Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Treatment with beta-adrenoceptor antagonists in vivo can alter adenylate cyclase responsiveness in the human heart. We have determined the effects of treatment with four different beta-adrenoceptor antagonists in vivo on the responsiveness of lymphocyte and platelet adenylate cyclase in vitro in healthy volunteers. 2. Propranolol (non-selective, 4 x 40 mg day), bisoprolol (beta 1-selective, 1 x 10 mg day), and ICI 118.551 (beta 2-selective, 3 x 25 mg day) were tested as drugs without and pindolol (non-selective, 2 x 5 mg day) as a drug with intrinsic sympathomimetic activity. Adenylate cyclase stimulation by GTP, prostaglandin E1 and forskolin was determined before, after a 7 day treatment period and 7 days after drug withdrawal. 3. Neither treatment with or withdrawal of any of the beta-adrenoceptor antagonists altered adenylate cyclase responsiveness. 4. We conclude that adenylate cyclase responsiveness in circulating blood cells underlies different regulatory mechanisms than that in solid tissues such as the human heart. Our data suggest that circulating blood cells do not always reflect alterations in solid tissues.
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PMID:Does treatment with beta-adrenoceptor antagonists in vivo alter human adenylate cyclase responsiveness in vitro? 167 57

This study was conducted to further characterize the previously described phenomenon of growth inhibition of neoplastically transformed C3H/10T1/2 cells (T10T1/2) by nontransformed C3H/10T1/2 clone 8 mouse embryo fibroblast (10T1/2) cells in the presence of inhibitors of cyclic adenosine 3':5'-monophosphate (cAMP) phosphodiesterase. The cAMP phosphodiesterase inhibitor dl-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO20-1724) was shown to be completely nontoxic to T10T1/2 cells at 10(-4) M, yet when added to mixed cultures of T10T1/2 cells and postconfluence growth-arrested 10T1/2 cells, colony formation and [3H]thymidine incorporation into T10T1/2 cells were virtually eliminated. This effect was dose dependent and was reversible upon drug withdrawal. In 10T1/2 cells, RO20-1724 caused a dose-dependent increase in cAMP levels from about 5 to 150 pmol/10(6) cells; in T10T1/2 cells, 10(-4) M drug treatment caused a 5-fold elevation in cAMP without a clear dose dependency. Cyclic guanosine 3':5'-monophosphate levels in 10T1/2 cells fell by 50% with drug treatment but were unmeasurable in T10T1/2 cells. When intracellular cyclic AMP levels were elevated by the adenyl cyclase stimulator forskolin, growth inhibition of T10T1/2 cells was again induced in mixed cultures but was not observed when added to T10T1/2 cells alone. Addition of RO20-1724 to low concentrations of forskolin produced a greater than additive effect on growth inhibition. Growth inhibition of T10T1/2 cells by RO20-1724 was shown to (a) require contact with, or extremely close proximity to, a confluent monolayer of 10T1/2 cells, (b) be maximum when seeded upon a growth-inhibited monolayer and not an actively growing 10T1/2 culture, and (c) not be decreased by continuous agitation of the culture medium, indicating that readily diffusible inhibitory factors are not involved. A model is presented whereby transformed cells can respond to but cannot themselves generate growth-inhibitory signals produced by post-confluence growth-inhibited nontransformed cells. The existence of these cellular interactions may well explain problems in the quantitation of transformed foci encountered in the use of this cell line as an assay system for chemical and physical carcinogens.
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PMID:Requirements for and kinetics of growth arrest of neoplastic cells by confluent 10T1/2 fibroblasts induced by a specific inhibitor of cyclic adenosine 3':5'-phosphodiesterase. 298 40

We have investigated the effects of glucagon and forskolin upon pancreatic islet cell electrical activity using intracellular recordings from single mouse islets. Glucagon (0.1-2.0 microM) and forskolin (0.5-5.0 microM), both adenylate cyclase activators, potentiated glucose (200 mg/dl)-induced electrical activity. In the steady-state, islet cells have cyclic electrical activity with periodically recurring "plateau" depolarizations (with superimposed Ca++ action potentials) separated by silent hyperpolarizations. Both glucagon and forskolin mimicked glucose stimulation by increasing the fraction of each cycle spent in the plateau phase (the "plateau fraction"). Unlike glucose, however, glucagon and forskolin increased, rather than decreased, the overall frequency of plateaus, suggesting that plateau frequency is not tightly linked to changes of plateau fraction. This dissociation was also apparent during the onset of drug action. Plateau fraction increased immediately (within one minute), fell to a nadir and then rose to a new steady state level. Plateau frequency, however, rose slowly and monotonically to a new level. Following drug withdrawal plateau fraction returned to control levels several minutes before plateau fraction. From these results it was concluded that cAMP has two effects upon islet cell electrical activity: one is to increase plateau fraction possibly by stimulating glucose-dependent process, which results in increasing in Ca++ influx, and the other to increase plateau frequency possibly by reducing intracellular Ca++ buffering.
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PMID:Glucagon and forskolin have dual effects upon islet cell electrical activity. 608 71

