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)

1. The activities of the enzymes involved in the metabolism of cyclic nucleotides were studied in sarcolemma prepared front guinea-pig heart ventricle; the enzyme activities reported here were linear under the assay conditions. 2. Adenylate cyclase was maximally activated by 3mM-NaF; NaF increased the Km for ATP (from 0.042 to 0.19 mM) but decreased the Ka for Mg2+ (from 2.33 to 0.9 mM). In the presence of saturating Mg2+ (15 mM), Mn2+ enhanced adenylate cyclase, whereas Co2+ was inhibitory. beta-Adrenergic amines (10-50 muM) stimulated adenylate cyclase (38+/-2%). When added to the assay mixture, guanyl nucleotides (GTP and its analogue, guanylyl imidophosphate) stimulated basal enzyme activity and enhanced the stimulation by isoproterenol. By contrast, preincubation of sarcolemma with guanylyl imidodiphosphate stimulated the formation of an 'activated' form of the enzyme, which did not reveal increased hormonal sensitivity. 3. The guanylate cyclase present in the membranes as well as in the Triton X-100-solubilized extract of membranes exhibited a Ka for Mn 2+ of 0.3 mM; Mn2+ in excess of GTP was required for maximal activity. Solubilized guanylate cyclase was activated by Mg2+ only in the presence of low Mn2+ concentrations; Ca2+ was inhibitory both in the absence and presence of low Mn2+. Acetylcholine as well as carbamolycholine stimulated membrane-bound guanylate cyclase. 4. Cylic nucleotide phosphodiesterase activities of sarcolemma exhibited both high-and low-Km forms with cyclic AMP and with cyclic GMP as substrate. Ca2+ ions increased the Vmax. of the cyclic GMP-dependent enzyme.
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PMID:Adenylate cyclase, guanylate cyclase and cyclic nucleotide phosphodiesterases of guinea-pig cardiac sarcolemma. 1 Aug 95

The metabolic effects of imidazole were tested in rat renal cortex. Imidazole enhanced the activity of renal cortical phosphodiesterase in vitro. Imidazole inhibited glucose production in a dose-dependent fashion from a variety of substrates in the gluconeogenic pathway proximal to the triose phsophates. The stimulation in renal gluconeogenesis resulting from isoproterenol and parathyroid hormone was inhibited by imidazole. These changes correlated with an inhibition of the augmented levels of renal cortical cyclic AMP levels produced by these hormones. These studies indicate that imidazole is an effective activator of phosphodiesterase in intact renal cells and lend further support to the suggestion that the stimulation of renal gluconeogenesis produced by isoproterenol and parathyroid hormone is mediated by a release of cyclic AMP.
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PMID:Effect of imidazole on renal gluconeogenesis. 1 Sep 72

Experiments were made to determine whether cyclic AMP plays a role in transmission at identified dopaminergic synapses in the water snail Planorbis corneus. Intracellular stimulation of a specific dopamine neuron produces direct inhibitory postsynaptic potentials (ipsps) in a number of other neurons. These ipsps, which are mediated by dopamine, were potentiated by as much as 120% by caffeine, theophylline or dibutyryl cyclic AMP, although they were unaffected by cyclic AMP and prostaglandin E1. Caffeine and theophylline also potentiated the inhibitory response to dopamine, applied to the postsynaptic neurons by perfusion or iontophoresis, but the effects were generally much smaller (maximum potentiation 30%). The results provide evidence that postsynaptic cyclic AMP is involved in transmission at these synapses, but that the phosphodiesterase inhibitors may also have a presynaptic effect.
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PMID:Potentiation of dopaminergic transmission by phosphodiesterase inhibitors and cyclic nucleotides. 1 61

The influence of amitryptiline, theophylline and furosemide on the concentration of cyclic-AMP and plasma renin activity (PRA) was investigated in renal vein plasma. Additionally, the stimulating effect of furosemide on the PRA after application of the beta-adrenergic receptor antagonists propranolol and practolol and the cyclic AMP concentration in the plasma were measured. All drugs were given intravenously. After amitryptiline cyclic-AMP concentration increased about 1.5-fold compared with the basal value,PRA was not altered. After theophylline cyclic-AMP concentration increased about 1.2-fold, PRA 2.0-fold compared with the basal value, PRA was not altered. After theophylline cyclic-AMP concentration increased about 1.2-fold, PRA 2.0-fold coa increased within 7 min and no further increase was observed till the 15th min. After practolol cyclic-AMP concentration and PRA decreased about 20% compared with the basal value within 10 min. The stimulating effect of subsequently applied furosemide on PRA was not altered, but the cyclic-AMP concentration was not changed in this time by furosemide. After propranolol cyclic-AMP concentration and PRA decreased about 20% compared with the basal value. The cyclic-AMP concentration was not influenced by the following furosemide application, in agreement with the findings after practolol, however, PRA could be stimulated only in 36% of these patients under beta-receptor blockade. Our results show that changes of the concentrations of cyclic-AMP and of PRA are independent of each other. An elevated intracellular cyclic-AMP level due to the inhibition of phosphodiesterase is as a single factor unable to stimulate renin release. Our results give no evidence of a direct involvement of the adenylcyclase-system in the mechanism of renin release. The effect of propranolol and practolol on the basal value of PRA and cyclic-AMP is equal. The different influence of 10 mg propranolol and 20 mg practolol on the stimulating effect of 40 mg furosemide on the PRA can be interpreted as a dosage problem.
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PMID:[Cyclic AMP and plasma renin activity in renal vein blood after amitryptiline, theophylline, furosemide and beta adrenergic blocking substances (author's transl)]. 1 4

