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)

Evidence has steadily accumulated to indicate that the rapid fluctuations in cyclic nucleotides during primary and secondary stroke are more than epiphenomena of the disease. During acute phases of ischemia, anoxia or hypoxia cyclic AMP rapidly accumulates in cerebral tissue, cerebrospinal fluid (CSF) and venous plasma, while cyclic GMP either remains unchanged or declines. The massive release of transmitters (catecholamines and adenosine) or ionic fluxes (Na+ and K+) may account for these observations. If reflow is established through a previously occluded vessel cyclic AMP content rises even higher in conjunction with a sharp rise in cyclic GMP. It is during this reflow period subsequent to longer term stroke (30-60 min) that the synaptic membrane enzyme, adenylate cyclase, is especially vulnerable. Presumably the cause of injury to cell membrane systems results from excess lactic acid accumulation and/or Ca++ entry through the damaged blood-brain barrier. The latter initiates breakdown of membrane phospholipids with resultant synthesis of vasoactive prostaglandins and formation of free radicals causing further insult to membrane phospholipids. Thus drugs acting to inhibit formation of prostaglandins, scavenge free radicals, reduce lactate formation, inhibit Ca++ entry or stabilize cell membranes have been shown to possess varying degrees of protective action toward adenylate cyclase. Moreover, cyclic AMP has been found to reverse stroke-induced vasospasm in central vessels. Reduced cyclic AMP content in CSF has been used to monitor the severity of coma, whereas clinical improvement was associated with predictable increases in the cyclic nucleotide. Therefore, cyclic nucleotides and related membrane enzyme systems might be used as target molecules in which to develop future therapeutic strategies for prevention or treatment of stroke.
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PMID:Cyclic nucleotides in stroke and related cerebrovascular disorders. 286 May 49

A therapeutic role for naloxone during stroke has been suggested, but a neurochemical site of action remains to be determined. Previous work with the gerbil cerebral cortex has shown that either bilateral secondary ischemia (60-min occlusion of the carotid arteries followed by 40-min reflow) or unilateral primary ischemia (permanent ligation of one carotid artery for 6 hr in symptomatic animals) produced deficits in both Na+, K+-ATPase (EC 3.6.1.3) activity and various parameters of activation of adenylate cyclase (EC 4.6.1.1). Pretreatment of gerbils with either naloxone or morphine failed to ameliorate or exacerbate, respectively, the neurological signs of ischemia; however, morphine did reduce mortality. Infusion of naloxone prior to ischemia afforded varying degrees of protection to forskolin, GTP analogs, and NE (norepinephrine) activation of adenylate cyclase, as well as to Na+, K+-ATPase (bilateral ischemia only). Similarly, morphine inhibited damage to basal activity of adenylate cyclase and to stimulation by NE, forskolin, and Gpp (NH)p (5'-guanylyl imidodiphosphate). Under in vitro conditions morphine increased the basal activity of adenylate cyclase but reduced responses to NE and forskolin. Furthermore, morphine injected into control gerbils elevated basal- and forskolin-elicited activities but reduced the activation of adenylate cyclase by NE.
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PMID:Effects of naloxone and morphine on cerebral ischemia in gerbils. 294 23

The cAMP levels and adenylate cyclase activity have been studied in the grey brain substance and striatum system of dogs during circulation arrest due to electrotrauma of different duration (1-2, 15, 45 min) and in postresuscitation period in animals recovered after 15-min clinical death. Adenylate cyclase is strongly activated and cAMP levels are increased in the brain areas under study during complete brain ischemia. The cAMP levels in the grey substance and in striatum system are reduced considerably compared to the control, accounting for 12-20 on days 2-5 of postresuscitation period in animals with neurologic deficit. Adenylate cyclase and phosphodiesterase enzyme activity is twice higher in the striatum system and 50% lower in the grey brain substance than the baseline. The disturbances in cyclic nucleotide exchange, along with other factors seem to play an important role in the pathogenesis of postresuscitation encephalopathy.
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PMID:[Adenylate cyclase activity and cyclic AMP content in brain tissue of dogs during clinical death and in the post-resuscitation period]. 299 52

