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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Affinity, specificity and kinetics for [3H]-DHA binding to human red cell ghost were determined by ultra-filtration. At 2 degree an apparent dissociation constant of 0.96 nM was found with maximum specific binding of 29 fmoles per mg protein. The low dissociation constant was confirmed by kinetic studies with a value of 0.86 nM. Propranolol and isoproterenol inhibited [3H]-DHA binding stereo specifically. Agonist potency (IPR greater than EPI greater than NE) indicated that human erythrocytes had an adrenergic receptor of beta-2 subtype. Isoproterenol in the presence of theophylline resulted in a concentration-dependent increase of intracellular cAMP levels in intact cells. Basal and maximal levels were 2.3 and 7.5 pmoles/108 cells respectively after 2.5 min stimulation. EC50 for isoproterenol was 0.27 microM. Propranolol shifted the isoproterenol concentration response curve to the right. The present results show that human erythrocytes possess recognition sites for beta-adrenergic ligands with binding characteristics similar to that of adrenergic receptors of beta-2 subtype. At least a small number of these binding sites are functionally coupled to adenylate cyclase.
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PMID:Receptor binding sites for beta-adrenergic ligands on human erythrocytes. 627 38

Prolactin possesses positive inotropic actions in isolated heart preparations although the mechanism of this influence is not understood. Our study was designed to investigate the mechanism of this effect on the rat heart. Prolactin (50 ng/ml) produced a time-dependent increase (60%) in contractile force that reached maximum after 30 min and remained steady for a further 30 min. A similar time-dependent phenomenon was seen with 200 ng/ml prolactin although the maximum inotropic effect was reduced. Indomethacin (30 micrograms/ml) significantly reduced the inotropic effect of both prolactin concentrations although the effect of the hormone was not related to the release of 6-keto-PGF1 alpha, the prostacyclin metabolite. Propranolol (1-20 micrograms/ml) significantly reduced the positive inotropic effect of prolactin. Prolactin however had no influence on myocardial adenylate cyclase activity. Hearts that were removed from animals pretreated with 1.25 or 2.50 mg/kg reserpine did not respond to prolactin administration. It is suggested that the inotropic influence of prolactin is mediated by endogenous catecholamine liberation.
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PMID:A possible mechanism of inotropic action of prolactin on rat heart. 629 10

Previous studies have shown that sympathetic factors and blood glucose are of importance in the development of seizures and lung damage from OHP. In the present study we examined the influence of beta sympathetic agonists and blocking agents and glucagon on OHP toxicity. Rats were exposed to 6 ATA OHP and examined for time-to-seizure and lung damage. Pretreatment with propranolol increased the time-to-seizure by 70% and practolol by 50% without altering gross lung appearance or lung wet wt/dry wt. Propranolol and practolol also prevented brain glycogen depletion prior to seizure which otherwise occurred in subconvulsive exposure to OHP. Isoproterenol and glucagon pretreatment had no effect on time-to-seizure but isoproterenol did increase lung injury. Both practolol and propranolol block the beta-receptor influence on adenyl cyclase-stimulated second messenger production, while both isoproterenol and glucagon activate adenyl cyclase to produce second messenger. Our results may suggest a possible role for second messenger in mediating some of the acute toxic effects of OHP on the CNS.
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PMID:Beta adrenergic receptors and glucagon in seizures from exposure to oxygen at high pressure (OHP). 631 53

