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

ORF 12592 caused concentration-dependent inhibition of isoproterenol stimulated adenylate cyclase activity in sarcolemma-enriched membrane preparations of guinea-pig myocardium. Its potency was slightly less than that of d,l-propranolol. ORF 12592 did not stimulate basal enzyme activity, suggesting it to be devoid of intrinsic sympathomimetic activity. It produced no marked inhibition of basal activity, nor did it inhibit sodium fluoride stimulated enzyme activity, indicating that the compound acts at the receptor rather than the catalytic site of the beta-adrenergic receptor-adenylate cyclase complex. ORF 12592 competed for binding of 3H-dihydroalprenolol to specific beta1 and beta2-adrenergic binding sites on turkey and leopard frog erythrocyte membranes respectively. Concentration-binding inhibition curves indicated that ORF 12592 is a non-selective beta-blocker with slightly less affinity for each beta-adrenergic receptor than propranolol.
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PMID:In vitro measurement of the beta-adrenergic blocking properties of ORF 12592, the 5-hydroxy analog of propranolol. 2 4

Pretreatment of guinea pigs with 5 microgram/kg isoprenaline or 10 microgram/kg salbutamol s.c. thrice daily for 7 days reduced the responsiveness of lung slice and tracheal ring adenylate cyclase to isoprenaline, but not to prostaglandin E1. Pretreatment of guinea pigs with isoprenaline also reduced the sensitivity of tracheal smooth muscle strip adenylate cyclase to isoprenaline. Cross-tolerance developed to noradrenaline in lung slices obtained from guinea pigs pretreated with isoprenaline. Propranolol blocked the response of lung slice adenylate cyclase of control and isoprenaline-pretreated animals to approximately the same degree. The presence of phentolamine in the incubation medium did not affect the reduced sensitivity to isoprenaline. Possible mechanisms of development of tolerance to sympathomimetic bronchodilator drugs are discussed.
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PMID:Effect of pretreatment with bronchodilator drugs on in vitro responsiveness of guinea pig lung adenylate cyclase. 21 90

Non-nucleated red blood cells from rats contain adenyl cyclase, the activity of which is predominantly localized in the reticulocytes. Basal enzyme activities in membrane preparations from reticulocyte-rich blood (pretreatment of rats with acetyl-phenylhydrazide: about 60% reticuloytes) are about 5 times higher than in preparations from reticulocyte-poor blood (untreated animals: 2-3% reticulocytes). The enzyme activities are stimulated 10-fold by sodium fluoride (10(-2)M) and 6 to 8-fold by isoprenaline (10(-4)M). Adenyl cyclase activities in membrane preparations from reticulocyte-rich and reticulocyte-poor blood can be ascribed to identical enzymes since identical apparent Km (ATP; 3 times 10(-4)M, Ka (isoprenaline; 3 times 10(-6)M) and Ki (propranolol vs. isoprenaline; 3 times 10(-7)M) values were obtained in both preparations. Besides NaF, only phenylethanolamine derivatives with beta-adrenergic receptor stimulant properties were effective as stimulators of adenyl cyclase activity. The affinities (apparent Ka values) of the investigated compounds decreased in the order isoprenaline--hexoprenaline--fenoterol--salbutamol--adrenaline--terbutalin--noradrenaline--phenylephrine. For maximal intrinsic activity, the catechol structure was essential; the relative intrinsic activities of resorcinol derivatives did not exceed 0.6. The isoprenaline-stimulated adenyl cyclase activities in erythrocyte membrane preparations were competitively inhibited by beta-adrenergic blocking drugs, the affinities (apparent Ki values) decreasing in the order prindolol--penbutolol--propranolol--practolol. The dextrorotatory enantiomers of penbutolol and propranolol were 1/100 to 1/200 as active as the resp. levorotatory enantiomers. From experiments with alpha-adrenergic agonists (e.g. phenylephrine) and antagonists (e.g. phentolamine), it is concluded that alpha-adrenergic receptors do not interfere with the beta-adrenergically-mediated cAMP formation in these particular membranes. A variety of hormones and drugs known to stimulate denyl cyclase activities in various tissues, e. g. ACTH, glucagon, STH, erythropoietin, prostaglandin E1 etc. did not affect adenyl cyclase activity in reticulocyte-rich erythrocyte membrane preparations. In contrast to adenyl cyclase activity, phosphodiesterase activities in erythrocyte membrane and cytoplasmic fractions were only twice as high in reticulocyte-rich as in reticulocyte-poor preparations. From the experiments described, it is obvious that the adenyl cyclase of the rat reticulocyte is subject to monovalent-hormonal, i.e. beta-sympathomimetic stimulation. Moreover, the premature red blood cell provides a useful model for quantitative studies of the interaction of drugs with the beta-adrenergic receptor.
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PMID:The beta-adrenergic receptor-adenyl-cyclase system of rat reticulocytes: effects of adrenergic stimulants and inhibitors. 24 Jan 35