It has been proposed that increases in tissue cyclic adenosine monophosphate during ischemia may be responsible for the induction of arrhythmias that occur during the early minutes of ischemia. We have tested this hypothesis using the isolated perfused rat heart with coronary artery occlusion for 30 minutes. In control hearts, after a transient small rise, cyclic adenosine monophosphate content remained close to its preischemic value (3.0 +/- 0.1 nM/g dry weight) throughout the period of occlusion. Eight percent (1/12) of the hearts fibrillated. Ninety-two percent (11/12) of the hearts exhibited ventricular tachycardia, and the mean total number of premature ventricular complexes was 528 +/- 121. Inclusion of epinephrine (1.0 microM) in the perfusion fluid elevated cyclic adenosine monophosphate prior to coronary occlusion (to 10.7 +/- 0.6 nM/g dry weight) and also throughout the ischemic period. It also increased arrhythmias such that 83% (20/24) of hearts fibrillated, 100% exhibited ventricular tachycardia, and the mean number of premature ventricular complexes increased to 747 +/- 86. Inclusion of forskolin (0.2 microM), which stimulates adenyl cyclase independently of the beta-receptor, increased cyclic adenosine monophosphate content to a greater extent than epinephrine, to 14.1 +/- 0.9 nM/g dry weight before the onset of ischemia and to 8.2 +/- 0.4 nM/g dry weight after 30 minutes of ischemia. Despite the large increase in cyclic adenosine monophosphate, there was no increase in rhythm disturbances which were less than those seen in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat. 299 4

We evaluated the effects of ischemic injury on the myocardial adenylate cyclase system, 5 h after ligation of the left anterior descending coronary in 5 anesthetized dogs. Crude cardiac membrane preparations were isolated from control and ischemic areas of ventricular myocardium and tested for: 1. L-(125I)iodocyanopindolol binding, in the absence and presence of +/- -isoprenaline and GTP, and 2. adenylate cyclase activity. The density of beta-adrenoceptors increased by 35% in membranes from ischemic areas while the proportion of receptors in a high affinity state for +/- -isoprenaline decreased from 43% to 20%. Adenylate cyclase activities in the basal state and under stimulation with NaF, forskolin, Gpp(NH)p, +/- -isoprenaline and VIP were all markedly and similarly reduced, being only about 30% of comparable activities in membranes from control areas. The +/- -isoprenaline subsensitivity of cardiac adenylate cyclase can, thus, be attributed to a defective enzymatic system and not to a reduction in the number of beta-adrenoceptors implying that the internal components of the system were more sensitive to acute ischemia than the outward oriented hormone receptors. It is tempting to ascribe this uncoupling to a functional depletion in the guanine nucleotide-binding regulatory protein Ns that might reflect a loss of high energy phosphate stores including GTP.
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PMID:Uncoupling between beta-adrenoceptors and adenylate cyclase in dog ischemic myocardium. 299 17

The report deals with the effect of ischemia and reperfusion on purified sarcolemma obtained from canine myocardium of perfused supported heart preparations. Perfusion was carried out with a perfluorochemical (FC-43). Ischemia was produced by intermittent total clamping of inflow and outflow followed by release until the decrease in dP/dtmax had become stabile. Purity of sarcolemmal vesicles was ascertained with marker enzymes: succinate cytochrome c reductase (for mitochondria), K+-stimulated p-nitrophenylphosphate (K+-pNPPase), (Na+/K+)ATPase and adenylate cyclase (for SL). In addition Na+/Ca2+-exchange characteristics for SL were determined. Sidedness of vesicles was ascertained by means of adenylate cyclase activity using sarcolemmal preparations treated and untreated with alamethicin. Emphasis was placed on ATP-dependent Ca2+ uptake, phosphorylation of sarcolemmal vesicles and yield of SL proteins. Ischemia and reperfusion resulted in a significant reduction in adenylate cyclase activity. This decline was significant following ischemia and reperfusion. The yield of protein recovered from SL vesicles from ischemic-reperfused heart preparations was also significantly decreased. Both initial rate of ATP-dependent Ca2+ uptake and maximal Ca2+ uptake fell significantly following ischemia and reperfusion. The initial rate of phosphorylation also dropped significantly. These disturbances in SL Ca2+ transport following ischemia and reperfusion are probably a part of the general deficit in Ca2+ translocation.
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PMID:The effect of ischemia and reperfusion on sarcolemmal function in perfused canine hearts. 300 67

