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)

The adenylate cyclase activity was determined in the left ventricles of rat hearts up to 60 min after severe ischemia and 24 hours after injection of a high dose of isoproterenol. The quantitative data show a progressive decline in the activity after 20 min of ischemia. Isoproterenol- and fluoride-stimulated activities were influenced in the same manner. The cytochemical localization showed no changes in the localization of the enzyme. But the number of cells with reaction products of the adenylate cyclase activity were decreased. The quantitative analysis of the adenylate cyclase activity in the myocardial necrosis produced by a single injection of 80 mg isoproterenol per kg body weight showed no changes in the basal activity of the enzyme however a significant reduction of the isoproterenol stimulation and a slight decrease of the fluoride-stimulated activity compared to the non-necrotic area of the same left ventricle. In cytochemical investigations no reaction of the adenylate cyclase activity was found in the centre of the necroses. But in the border zone of the basis the reaction product of the plasma membrane of the sarcolemma the main localization site of the enzyme activity was failed whereas the activity of the junctional SR was preserved. It was concluded that this activity is responsible for the unchanged basal activity in the necrotic and non-necrotic area.
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PMID:[Behavior of adenylate cyclase in ischemic and necrotic myocardial tissue]. 642 38

A model is proposed for the role of the kidney in the control of erythropoietin production in which the initial trigger is an oxygen deficit created by anemia, hypobaria or ischemia. It is postulated that hypoxia creates a decrease in the oxygen level in a critical renal sensor cell, perhaps in the glomerular tuft, which eventually leads to the production of prostacyclin. It is possible that the endothelial cell in the glomerular tuft responds to this oxygen deficit to produce prostacyclin to trigger erythropoietin production. Recent studies on prostaglandin synthesis by human isolated glomeruli indicate that the most abundant prostanoid synthesized by the glomerular tuft cells was 6-keto PGF1 alpha, a metabolite of prostacyclin (PGI2). PGI2 has also been reported to be produced by isolated vascular endothelial cells. The mechanism by which hypoxia may initiate the synthesis and/or release of prostaglandins and prostacyclin in the renal cell has not been elucidated. Significant to erythropoietin production is the production by hypoxia of prostacyclin which eventually leads to the production of the metabolite 6-keto PGE1. We further propose that 6-keto PGE1 is the prostanoid which activates a specific cell membrane adenylate cyclase, causing the conversion of ATP to cyclic AMP. This is a very critical step in that there must be a sufficient amount of ATP remaining to generate cyclic AMP in order for erythropoietin biosynthesis to occur with the reduced level of ATP which may have caused a perturbation of the cell membrane. The elevated cyclic AMP leads to the activation of protein kinases which are essential in phosphorylating the lysosomal hydrolases released by hypoxia into the cytosol of the cell and may be the precursors of erythropoietin. Neutral proteases and lysosomal hydrolases, documented triggers of erythropoietin production, have been demonstrated to be elevated in the kidney after hypoxia. The mechanism of labilization and release of these enzymes from the renal lysosomes has been postulated to be related to increases in cyclic GMP levels in a renal cell. Hypoxia causes the release of renal lysosomal hydrolases which then undergo phosphorylation through activation by protein kinases following prostanoid stimulation of renal adenylate cyclase to generate cyclic AMP, resulting in increased biosynthesis of erythropoietin.
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PMID:Prostanoid activation of erythropoiesis. 654 29