ADP-induced platelet aggregation and shape change were monitored optically in citrated rabbit platelet-rich plasma (PRP) diluted with isotonic salt solutions. Lithium (Li) produced a concentration-dependent reduction in the rate of platelet aggregation but had no discernible effect on the shape change which precedes aggregation. When PRP was pre-incubated with Li, the inhibitory effect of the ion was independent of the duration and temperature of the treatment. The inhibitory effect of Li also was observed in heparinized PRP or when 5-HT was used as the aggregation-inducing agent. When Li was combined with aggregation inhibitors which enhance platelet cyclic AMP content either by activating adenylate cyclase or by inhibiting phosphodiesterase, only additive effects were observed. The inhibitory effect of Li was opposed by added calcium. Kinetic evaluation of the interaction between Li and Ca indicated that their antagonism was competitive. Added calcium also displayed competitive antagonism toward the aggregation inhibiting effect of increased hydrogen ion concentration in the pH range between 6 and 8.
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PMID:Competitive inhibition by lithium and hydrogen ions of the effect of calcium on the aggregation of rabbit platelets. 1 92

A highly purifed preparation of rat intestinal phosphodiesterase II (oligonucleate 3'-nucleotidohydrolase, EC 3.1.4.18) has been studied using a synthetic substrate, thymidine 3'(2,4-dinitrophenyl) phosphate. The enzyme was most active between pH 6.1 and pH 6.7 and was inhibited by Cu2+ and Zn2+ but unaffected by EDTA, Mg2+, Co2+, and Ni2+. The reaction rate decreased at high levels of enzyme because of competitive inhibition by deoxythymidine 3'-phosphate, a reaction product, which showed a Ki of 2-10(-5) M. The molecular weight of the enzyme by gel-filtration was 150 000-170 000. In electrofocusing experiments multiple peaks of activity were found at pH 3.4, 4.2-4.5and 7.2. Polyacrylamide gel electrophoresis of freshly purified phosphodiesterase II showed up to 10 protein bands in the gels. If the preparations were stored at 4 degrees C for some time only one or two bands appeared. Investigation of the reaction of rat intestinal phosphodiesterase II with a number of possible phosphodiesterase substrates indicated that the enzyme required a nucleoside 3'-phosphoryl residue for the initiation of hydrolysis. Thus compounds such as NAD, ATP, bis-(p-nitrophenyl)phosphate, thymidine 5'-(p-nitrophenyl)phosphate, glycerylphosphorylcholine, guanylyl-(2' leads to 5')-adenosine and 3',5'-cyclic AMP which contain phosphodiester bonds, nevertheless were not substrates for the enzyme. The enzyme was inhibited reverisbly by p-chloromercuribenzoate and p-chloromercuriphenylsulfonate and inactivated irreversibly by iodoacetic acid. Activity of the phosphodiesterase II was reduced to 50% by incubation with 2.0-10(-3)--5.0-10(-3) M iodoacetate for 20--30 min at 24 degrees C at pH 5.0--6.1. Iodoacetamide had no effect. The degree of inactivation by iodoacetate was reduced by the presence of a substrate for the enzyme or, more effectively by deoxythymidine 3'-phosphate, a competitive inhibitor. It is concluded that iodoacetic acid alkylates an essential residue at the active centre of the enzyme.
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PMID:Rat intestinal phosphodiesterase II. Properties of the highly purified enzyme and its inactivation by iodoacetic acid. 1 24