Cumulative concentration-effect curves of oxytocin alone and with various antagonists were obtained in vitro on uteri from estrogen-treated rats. Graded concentrations of salbutamol, isoproterenol, papaverine, theophylline, thioglycollate, and MgCl2 produced a decrease in the maximal effect of oxytocin and a shift of the concentration-effect curves to the right. Salbutamol and isoproterenol appeared to act as functional antagonists of oxytocin in which agonist and antagonist each interacted with its own specific receptor to produce a decreased combined effect on a common effector. Antagonism by papaverine or theophylline was increased by prior or simultaneous treatment with salbutamol, isoproterenol, epinephrine, or norepinephrine. The potentiation had a rapid onset, was partially blocked by propranolol, persisted for at least 85 minutes following washout of salbutamol, and was not due to a residual effect of salbutamol. This interaction could result from phosphodiesterase inhibition by papaverine and the accumulation of higher levels of cyclic 3',5'-adenosine monophosphate brought about by adenyl cyclase activation with the sympathomimetic amines.
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PMID:Antagonism of the uterotonic action of oxytocin in vitro. 111 25

Prenalterol, an allegedly beta 1-selective adrenergic agonist with high intrinsic sympathomimetic activity (ISA), was shown to be weakly lipolytic in rat adipocytes. However, in pertussis-toxin-treated adipocytes, the ISA of prenalterol was markedly increased (from 10-20% to approx. 100% of that of isoprenaline). The cellular sensitivity was also increased (EC50 approx. 60 nM and approx. 3 microM in pertussis-toxin-treated and control cells respectively). A similar effect was seen for other partial agonists such as the beta 2-selective agonist terbutaline and for beta-adrenergic antagonists with some intrinsic activity (metoprolol, pindolol). There was no clear change in sensitivity to isoprenaline's ability to stimulate adenylate cyclase in adipocyte membranes from pertussis-toxin-treated animals but the cyclase activity was increased approx. 4-fold in the presence of 1 microM-GTP. Prenalterol stimulated lipolysis by only small increases in intracellular cyclic AMP (cAMP) levels (less than 10% of that seen with isoprenaline). Basal lipolysis was increased in cells from pertussis-toxin-treated rats and the cellular sensitivity to the non-degradable cAMP analogue, N6-monobutyryl-cAMP, was increased. In control cells, a submaximal concentration of prenalterol (0.1 microM) increased the sensitivity to the cAMP analogues, N6-monobutyryl-cAMP and 8-bromo-cAMP. A low concentration (1 mM) of 8-bromo-cAMP also increased the effect of prenalterol. Similar effects were seen when the phosphodiesterase was inhibited. Thus (1) lipolysis is extremely sensitive to small increases in intracellular cAMP; (2) the degree of activation of adenylate cyclase and thus cAMP formation is the rate-limiting step for the biological response of partial agonists; (3) the inhibitory GTP-binding protein, Gi, is an important modulator ('tissue factor') of the beta-adrenergic agonistic property; (4) low levels of cAMP exert a priming effect on protein kinase A.
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PMID:The inhibitory GTP-binding protein (Gi) regulates the agonistic property of beta-adrenergic ligands in isolated rat adipocytes. Evidence for a priming effect of cyclic AMP. 128 Jan 15