Adenylate cyclase activity was investigated in either homogenate or particulate fractions from the frontal cerebral cortex of the gerbil following five experimental conditions of bilateral ischemia. After periods of 15 min ischemia, 15 min ischemia plus 15 min of recirculation or 60 min ischemia the enzyme generally displayed enhanced responses to GTP, norepinephrine (NE), dopamine (DA), NE + GTP and DA + GTP. Pretreatment of the gerbils with methylprednisolone, allopurinol or indomethacin did not significantly influence the outcome of these findings. When the animals were subjected to 60 min ischemia plus 15 min of reflow, enzyme responses to the stimulatory agents including forskolin and NaF were all reduced. Pretreatment with methylprednisolone, allopurinol or indomethacin prevented the damage to adenylate cyclase in the 60 min ischemia plus 15 min reflow animals. When animals were made ischemic for 15 min followed by one week of recovery, enzyme sensitivity to GTP, calmodulin-Ca++, NE, combinations thereof and forskolin were reduced in only the particulate fractions. Enzyme damage was reversed following methylprednisolone. Enzyme damage may result from generation of free radicals during reflow and drugs that either inhibit synthesis pathways generating free radicals, stabilize cell membranes or act as free radical scavengers may be therapeutically beneficial under specific conditions of stroke.
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PMID:Protective action by methylprednisolone, allopurinol and indomethacin against stroke-induced damage to adenylate cyclase in gerbil cerebral cortex. 670 40

It has been reported that the function of the guanine-binding regulatory protein (G protein), especially the alpha subunit of the stimulatory G protein (Gs alpha), in myocardium is decreased with acute ischemia. However, it is unclear whether this decrease is due to transcriptional or post-transcriptional changes. Moreover, no studies have examined the distribution of G protein mRNA in ischemic myocardium using in situ hybridization. The purpose of this study was to explore alterations in mRNA of G proteins (Gs and Gi) in ischemic hearts using in situ hybridization. We measured the levels of mRNA for Gs alpha and Gi alpha in ischemic and non-ischemic myocardium by in situ hybridization using a radioisotope imaging system. We compare these mRNA levels in ischemic and non-ischemic myocardium with Northern blot analysis and the protein levels of G proteins by Western blot analysis. The mRNA for Gs alpha and Gi alpha was distributed diffusely in normal hearts. Levels of mRNA detected by in situ hybridization were substantially reduced by acute ischemia, and these results were confirmed by Northern and Western blot analysis. These results suggest that decreased levels of mRNA and protein for G proteins may underlie the impaired function of the receptor--G protein--adenylate cyclase system in ischemic myocardium. In addition, quantitative evaluation of mRNA is possible by in situ hybridization and correlates well with Northern analysis.
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PMID:Messenger RNA for the guanine nucleotide-binding regulatory protein (G protein) is reduced in the acute ischemic myocardium. 747 71

Although the autonomic nervous system has been implicated in the formation of ventricular fibrillation, the precise mechanism by which this is mediated remains undetermined. In particular, the role of second messengers, generated by beta-adrenoceptor activation, has been postulated to mediate the pro-arrhythmic effects of the sympathetic nervous system. Thus, a 2 min occlusion of the left circumflex coronary artery was initiated during the last minute of exercise in canines with healed myocardial infarctions (produced by ligation of left anterior descending artery). Fifteen dogs were found to be susceptible to the formation of ventricular fibrillation while 17 animals were resistant. Nine resistant dogs were treated with the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX, 1 mg/kg) in combination with an infusion of 8-bromo-cAMP (100-150 micrograms/kg/min beginning 45 min prior to exercise). Heart rate and left ventricular dP/dtmax significantly increased, but failed to elicit, arrhythmias during the exercise and ischemia test. Nine resistant animals were also treated with the adenylate cyclase activator forskolin, (100 micrograms/kg), which provoked the same hemodynamic changes as the cyclic AMP infusion but also failed to induce ventricular fibrillation. Both forskolin (n = 3) and IBMX (n = 3) induced large increases in myocardial cAMP levels (control 5.2 +/- 0.5, forskolin 8.1 +/- 0.8 pmol/mg non-collagen protein; control 5.0 +/- 0.8, IBMX 6.8 +/- 0.3 pmol/mg non-collagen protein). Ten resistant animals were treated with the beta-adrenoceptor agonist isoproterenol (1-10 micrograms/kg/min), which failed to cause ventricular fibrillation despite significant increases in the hemodynamic parameters described above. Finally, experiments were repeated after 8-bromo-cAMP infusion and IBMX pretreatment in 8 susceptible animals with pharmacologic denervation (atropine+propranolol+prazosin). In spite of hemodynamic increases indicative of an increase in myocardial cyclic AMP levels, arrhythmias were not re-introduced. These data suggest that changes in cAMP may not be responsible for ventricular fibrillation in this model of sudden cardiac death.
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PMID:Effect of interventions that increase cyclic AMP levels on susceptibility to ventricular fibrillation in unanesthetized dogs. 751 86