Purified sarcolemmal and light vesicle (intracellular) fractions of beta-adrenergic receptors were used to examine the effects of propranolol on receptor translocation in guinea pig heart. Guinea pigs were given propranolol (0.15 mg/kg/hr) via minipumps for 7 days and either killed or made ischemic for 1 hour via a coronary ligature. Propranolol treatment led to an externalization of beta-receptors from light vesicle to sarcolemmal fractions. This externalization increased the number of surface beta-adrenergic receptors that were functional, as assessed by isoproterenol-stimulated adenylate cyclase activity. After chronic propranolol treatment, ischemia did not further alter receptor distribution. These results suggest that externalization of beta-adrenergic receptors from a light vesicle fraction to the sarcolemma contributes to up-regulation of beta-receptors that occur in response to both propranolol treatment and ischemia. Because propranolol-treated animals show blunting in externalization after myocardial ischemia, propranolol treatment and myocardial ischemia appear to access the same pool of intracellular beta-adrenergic receptors. Depletion of this pool of receptors along with receptor blockade may thus contribute to the mechanism by which the drug is efficacious in preventing some adverse effects of ischemia.
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PMID:Propranolol treatment externalizes beta-adrenergic receptors in guinea pig myocardium and prevents further externalization by ischemia. 303 72

A variety of pharmacological agents were used as experimental probes to determine with greater precision the site(s) of damage to cerebral adenylate cyclase as a consequence of postischemic reperfusion in the gerbil. A paradigm of 60-min bilateral ischemia followed by 40-min reperfusion results in a decreased sensitivity of the catalytic site of adenylate cyclase to Mn2+. Likewise, the GTP-transducer site (guanine nucleotide regulatory or G protein) revealed depressed responses to GTP in the absence or presence of norepinephrine, dopamine agonists, substance P, yohimbine, and cholera and pertussis toxins. Moreover, a crude preparation of GTPase disclosed that damage elicited by postischemic reperfusion was directed to the higher-affinity form of this enzyme, which is associated with the overall function of the guanine nucleotide regulatory protein. Injury to adenylate cyclase was unrelated either to the ability of adrenergic ligands to bind to associated receptor sites or to the capacity of the brain to generate visual evoked potentials in response to visual stimuli.
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PMID:Further probes into the molecular sites of damage to cerebral adenylate cyclase following postischemic reperfusion. 310 40

The effect of the ganglioside GM1 on amplitude of the electroencephalogram, neurologic function, and histology has been studied in chronic middle cerebral artery occlusion in cats. Ischemia was produced by a 2-hour occlusion of the left middle cerebral artery and was followed by a 7-day observation period. GM1 was intravenously administered 30 minutes after occlusion and daily during the observation period. Using the reduction in the electroencephalogram amplitude to measure stroke severity, three cats with mild, three cats with moderate, and three cats with severe stroke were treated with 5 mg/kg GM1. Nine cats, three in each group, were treated with 30 mg/kg GM1, while nine cats, three in each group, received middle cerebral artery occlusion but no treatment. In all cats there was a precipitous fall in mean electroencephalogram amplitude during occlusion, followed by a secondary fall during the observation period. Treated cats showed better recovery of electroencephalogram amplitude during the first 4 hours of reperfusion and a smaller secondary fall than untreated cats. Treated cats, especially those treated with 5 mg/kg GM1, showed significant recovery of neurologic deficits compared with untreated cats. Histologic damage was less in treated cats than in untreated cats. Some cats treated with 30 mg/kg GM1 exhibited convulsions, whereas no untreated cat showed any seizure activity. Our findings suggest that gangliosides may improve the recovery of both neurologic deficits and morphologic damage in the central nervous system. These positive effects might be tentatively explained by stimulation of enzymatic activities such as Na+, K+-ATPase and adenyl cyclase.
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PMID:Effect of the ganglioside GM1 on neurologic function, electroencephalogram amplitude, and histology in chronic middle cerebral artery occlusion in cats. 340 Jan 1

It has been previously established that prolonged bilateral carotid occlusion followed by recirculation produces damage to the synaptic enzyme adenylate cyclase in the frontal cortex of the gerbil. Since calcium entrance into the brain may account in part for the deleterious consequences of stroke, the present study examined whether pretreatment with calcium channel blockers would modify the effects of 60 min of bilateral ischemia plus 40 min of reflow on various parameters of cortical adenylate cyclase activation. In this context activation of cerebral homogenates by norepinephrine with or without 5'-guanylyl imidodiphosphate was preserved by pretreatment of ischemic gerbils with verapamil but worsened by flunarizine. In contrast, in particulate fractions (treated with EGTA to reduce metallic ion levels) the damage to the Mn2+-sensitive catalytic site of adenylate cyclase was prevented only by flunarizine. Pretreatment with the two calcium channel blockers resulted in an elevated basal activity of the enzyme, thereby reducing the response in the homogenate preparation to forskolin. Gerbils pretreated with verapamil tended to have an increased ability for survival resulting from the ischemic episode. Under in vitro conditions the enzyme preparations were not markedly influenced by either drug.
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PMID:Modulation of ischemic-induced damage to cerebral adenylate cyclase in gerbils by calcium channel blockers. 350 45


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