperminine (25 and 50 microM) caused a 2.4- and 5.0-fold, respectively, potentiation of the action of forskolin to cause tracheal relaxation but did not potentiate the action of sodium nitroprusside or cromakalim. Atherosperminine (50 microM) potentiated the action of forskolin to increase tissue cAMP content and, in higher concentrations (100 and 250 microM), itself increased tissue cAMP but not cGMP content. Atherosperminine markedly inhibited cAMP phosphodiesterase but not cGMP phosphodiesterase in homogenates of guinea-pig trachealis. It is concluded that atherosperminine exerts a non-specific relaxant effect on the trachealis. Its major mechanism of action appears to be inhibition of cAMP phosphodiesterase, perhaps with a minor effect on cGMP phosphodiesterase at higher concentrations.
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PMID:The relaxant actions on guinea-pig trachealis of atherosperminine isolated from Fissistigma glaucescens. 839 88

To investigate whether a Ca2+ sensitizer increases sinus rate, we studied the effects of racemic thiadiazinone, EMD 53998 (a Ca2+ sensitizer with phosphodiesterase inhibitory action) and its (+)-enantiomer EMD 57033 (a relatively pure Ca2+ sensitizer) on isolated, blood-perfused spontaneously beating right atria and paced left ventricles of the dogs. EMD 53998 increased sinus rate dose-dependently, but EMD 57033 did not. Both substances increased atrial and ventricular contractile force. Propranolol did not affect the responses to each substance. These results suggest that the Ca2+ sensitizing action induced by EMD 57033 does not affect pacemaker currents directly.
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PMID:Different chronotropic and inotropic effects of EMD 57033 and EMD 53998, Ca2+ sensitizers, on isolated, blood-perfused dog heart preparations. 962 23

This study investigates the role of adrenal-derived catecholamines and corticosterone on the inhibition by rolipram, a phosphodiesterase (PDE)-4 inhibitor, of pulmonary eosinophilia and airway hyperresponsiveness (AHR) in allergic mice. The following experimental groups were studied in mice sensitized and challenged with ovalbumin (OVA): normal, adrenalectomized, propranolol (beta-adrenoceptor antagonist) and metyrapone (corticosterone synthesis inhibitor) treated. These interventions were studied both in the absence and in the presence of rolipram. Eosinophil numbers in the bronchoalveolar lavage (BAL) and AHR to methacholine were measured 24 h after OVA challenge. Treatment of sensitized mice with rolipram (0.3 - 10 mg kg(-1), p.o.), inhibited pulmonary eosinophilia and the AHR to methacholine in OVA-challenged mice. Adrenalectomy increased the number of eosinophils in the BAL of OVA-challenged mice but had no effect on AHR to methacholine. Adrenalectomy attenuated both the rolipram-induced inhibition of BAL eosinophilia and AHR to methacholine in OVA challenged mice. Propranolol (10 mg kg(-1), p.o.) had no effect on the inhibition of eosinophilia by rolipram but attenuated the inhibition of AHR to methacholine in OVA challenged mice. On the other hand, metyrapone (10 mg kg(-1), p.o.) attenuated the inhibition of eosinophilia by rolipram but had no effect on the inhibition of AHR to methacholine in OVA challenged mice. Metyrapone-treatment alone increased the number of eosinophils in the BAL of OVA-challenged mice. These results identify an important role for adrenal-derived catecholamines and corticosterone on the inhibition of pulmonary eosinophilia and AHR by rolipram in allergic mice.
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PMID:Inhibition of pulmonary eosinophilia and airway hyperresponsiveness in allergic mice by rolipram: involvement of endogenously released corticosterone and catecholamines. 1080 86


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