Phosphodiesterase activities of horse (and dog) thyroid soluble fraction were compared with either cyclic AMP (adenosine 3':3'-monophosphate) or cyclic GMP (guanosine 3':5'-monophosphate) as substrate. Optimal activity for cyclic AMP hydrolysis was observed at pH 8, and at pH 7.6 for cyclic GMP. Increasing concentrations of ethyleneglycol bis(2-aminoethyl)-N,N'-tetraacetic acid inhibited both phosphodiesterase activities; in the presence of exogenous Ca2+, this effect was shifted to higher concentrations of the chelator. In a dialysed supernatant preparation, Ca2+ had no significant stimulatory effect, but both Mg2+ and Mn2+ increased cyclic nucleotides breakdown. Mn2+ promoted the hydrolysis of cyclic AMP more effectively than that of cyclic GMP. For both substrates, substrate velocity curves exhibited a two-slope pattern in a Hofstee plot. Cyclic GMP stimulated cyclic AMP hydrolysis, both nucleotides being at micromolar concentrations. Conversely, at no concentration had cyclic AMP any stimulatory effect on cyclic GMP hydrolysis. 1-Methyl-3-isobutylxanthine and theophylline blocked the activation by cyclic GMP of cyclic GMP of cyclic AMP hydrolysis, whereas Ro 20-1724 (4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone), a non-methylxanthine inhibitor of phosphodiesterases, did not alter this effect. In dog thyroid slices, carbamoylcholine, which promotes an accumulation of cyclic GMP, inhibits the thyrotropin-induced increase in cyclic AMP. This inhibitory effect of carbamoylcholine was blocked by theophylline and 1-methyl-3-isobutylxanthine, but not by Ro 20-1724. It is suggested that the cholinergic inhibitory effect on cyclic AMP accumulation is mediated by cyclic GMP, through a direct activation of phosphodiesterase activity.
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PMID:Cyclic nucleotide hydrolysis in the thyroid gland. General properties and key role in the interrelations between concentrations of adenosine 3':5'-monophosphate and guanosine 3':5'-monophosphate. 1 74

The understanding of the properties of adrenergic receptors and modification of ring and the N-alkyl side chain constituents have resulted in adrenergic agents with a high degree of specificity for the lung and few cardiac and central nervous system stimulating problems. These agents are useful by aerosol and oral routes, alone and in addition to theophylline for asthma. Theophylline, which acts to increase cyclic AMP by inhibition of phosphodiesterase and beta 2 adrenergic agents which increase cyclic AMP by stimulating adenylate cyclase, are the mainstays of asthma therapy. Therapy is usually begun with theophylline. Persistent symptoms with adequate theophylline levels (10-20 mug/ml) indicates the need for a beta 2 adrenergic agent by aerosol or orally as a supplement. Occasional patients will not tolerate theophylline in any preparation and can be treated with beta 2 adrenergic agents with success. The future holds great promise for improved and safer beta 2 adrenergic agents which will offer the physician a more effective means of treating asthma.
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PMID:Treatment of asthma with theophylline and beta adrenergic agents. 1 64

Two soluble forms of 3':5'-cyclic-nucleotide phosphodiesterase (o':5'-cyclic-nucleotide 5'-nucleotidohydrolase, EC 3.1.4.17) were found in the larval fat body of the silkmoth Hyalophora cecropia. These differ in elution profile on Sephadex G-200, solubility in ammonium sulfate, metal ion requirements and kinetic properties. Phosphodiesterase I has Km values of 11 muM and 1.8 muM for cyclic AMP and cyclic GMP, respectively, has 5-fold greater maximal activity with cyclic AMP than with cyclic GMP, and is activated by Mg2+ and Co2+, and inhibited by EDTA. phosphodiesterase II has Km values of 625 muM and 125 muM for cyclic AMP and cyclic GMP, respectively, has similar maximal activity with both substrates, and is not activated by divalent metal ions or inhibited by EDTA. Cyclic nucleotides and methylxanthines competitively inhibit both enzymes. Phosphodiesterase is found in both soluble and particulate fractions of homogenates. Total activity is highest during the larval stage of the insect, drops markedly following pupation, and rises again during pharate adult development.
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PMID:Cyclic nucleotide phosphodiesterases of Hyalophora cecropia silkmoth fat body. 1 89

Beta-Adrenoceptor tachyphylaxis was induced by incubating spirally cut guinea pig tracheas with isoproterenol (2.4 x 10(-7) M) for 20 min. This incubation reduced the relaxant effects of catecholamines but not of dibutyryl cyclic AMP, theophylline or sodium nitrite. Tracheas incubated with norepinephrine, phosphodiesterase inhibitors or cyclic nucleotides became tachyphylactic to isoproterenol. Pretreatment with indomethacin prevented induction of tachyphylaxis. Incubation with adenosine, methoxamine or sodium nitrite did not induce beta-adrenoceptor tachyphylaxis. When we gave isoproterenol intramuscularly to guinea pigs, airway sensitivity to aerosolized histamine was unchanged but the toxicity of parenterally administered histamine was increased. A prolonged treatment with isoproterenol reduced airway sensitivity to histamine aerosols; this reduced sensitivity was reversed by indomethacin. Thus, beta-adrenoceptor tachyphylaxis may not explain increased toxicity of parenteral histamine after isoproterenol treatment. Elevated levels of cyclic AMP and an increased synthesis of prostaglandins may result in diminished response to beta-receptor stimulation.
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PMID:Tachyphylaxis to beta-adrenoceptor agonists in guinea pig airway smooth muscle in vivo and in vitro. 1 46


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