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)

Cardiomyopathic hamsters (UM-X7.1) show clinical signs of congestive heart failure and an abnormal EKG pattern. The sarcolemmal fraction obtained from the failing hearts at advanced stages of myopathy exhibited no change in the basal adenylate cyclase activity; however, the activity of this enzyme in the presence of catecholamines or NaF was lower in the failing heart sarcolemma than that in the control. The activities of Ca2+-ATPase, Mg2+-ATPase, and Na+-K+-ATPase in the failing heart sarcolemma were also less than the control values. These results suggest an association of membrane defect with heart failure.
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PMID:Membrane alteration in failing hearts of cardiomyopathic hamsters. 12 77

Acidic phospholipids play a critical role in the hormone activation of adenylate cyclase. Solubilized myocardial adenylate cyclase is unresponsive to glucagon and the catecholamines, two of the hormones which activate the membrane-bound enzyme. Phosphatidylserine, purified from bovine brain restored glucagon responsiveness of the solubilized adenylate cyclase. Monophosphatidylinositol, also purified from bovine brain, restored catecholamine responsiveness. Solubilized preparations of myocardial adenylate cyclase bind 125-I-glucagon either in the presence of added phosphatidylserine, thereby providing a clear separation of the processes of activation and binding. Solubilized myocardial adenylate cyclase has a molecular weight of about 160,000. Sephadex G-100 chromatography of the solubilized enzyme following the binding of 125-I-glucagon to its myocardial receptor reveals two distinct peaks; one, having catalytic activity and a molecular weight greater than 100,000 and two, the binding material having no catalytic activity and a molecular weight of 24,000-28,000. These data are consistent with the presence of a dissociable glucagon receptor site. The role of this dissociation in the activation-inactivation of the enzyme remains to be explored. It is postulated that phospholipids induce the required configurational change in the catalytic site following the binding of hormone to its receptor, and by this means couples the receptor to the catalytic site. This model may be applicable to certain clinical situations. Cardiac adenylate cyclase is unresponsive to glucagon in chronic congestive heart failure. The defect may reside either in the binding of glucagon to its receptor site or in the metabolism of a specific acidic phospholipid such as phosphatidylserine.
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PMID:The glucagon receptor and adenylate cyclase. 16 52

Eicosanoids (prostaglandins, leukotrienes, thromboxane A2 and other metabolites of C-20 polyunsaturated fatty acids) have numerous effects in the cardiovascular system. Direct inotropic actions have been repeatedly described, but appear in only very few cases to be due to direct modification of the inotropic state of the heart. Specific eicosanoid receptors have been identified on the surface of the sarcolemmal membrane. Signal transduction pathways in the cardiac myocyte involve the adenylate cyclase/cAMP system or stimulation of the phospholipase C/IP3 pathway. In general, concentrations of eicosanoids which affect myocardial contractility are higher as the response is less predictable than the effects on platelet function or vessel tone. Therefore, eicosanoid-induced extracardiac effects may be superimposed to more direct changes in the contractile state of the intact heart in vitro or in vivo. In contrast to non-failing hearts, there is a significant improvement of the contractile function in contractile failure ("stunning", ischemia, congestive heart failure) by vasodilating prostaglandins (e.g., PGI2). The mechanism of this action is still unknown.
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PMID:Inotropic actions of eicosanoids. 131 58

In order to determine the possible etiology for diminished inotropic responsiveness to catecholamines in the infarction model of chronic congestive heart failure in rats, we studied beta-adrenoceptor number and site-specific stimulated adenylate cyclase activity in noninfarcted left ventricular tissue of rats at 3 months after ligation of the left coronary artery. Rats were divided into sham, small infarct, and large infarct groups according to infarct size. The large infarct groups showed increased right ventricle to body weight ratio (0.93 +/- 0.07 mg/g for the large infarcts vs 0.52 +/- 0.02 and 0.54 +/- 0.02 mg/g for the shams and small infarcts, respectively). Beta-Adrenoceptor number among the groups was similar (shams, 27 +/- 1 fmol/mg; small infarcts, 26 +/- 1 fmol/mg; and large infarcts, 29 +/- 1 fmol/mg), as was Kd (20 +/- 1 pmol, 18 +/- 2 pmol, and 18 +/- 2 pmol, respectively). Site-specific stimulation of adenylate cyclase using isoproterenol, Gpp(NH)p, forskolin, and MnCl2 revealed no significant differences among the groups. We conclude that this system is not responsible for the altered inotropic responsiveness to catecholamines seen in this model.
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PMID:Beta-adrenoceptor and adenylate cyclase function in the infarct model of rat heart failure. 131 60