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

To investigate further the mechanism of dopamine (DA)-stimulated and parathyroid hormone (PTH) secretion, we have identified and studied DA-sensitive adenylate cyclase in a particulate preparation of osmotically lysed dispersed bovine parathyroid cells. Adenylate cyclase was responsive to DA at concentrations as low as 0.3 microM, and the maximal stimulation in the presence of GTP was 2- to 4-fold that of activity with GTP alone. (-)Propranolol (1 microM) abolished the stimulation by (-)isoproterenol but did not inhibit the DA-stimulated adenylate cyclase, whereas alpha-flupenthixol (1 microM) inhibited DA stimulation but not that of (-)isoproterenol. The dopaminergic agonists epinine and 6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene were nearly as effective as DA in stimulating the enzyme, while apomorphine displayed partial agonist activity. The dopaminergic antagonists chlorpromazine, fluphenazine, and haloperidol inhibited the DA-stimulated adenylate cyclase. There was a close correspondence between the Ka values for DA and the Ki values of the dopaminergic antagonists for particulate adenylate cyclase activity, cellular cAMP accumulation, and PTH release. These results indicate that DA-stimulated cAMP accumulation and PTH release are mediated through specific activation of a DA receptor linked to adenylate cyclase.
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PMID:Characterization of the dopamine-responsive adenylate cyclase of bovine parathyroid cells and its relationship to parathyroid hormone secretion. 742 92

Amiodarone and its major metabolite desethylamiodarone are potent antiarrhythmic drugs that have multiple pharmacological effects on the heart. We examined the effect of both drugs on the neonatal rat heart monolayer cell culture. The cells were stimulated with L-arterenol (10(-7) M) and choleratoxin (1.5 micrograms/ml). Both the spontaneous pulsation rate and intracellular cAMP level were followed. Amiodarone (10(-7) M) or desethylamiodarone (10(-7) M), incorporated into phosphatidylcholine vesicles, decreased the stimulated cell pulsation rate 3 min after addition of drugs, and the level of intracellular cAMP 30 min after addition as well. Propranolol (10(-7) M) had no further effect on the pulsation rate after 3 min. In the presence of amiodarone and propranolol the stimulation of L-arterenol was completely abolished and both the pulsation rate and cAMP level proved to be lower than the control values. The stimulation of choleratoxin on pulsation rate was also decreased by addition of amiodarone and the cAMP level was lowered after 30 min as well. Desethylamiodarone exhibited similar behavior to amiodarone although it proved to be less effective. It is unlikely that amiodarone and desethylamiodarone act on beta-adrenergic receptors in a competitive manner. Our data suggests that amiodarone and its metabolite could act in a nonspecific manner perturbing the hydrophobic interaction in the cell membrane and thereby decoupling the receptor or the nucleotide regulator protein and adenylate cyclase.
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PMID:A possible nonspecific site of action of amiodarone on newborn rat heart cell in culture. 774 56

This study was designed to examine the effects of an adenylate cyclase activator, NKH477, on epicardial and endocardial contraction and coronary blood flow (CoF) in the presence or absence of ischemia and to compare it to those of adenosine. We measured coronary pressures (CoP), coronary blood flow, epicardial and endocardial wall thickening (i.e., %EPWT and %ENWT, respectively, by sonomicrometry) in 18 anesthetized dogs. The left circumflex coronary artery was perfused with arterial blood using a pressure controlled servo pump. Propranolol (0.5 mg/kg) and atropine (0.25 mg) were used to minimize the neurogenic effects. CoP decreased from 100 mm Hg to 40 mm Hg with and without drugs. At CoP of 100 mm Hg, intracoronary infusion of NKH477 (10(-8) M/kg/min) produced a two-fold increase in CoF, but there were no changes in either the %EPWT or the %ENWT. During coronary hypofusion at coronary pressures equal to 40 mm Hg, NKH477 increased CoF from 16 +/- 2 to 28 +/- 4 mL/min (p < 0.05) and improved %ENWT significantly from 6 +/- 7 to 23 +/- 7% (p < 0.05). However %EPWT was not improved by NKH477. On the other hand, the intracoronary infusion of adenosine (10 micrograms/kg/min) increased CoF from 16 +/- 5 to 21 +/- 6 mL/min (p < 0.05) at CoP of 40 mm Hg. However, this dose of adenosine failed to improve %ENWT (16 +/- 10% vs. 14 +/- 10%, n.s.). Thus, the improvement of subendocardial function by NKH477 might be related to the improvement of subendocardial perfusion which could be induced by the potentiation of endogenously released adenosine as well as the direct vasodilator effect. This contrasts with the effects of exogenously administered adenosine, which failed to improve subendocardial contractility.
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PMID:Adenylate cyclase activation promotes the recruitment of coronary vasodilator reserve and improves subendocardial contractility during coronary hypoperfusion. 801 Sep 38