The current status and future directions of the pharmacotherapy of dilated cardiomyopathy are reviewed. The Japanese multicenter study on the effect of beta-blockers revealed significant improvement of NYHA functional classification, LV end-diastolic dimension, ejection fraction, and exercise tolerance time in patients with dilated cardiomyopathy. From our study using normal rabbits, metoprolol augmented adenylate cyclase activity without upregulation of the beta-adrenergic receptor number. Carteolol, a beta-adrenergic blocker with intrinsic sympathomimetic action, prevented the development of dilatation and hypertrophy of the heart in the chronic stage following murine encephalomyocarditis (EMC) viral myocarditis. Metoprolol exerted no such effect. Animal experiments indicated that immunosuppressive treatment for inflammatory myocarditis may aggravate the clinical course of the disease. However, immunosuppressive treatment in acute myocarditis should be reevaluated with the use of newly developed antiviral agents. A new synthetic immunoactive peptide FK 565, given before or simultaneously with viral inoculation, proved effective in inhibiting myocardial virus replication and myocardial damage in murine EMC viral myocarditis. Beneficial effects of captopril on survival rate and myocardial injury were demonstrated dose dependently in murine EMC viral myocarditis, even when the treatment was started around the peak of virus replication, namely, on day 4-14 after inoculation. Captopril may be promising for the treatment of acute myocarditis, and hopefully for prevention of the progression from myocarditis to dilated cardiomyopathy.
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PMID:Pharmacotherapy of dilated cardiomyopathy: current status and future directions. 134 97

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

The mechanism of action of the beta-receptor antagonist bucindolol was examined in human ventricular myocardium. Bucindolol was found to be a high-affinity competitive beta-blocking agent as determined by bucindolol-[125I]iodocyanopindolol (ICYP) competition curves (KI = 3.7 +/- 1.3 x 10(-9) M, n = 10). This value was in general agreement with bucindolol KB's, determined by antagonism of isoproterenol-stimulated adenylate cyclase activity (KB = 2.8 +/- 0.55 x 10(-9) M, n = 5) or isoproterenol-augmented contraction of right ventricular trabeculae (KB = 2.9 +/- 1.9 x 10(-9) M, n = 3). In contrast, the alpha 1-receptor KI, determined at bucindolol-125IBE2254 (IBE) competition binding in rat cardiac membranes, was 1.2 x 10(-7) M. Bucindolol exhibited no beta 1- or beta 2-receptor subtype selectivity as deduced from blockade of the beta-agonist-coupled adenylate cyclase system, receptor-binding studies with preparations of human ventricular myocardium with predominantly beta 1 or beta 2 receptors, or receptor-binding studies in model systems consisting of beta 1 (guinea pig myocardial membranes) or beta 2 receptors (human mononuclear and frog myocardial membranes). In membranes derived from human ventricular myocardium and human lymphocytes, bucindolol recognized a high-affinity agonist-binding site as determined by guanine nucleotide modulation of competition-binding curves. Although bucindolol has measurable intrinsic sympathomimetic activity (ISA) in some animal systems, no increase in adenylate cyclase activity or muscle contraction was detected in preparations of human heart. In conclusion, bucindolol is a high-affinity nonselective beta-receptor antagonist with no evidence of intrinsic sympathomimetic activity in human ventricular myocardium.
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PMID:Mechanism of action of bucindolol in human ventricular myocardium. 169 19