Continuous administration of trifluoperazine (2.5--3.5 mg/kg/day) or thioridazine (30--40 mg/kg/day) to rats for 12 months enhanced the stereotyped response to apomorphine (0.5 mg/kg s.c.), increased dopamine 1--150 muM) stimulation of striatal adenylate cyclase, increased KD and Bmax for dopamine (10(-4) M) specific 3H-spiperone striatal binding and produced spontaneous mouthing movements. On drug withdrawal, spontaneous locomotor activity was enhanced after 2 weeks and the enhanced stereotyped response was maintained for up to 1 month. Spontaneous mouthing had disappeared 2 weeks after drug withdrawal. The increase in Bmax for 3H-spiperone binding was maintained for up to 3 months after drug removal, but KD reverted to control levels by 2 weeks. In contrast, the dopamine stimulation of striatal adenylate cyclase remained enhanced for the 6 month withdrawal period. Administration of trifluoperazine (0.7--0.9 mg/kg/day) or thioridazine (6--8 mg/kg/day) for 12 months produced a less marked effect than administration of the higher dose. No enhancement of effect was observed on drug withdrawal and the initial changes disappeared rapidly on removal of drug. Supersensitivity of striatal dopamine mechanisms produced by continuous long-term neuroleptic administration differs from that produced by shorter treatment periods since no enhancement of effect occurs on drug withdrawal. The behavioural and biochemical components of the supersensitivity show variable time courses and in particular the enhanced stimulation of striatal adenylate cyclase persists for at least 6 months. Such effects may be of relevance to tardive dyskinesias in man.
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PMID:Cerebral dopamine function in rats following withdrawal from one year of continuous neuroleptic administration. 610 14

Administration of haloperidol (5 mg/kg i.p.), cis-flupenthixol (2.5 mg/kg i.p.) or sulpiride (2 X 100 mg/kg i.p.) daily for 21 days followed by a 3-day drug withdrawal period caused equivalent cerebral dopamine receptor supersensitivity as judged by enhanced apomorphine-induced stereotypy. These treatments also produced equivalent rises in the number of adenylate cyclase-independent dopamine receptors (D-2) in both striatal and mesolimbic tissue as assessed by specific [3H]spiperone and [3H]N,n-propylnorapomorphine (NPA) binding. No change in the dissociation constant (KD) was apparent in response to neuroleptic treatment. However, only repeated administration of cis-flupenthixol caused an increase in the number of adenylate cyclase-linked dopamine receptors (D-1) in striatum as assessed by enhanced [3H]piflutixol binding and increased dopamine-stimulated cyclic AMP formation. The dissociation constant for [3H]piflutixol binding was unchanged by cis-flupenthixol administration. No change in D-1 receptor numbers or dopamine stimulation of adenylate cyclase occurred in mesolimbic tissue. Repeated treatment with sulpiride or haloperidol was without effect on either [3H]piflutixol binding to D-1 receptors or cyclic AMP formation. In conclusion, increased apomorphine-induced stereotypy following subacute neuroleptic treatment correlates with changes in D-2 receptor numbers, but not with changes in D-1 receptors.
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PMID:Changes in apomorphine-induced stereotypy as a result of subacute neuroleptic treatment correlates with increased D-2 receptors, but not with increases in D-1 receptors. 613 43

The biochemical and physiological aspects of isoprenaline sensitivity in normotensive rats were examined during and after abrupt withdrawal of chronic propranolol treatment. Serum propranolol concentrations in rats chronically treated for one month (0.125% propranolol in drinking water: 75-100 mg/kg/day) ranged from 7 to 23 ng/ml. At the height of the blockade, rats showed a decreased responsiveness in vivo to isoprenaline-induced increase in heart rate and fall in blood pressure; the ED50 values for isoprenaline being increased some 20- and 4-fold respectively. There was a 180% increase in beta-receptor number in sarcolemmal membranes isolated from ventricular muscle of these animals, together with increased basal (290%), fluoride- (100%), forskolin- (80%) and isoprenaline-stimulated (125%) adenylate cyclase activity. Twenty-four hours after propranolol withdrawal, serum propranolol concentrations were reduced by over 95%. At this time rats exhibited increased chronotropic and blood pressure responses to i.v. isoprenaline, indicated by the reduced ED50 values (2-fold and 12-fold respectively compared to controls). In addition, cardiac sarcolemmal beta-receptor number and adenylate cyclase activities were still significantly elevated above those of controls; 35% increase in beta-receptor number and increases of 96, 26, 13 and 37% in basal, fluoride-, forskolin- and isoprenaline-stimulated adenylate cyclase activities respectively. Forty-eight hours after drug withdrawal serum propranolol concentrations were only just detectable at 0.5 +/- 0.1 ng/ml. Although sarcolemmal beta-receptor numbers were still elevated (23%) isoprenaline-stimulated adenylate cyclase activity had returned to control values. However, both the fluoride- and forskolin-stimulated enzyme activities were decreased below control values by 12 and 23% respectively, suggestive of a reduction in the catalytic capacity of the adenylate cyclase complex. In parallel with the reduction in beta-receptor number and adenylate cyclase activity, the chronotropic response to i.v. isoprenaline had also returned to control values. In contrast, the blood pressure response to i.v. isoprenaline was still elevated in these animals indicated by the 5-fold reduction in the ED50 value compared with control animals.
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PMID:Biochemical and physiological adaptation to chronic propranolol treatment in the rat. 632 27