1. The effect of long-term treatment with the beta-adrenoceptor antagonists (--)-tertatolol and (--)-propranolol was studied. Sprague-Dawley rats were treated with either (--)-tertatolol (50 micrograms kg-1 hr-1), (--)-propranolol (250 micrograms kg-1 hr-1) or vehicle (1 mM HCl) for 14 days with osmotic minipumps implanted subcutaneously. 2. The mean daily systolic blood pressure and heart rate of rats treated with either (--)-tertatolol (108 +/- 1 mmHg/330 +/- 3 bpm) or (--)-propranolol (103 +/- 1 mmHg/330 +/- 2 bpm) were lower than in the control (126 +/- 1 mmHg/405 +/- 3 bpm, P < 0.001, n = 8-10) indicating the effectiveness of drug delivery. 3. Autoradiographic studies in areas of heart, lung and skin showed that beta-adrenoceptor populations were not significantly affected by the drug treatment (all regions P > 0.05). Nevertheless, the receptor population in the homogenates of (--)-tertatolol treated lung were halved (194 +/- 28 fmol mg protein-1 compared with a control value of 388 +/- 54 fmol mg protein-1, P < 0.01, n = 6). 4. In the presence of CGP 20712A, the left atrial inotropic and right atrial chronotropic responsiveness to (--)-isoprenaline were hypersensitive in both (--)-tertatolol and (--)-propranolol-treated groups (P < 0.005, ANCOVA). 5. (--)-Propranolol treated left ventricular free wall had lower basal [3H]-forskolin binding to adenylate cyclase (14.45 +/- 1.20 fmol mg protein-1 compared with a control value of 18.91 +/- 0.78 fmol mg protein-1, P = 0.01, n = 6). (--)-Tertatolol treatment had no effect on the basal binding. In the presence of the G-protein activators NaF and Gpp(NH)p, the enhancement of [3H]-forskolin binding did not differ between control and the drug treated groups. 6. Chronic (--)-tertatolol or (--)-propranolol treatment therefore did not produce an increase in receptors in heart, lung or skin but the beta-adrenoceptor-mediated responses were enhanced. In addition, [3H]-forskolin binding did not increase suggesting that the hypersensitivity was not due to changes in the number of receptors or adenylate cyclase. Hypersensitivity following beta-adrenoreceptor antagonist administration may therefore involve enhanced coupling of receptors to G-proteins.
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PMID:beta-Adrenoceptor regulation in rat heart, lung and skin after chronic treatment with (--)-tertatolol or (--)-propranolol. 892 Jan 59