Although hypothermic cardioplegic arrest is a basic method of myocardial protection in cardiac surgery, the beta-adrenergic receptor (BAR) system has been little investigated in the heart subjected to hypothermic ischemia. Additionally, although the hypothermic arrest is often induced in hearts with preischemic desensitization of the BAR system by preceding congestive heart failure, the functional state of the BAR system after ischemia has not been studied in these hearts. We investigated alterations in the BAR system after hypothermic ischemia in normal rat hearts and in those with preischemic desensitization of the BAR system produced with isoproterenol (ISP: 400 micrograms/kg/hr for 24 hr). Both normal and BAR-desensitized hearts were isolated and subjected either to 40 min of hypothermic (10 degrees C) global ischemia followed by 40 min of reperfusion or subjected to time-matched aerobic perfusion with modified Krebs-Henseleit solution. At the end of perfusion (1) BAR binding properties with [3H]CGP-12177 and adenylate cyclase activity were measured in crude membrane fraction and (2) the inotropic response to ISP (delta LV + dP/dtmax) was evaluated in an isovolumetric contracting heart preparation. Following reperfusion, normal hearts without desensitized BAR showed a higher Bmax value than those of nonischemic time-matched hearts (41.8 +/- 3.1 vs 35.4 +/- 2.4 fmole/mg protein, P less than 0.05), whereas the Kd value was in a similar range in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in the beta-adrenergic receptor system after hypothermic ischemia in hearts with preischemic beta-receptor desensitization. 135 34

In patients with congestive heart failure, down-regulation of beta-adrenoceptors is present, probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy, beta 1-adrenoceptor density is markedly reduced, while beta 2-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to beta 2-stimulation, due to possible alterations in the beta-adrenoceptor/adenylate cyclase complex beyond the receptor. In some disease states, such as ischemic cardiomyopathy and mitral valve disease, there seems to be a concomitant reduction of the beta 1- and beta 2-adrenoceptor density. The finding of beta-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate beta receptors, and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity, such as forskolin, or that increase cyclic adenosine monophosphate degradation, such as the phosphodiesterase inhibitors, are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before beta-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the beta-adrenoceptor down-regulation. Studies testing whether beta-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.
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PMID:Receptor function in heart failure. 164 66

The functional integrity of the beta- and alpha-adrenergic stimulatory pathways in a rapid ventricular pacing model of congestive heart failure in dogs was investigated; normal dogs served as controls. Total beta-adrenergic receptor density was 35% lower (p less than 0.01) in the pacing-overdrive dogs, and the beta-adrenergic receptor-mediated stimulation of adenylate cyclase (Vmax) was found to be 68% and 72% lower (p less than 0.01) in the left and right ventricles of the paced dogs. In addition, the basal adenylate cyclase activity was found to be 56% and 68% lower (p less than 0.01) in the left and right ventricles of the failing heart. Similarly, the Vmax of 5'-guanylylimidodiphosphate (GppNHp) and forskolin stimulation of adenylate cyclase activity was significantly lower, 70% and 55%, respectively (p less than 0.01), in both ventricles of the paced dogs. However, although the concentration yielding half-maximal velocity for beta-agonist and GppNHp stimulation of adenylate cyclase was similar in both groups, that for forskolin stimulation of the enzyme was significantly increased (p less than 0.01). Pertussis toxin-mediated ADP-ribosylation of membranes from control and failing hearts revealed a significant decrease in the inhibitory guanine nucleotide binding protein content (48 +/- 9%, p less than 0.01) in the hearts of the paced dogs. Moreover, although the pertussis toxin treatment increased the basal and the forskolin-stimulated adenylate cyclase activity in both normal and failing heart membranes, the adenylate cyclase activity remained significantly depressed in the failing heart after pertussis toxin treatment (p less than 0.01). Consistent with the depressed adenylate cyclase activity, mechanical studies on isolated papillary muscles and trabeculae revealed a decrease in baseline total tension (from 7.0 +/- 0.7 to 3.8 +/- 0.4 g/mm2, p less than 0.01) and dT/dt (from 26 +/- 8 to 13 +/- 1 g/mm2/sec, p less than 0.01) in the pacing-overdrive model. Tension generation and dT/dt observed in the paced dogs in response to increasing concentrations of forskolin demonstrated a rightward shift in the dose-response curve and a decrease in maximal forskolin stimulation (p less than 0.01). Similarly, maximal tension and dT/dt in the presence of isoproterenol was significantly lower than in the normal dogs (p less than 0.01). The decrease in beta-adrenergic responsiveness was accompanied by a decrease and rightward shift in alpha 1-adrenergic responsiveness (increase in tension was 1.1 +/- 0.1 g/mm2 in paced dogs versus 2.1 +/- 0.1 g/mm2 in controls, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dysfunction of the beta- and alpha-adrenergic systems in a model of congestive heart failure. The pacing-overdrive dog. 165 Feb 96