Rats received therapeutically equivalent doses of either haloperidol (1.7-1.9 mg/kg/day), sulpiride (112-116 mg/kg/day) or clozapine 30-35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125-0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine. Bmax values for striatal 3H-spiperone binding were elevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in Bmax for striatal 3H-spiperone binding. Bmax values for striatal 3H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in Bmax for 3H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in Bmax for 3H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine. On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals. Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.
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PMID:Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol, sulpiride or clozapine in rats. 644 52

Administration of cis-flupenthixol to rats for 18 months enhanced apomorphine-induced stereotyped behaviour, increased the number of specific [3H]spiperone binding sites in striatum and potentiated striatal dopamine stimulated cyclic AMP formation, but did not alter specific [3H]piflutixol binding. Following withdrawal of cis-flupenthixol intake, apomorphine-induced stereotypy returned to control values after 1 month and Bmax for [3H]spiperone binding returned to normal after 3 months. In contrast, the increased dopamine stimulated adenylate cyclase activity remained elevated 6 months after drug removal, but was normal 1 year after drug withdrawal.
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PMID:Persistent increase in striatal dopamine stimulated adenylate cyclase activity persists for more than 6 months but disappears after 1 year following withdrawal from 18 months cis-flupenthixol intake. 668 29

Administration of sulpiride (2 X 100 mg/kg i.p.) or haloperidol (5 mg/kg i.p.) to rats for 3 weeks with subsequent withdrawal for 3 or 4 days induced cerebral dopamine receptor supersensitivity. Apomorphine-induced stereotyped behaviour after drug withdrawal was enhanced by pretreatment with either haloperidol or sulpiride both of which increased the number of specific striatal binding sites (Bmax) for [3H]spiperone, [3H]N,n-propylnorapomorphine and [3H]sulpiride. Neither drug altered the dissociation constant (KD) for the ligand binding assays. Striatal dopamine sensitive adenylate cyclase activity was unaltered by such a pretreatment with either haloperidol or sulpiride. The data show that sulpiride, like haloperidol, is capable of inducing behavioural and biochemical supersensitivity of cerebral dopamine receptors.
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PMID:Repeated administration of sulpiride for three weeks produces behavioural and biochemical evidence for cerebral dopamine receptor supersensitivity. 720 Mar 63

Beta(2)-Agonists blunt the function of the beta-adrenoceptor G-protein adenylate cyclase-signalling system, whereas glucocorticoids reverse the agonist-mediated diminished beta-adrenergic responses; however, these effects have not been reported in vivo in calf lymphocytes. In this study, we first investigated the presence of the beta(2)-adrenergic receptors on calf lymphocytes, and second we tested the effects of either clenbuterol alone or in combination with dexamethasone on receptor expression and function (isoproterenol-induced intracellular adenosine 3',5'-cyclic monophosphate (cAMP) formation) in vivo. (-)-[(125)I]-Iodocyanopindolol (ICYP) binding to intact calf lymphocytes was rapid, saturable (maximal number of binding sites 987 +/- 89 ICYP-binding sites/cell, n = 4) and of high affinity (K(D) value 17.23 +/- 2.8 pmol/l, n = 4). These binding sites were of the beta(2)-subtypes of adrenoceptors as indicated by the fact that beta-agonists inhibited ICYP binding with an order of potency: (-)-isoproterenol > (-)-adrenaline > (-)-noradrenaline. Furthermore, the selective beta(2)-adrenoceptor antagonist ICI 118.551 was about >1,500 times more potent in inhibiting ICYP binding than was the beta(1)-selective adrenoceptor antagonist CGP 20712A. Consequently, calves were treated with clenbuterol (1.0 microg/kg b.i.d., i.v.) for 9 days alone or simultaneously with dexamethasone (0.1 mg/kg, i.v., once a day for 4 days). Clenbuterol decreased the number of lymphocyte beta(2)-adrenergic receptors by about 40-50% after only 48 h of drug administration. This was accompanied by a decrement in isoproterenol-induced lymphocyte cAMP formation. Upon application of both drugs, dexamethasone restored the clenbuterol-mediated decrease in beta(2)-adrenoceptors and cAMP production. Dexamethasone elevated the number of beta(2)-adrenoceptors and cAMP almost 1.5- to 2-fold at 24 h of drug administration, an effect that persisted for up to 24 h following drug withdrawal. Neither clenbuterol nor the combination with dexamethasone had an influence on the affinity of the receptor for the ligand. The present results demonstrate that dexamethasone in vivo upregulates the number and function of calf lymphocyte beta(2)-adrenoceptors, and thus enhances the sensitivity of the beta(2)-adrenoceptor signal-transduction pathway for clenbuterol during concomitant treatment with both drugs.
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PMID:Possible role of dexamethasone in sensitizing the beta-2-adrenergic receptor system in vivo in calves during concomitant treatment with clenbuterol. 1545 69


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