Earlier experiments only revealed involvement of sympathetic pre-synaptic dopaminergic receptors in dopamine induced inotropism in myocardium. We therefore used electrically stimulated (1 Hz) isolated 7-day-old chick embryo heart ventricles, thought to be devoid of functional sympathetic nerves, to re-investigate post-synaptic receptors involvement and particularly that of dopaminergic receptors in the positive inotropic effect of dopamine. The results showed that noradrenaline, isoprenaline and dopamine produced a positive inotropic effect with a similar efficacy and with an order of potency as follows: Isoprenaline = Noradrenaline > Dopamine. Tyramine induced no significant modification of the "initial tension" indicating that functional sympathetic innervation and/or releasable endogenous catecholamines were not demonstrable in the 7-day-old chick embryo heart ventricle. Propranolol (1 microM) competitively antagonized the positive inotropic response to isoprenaline, noradrenaline and dopamine, meanwhile phentolamine (3 microM) failed to significantly modify the effects of both noradrenaline and dopamine, indicating that these catecholamines induced their positive inotropic effects via stimulation of beta-adrenoceptors; involvement of alpha-adrenergic receptors stimulation was not demonstrable in these effects. Moreover, haloperidol (2 microM) antagonized the positive inotropic response to dopamine but had not any significant effect on the response to isoprenaline. The combined application of both propranolol and haloperidol antagonized the positive inotropic response to dopamine to a greater extent than when these two antagonists were given alone. Consequently, post-synaptic dopaminergic receptors were also involved in the positive inotropic effect of dopamine. Furthermore, in preparations in which sodium channels were inactivated by high potassium physiological salt solution, high concentrations of dopamine (0.1 mM to 1 mM) induced a slow developing electrical and positive inotropic responses which were also inhibited by propranolol and haloperidol, but not by phentolamine. These latter results indicated that like beta-adrenergic stimulation, the slow inward calcium current activated by stimulation of adenylate cyclase, was at least in part involved in the positive inotropic response to dopamine. In conclusion, dopamine induced its positive inotropism via stimulation of post-synaptic beta-adrenergic and dopaminergic receptors. The contribution of dopaminergic receptors in this positive inotropic effect might be of the DA-2 receptors since haloperidol used had been reported to be more DA-2 than DA-1 antagonist. These DA-2 receptors subtypes would mediate activation of adenylate cyclase.
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PMID:Receptors involved in the positive inotropic action induced by dopamine on the ventricle of a 7-day-old chick embryo heart. 956 66

Alpha1-adrenoceptor agonists may potentiate relaxation to beta-adrenoceptor agonists, although the mechanisms are unclear. We compared relaxations induced by beta-adrenoceptor agonists and cyclic AMP-dependent vasodilators in rat pulmonary arteries constricted with prostaglandin F2alpha (PGF2alpha) or the alpha1-adrenoceptor agonist phenylephrine (PE). In addition, we examined whether differences were related to cyclic AMP- or nitric oxide (NO) and cyclic GMP-dependent pathways. Isoprenaline-induced relaxation was substantially potentiated in arteries constricted with PE compared with PGF2alpha. Methoxamine was similar to PE, whereas there was no difference between PGF2alpha and 30 mM KCl. The potentiation was primarily due to a marked increase in the NO-independent component of relaxation, from 9.1+/-1.7% for PGF2alpha to 55.1+/-4.4% for PE. NO-dependent relaxation was also enhanced, but to a lesser extent (50%). Relaxation to salbutamol was almost entirely NO-dependent in both groups, and was potentiated approximately 50% by PE. Relaxation to forskolin (activator of adenylate cyclase) was also enhanced in PE constricted arteries. Part of this relaxation was NO-dependent, but the major effect of PE was to increase the NO-independent component. Propranolol diminished but did not abolish the potentiation. There was no difference in response to CPT cyclic AMP (membrane permeant analogue) between PE and PGF2alpha, suggesting that mechanisms distal to the production of cyclic AMP were unchanged. Relaxation to sodium nitroprusside (SNP) was the same for PE and PGF2alpha, although relaxation to acetylcholine (ACh) was slightly depressed. This implies that potentiation by PE does not involve the cyclic GMP pathway directly. Mesenteric arteries constricted with PE did not show potentiation of isoprenaline-induced relaxation compared to those constricted with PGF2alpha, suggesting that this effect may be specific to the pulmonary circulation. These results clearly show that PE potentiates both the NO-independent and -dependent components of cyclic AMP-mediated relaxation in pulmonary arteries of the rat, although the effect on the former is more profound. We suggest that potentiation of both components is largely due to direct activation of adenylate cyclase via alpha1-adrenoceptors, within the smooth muscle and endothelial cells respectively.
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PMID:Potentiation of cyclic AMP-mediated vasorelaxation by phenylephrine in pulmonary arteries of the rat. 1036 85


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