Catecholamines (CAs) had been used for the treatment of congestive heart failure (CHF). However, since continuous administration of CAs develops tolerance in hemodynamics presumably due to desensitization of beta-adrenergic receptor (beta AR)-adenylate cyclase (AC) system, beta antagonist, instead of beta agonist, has recently been employed to treat CHF, in that it may recover beta AR-AC system. In this study, the precise mechanisms of alterations in cardiac beta AM-AC system after chronic administration of beta agonist or antagonist, were investigated. The rats were treated continuously for 14 days with saline, isoproterenol (ISO), atenolol (ATENO), or denopamine (DENO), a new positive inotropic agent with beta 1 selective AR agonistic properties, which is reported to hardly cause the tolerance in clinical studies. beta AR density (Bmax) was markedly reduced by ISO and slightly increased by ATENO. Forskolin stimulated cyclase activity was reduced markedly by ISO. Total amount of the pertussis toxin substrates (inhibitory G-protein; Gi) and cholera toxin substrates (stimulatory G-protein; Gs) were not different among 4 groups. However, Gs activity measured by human platelet reconstitutive assay was reduced by ISO and DENO. These results indicate that ISO-induced desensitization in caused by the reduction in Gs and AC-catalytic activity as well as by the down-regulation of beta AR. Furthermore, it is suggested that DENO may cause slight desensitization of beta AR-AC system due to reduced Gs activity.
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PMID:[Isoproterenol, denopamine, and atenolol-induced alterations in beta-adrenergic receptor-adenylate cyclase system of rat myocardium]. 168 39

Our knowledge and understanding of the structure, mechanism of action and regulation of receptor-adenylate cyclase systems have increased dramatically in the last few years. A family of receptors (including the beta-adrenergic receptors) and guanine nucleotide regulatory proteins (G proteins) have been purified and cloned. Structure-function studies are beginning to provide insight into how the various components of the transmembrane signaling apparatus interact to promote alterations in the activity of the effector systems. Much effort has been devoted to understanding how various pathophysiologic conditions, such as ischemia or congestive heart failure, and the therapeutic methods used to treat such conditions perturb or regulate receptor systems. It has become abundantly clear that such regulation does occur but is not restricted to simple alterations in receptor number, and may well involve covalent modification (phosphorylation) of receptors or alteration in the ability of receptors to interact with G proteins. In addition, regulation of the quantity or functionality of the various G proteins and the catalytic unit of adenylate cyclase itself appear to occur. For example, recent evidence suggests that congestive heart failure in humans is associated with a decreased number of beta-adrenergic receptors as well as an increased quantity of the inhibitory G protein (Gi). These alterations may provide important insight into how to develop new therapeutic methods. Mechanisms generally responsible for transmembrane signaling, how the components are regulated by pathophysiologic conditions, and drugs used to treat disease states are discussed in detail.
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PMID:Adrenergic receptor responsiveness and congestive heart failure. 185 May 73

Postsynaptic defects in this important pathway for regulating heart rate and contractile force may contribute to the etiology and pathogenesis of congestive cardiac failure. Such defects may involve the beta-adrenergic receptor, its associated G protein, or adenylate cyclase. Current knowledge about these components of transmembrane cardiac signaling is reviewed.
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PMID:The beta-adrenergic signaling pathway in the heart. 185 99


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