The purpose of the present study was to characterize the effects of xamoterol in the human myocardium. In the presence of forskolin or milrinone, xamoterol increased isometric force of contraction, contraction velocity, and relaxation velocity in isolated, electrically driven preparations from human myocardium, but had no effect alone. There was no difference in the effect of xamoterol between right atrial myocardium and left ventricular myocardium from nonfailing (NF), moderately failing (NYHA II-III), and severely failing (NYHA IV) human hearts. The positive inotropic and lusitropic effects of isoprenaline were reduced depending on the severity of heart failure in left ventricular myocardium (i.e., NF greater than NYHA II-III greater than NYHA IV). In the presence of norepinephrine, xamoterol produced negative inotropic effects similar to those of the beta-adrenoceptor antagonists pindolol and propranolol. Xamoterol alone had no effects on force of contraction, whereas pindolol and propranolol markedly reduced contractile force. In NYHA class IV, isoprenaline stimulated adenylate cyclase about twofold but xamoterol, like pindolol or propranolol, had no effect. Experiments with the beta 1- and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, showed that the positive inotropic and lusitropic effects of xamoterol were mediated by beta 1-adrenoceptors. Consistently, xamoterol had a selectivity of 13.8 at beta 1-adrenoceptors as measured in radioligand binding experiments. It is concluded that xamoterol acts as a beta 1-adrenoceptor antagonist with a selectivity of 13.8 in human ventricular myocardium. The compound has an intrinsic sympathomimetic activity, as it produces beta 1-adrenoceptor-mediated positive inotropic and lusitropic effects in the presence of forskolin. The beneficial effects of xamoterol in patients with heart failure could be due to prevention of the detrimental effects of norepinephrine such as beta 1-adrenoceptor downregulation of an increase of Gi (inhibitory guanine-nucleotide binding protein).
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PMID:Effects of xamoterol on inotropic and lusitropic properties of the human myocardium and on adenylate cyclase activity. 197 79

This study explores the mechanism of action of catecholamines on rostral medullary pacemaker neurons with putative sympathoexcitatory function, in tissue slices. The firing rate of the pacemaker neurons of nucleus reticularis rostroventrolateralis (RVL pacemakers) was reversibly increased by agents which elevate intracellular levels of cAMP (forskolin and 8-br-cAMP). Forskolin dideoxy, an analog without action on adenylate cyclase, was ineffective and adenosine, a potential degradation product of 8-br cAMP produced inhibition exclusively and only in high doses (0.1-1 mM). The firing rate of these cells was uniformly increased by epinephrine and isoproterenol (10 microM) but unaffected by both phenylephrine (100 microM) and clonidine (up to 1 microM). These effects were abolished by pretreatment with the beta-adrenoceptor antagonist propranolol (10 microM) but they were unaffected by the alpha-antagonist phentolamine (100 microM). The indirectly-acting sympathomimetic amine tyramine (0.1-1 mM) activated all the cells tested. The effect of tyramine was antagonized by the beta-blocker pindolol and was absent 7 days after microinjection of the neurotoxin 6-hydroxydopamine into the lateral aspect of the RVL. Intracellular recordings indicated that both isoproterenol and tyramine enhanced the rate of depolarization of the pacemaker neurons during the interspike interval and produced a decrease in input resistance. After tetrodotoxin (TTX) pretreatment, isoproterenol produced a depolarization also associated with a reduction in input resistance. Three conclusions are proposed. First, RVL pacemakers have functional beta-adrenergic receptors whose activation increases their discharge rate via the intracellular production of cAMP. The effect of cAMP is due at least in part to the activation of an inward current which may be carried by a cation. Secondly, RVL neurons are in close proximity to a releasable pool of catecholamines which is susceptible to destruction by the cytotoxic agent 6-hydroxydopamine (6-OHDA). Finally it is tentatively suggested that the reduction in sympathetic tone produced by centrally acting beta-blockers could be due, at least in part, to an action of these agents on RVL pacemaker cells.
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PMID:Excitation of rostral medullary pacemaker neurons with putative sympathoexcitatory function by cyclic AMP and beta-adrenoceptor agonists 'in vitro'. 215 55


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