Platelet activating factor (PAF) is an important mediator of pulmonary microvascular endothelial cell (PMVEC) injury in sepsis. Membrane receptors for PAF have been identified on PMVECs and mediate its actions at least in part by protein kinase C activation. Since rolipram, a family IV cyclic AMP phosphodiesterase inhibitor, and isoproterenol, an adenylate cyclase activator, both reverse ischemia-reperfusion-induced lung permeability, we studied the effects of these agents on PAF-induced pulmonary microvascular permeability. The isolated rat lung model was used in which lungs were ventilated and buffer perfused at constant flow while suspended from a force transducer to monitor lung weight along with arterial (P(a)) and venous (Pv) pressures. Control lungs (n = 6) were infused with PAF (40 nmole/kg) via an arterial port and the capillary permeability coefficient (Kf,c) was determined at 0, 15, and 60 min. The remaining lungs were randomized for infusion with either rolipram (n = 4, 20 mumole/kg) or isoproterenol (n = 4, 5 mumole/kg) via an arterial port 30 min after injury with PAF. In the rolipram- and isoproterenol-treated groups, the Kf,c was determined 15 and 60 min postinfusion with these agents. The control group showed significant elevation in the Kf,c and total pulmonary resistance (Rt). At 15 and 60 min, rolipram and isoproterenol reversed PAF injury as shown by the significant improvement in the Kf,c and Rt. These findings support the concept that increased cyclic AMP is an important mediator in the reversal of PAF-increased PMVEC permeability and pulmonary resistance.
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PMID:Rolipram and isoproterenol reverse platelet activating factor-induced increases in pulmonary microvascular permeability and vascular resistance. 763 Jan 21

Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of vascular endothelial growth factor in cardiac myocytes. 772 92

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

Autoradiographic visualization of the Bmax (maximal binding capacity) and Kd (dissociation constant) of [3H]phorbol 12,13-dibutyrate (PDBu) and [3H]forskolin (FK) was performed after 30-min unilateral carotid artery occlusion in the gerbil brain. These parameters and the local cerebral blood flow (CBF) were measured at the level of the caudate-putamen in the same brain using a digital image processing technique developed in our laboratory. The local CBF was measured at the end of the experiment. [3H]PDBu and [3H]FK were utilized as specific ligands to assess the activities of protein kinase C (PKC) and adenylate cyclase (AC), respectively. The local CBF on the occluded side was severely reduced and ranged from 0.2 to 9.0 ml/100 g/min, whereas the local CBF on the non-occluded side exhibited a moderate reduction except in the midline regions. The Bmax values of PDBu and FK were significantly increased not only on the occluded side but also on the non-occluded side in the ischemia group as compared to the corresponding values in the sham group. In contrast, the Kd value of each ligand remained unchanged in the ischemia group. These findings suggest that both the adenylate cyclase and protein kinase C systems may be significantly and diffusely activated in the initial stage of brain ischemia. Thus, severe hemispheric cerebral ischemia in the acute phase may induce severe perturbation of the second messenger systems in extensive bilateral regions.
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PMID:Enhanced maximal binding capacity (Bmax) of second messenger ligand in the acute phase of cerebral ischemia--direct visualization by digital image analysis. 809 Mar 67

Current organ preservation strategies subject graft vasculature to severe hypoxia (PO2 approximately 20 Torr), potentially compromising vascular function and limiting successful transplantation. Previous work has shown that cAMP modulates endothelial cell (EC) antithrombogenicity, barrier function, and leukocyte/EC interactions, and that hypoxia suppresses EC cAMP levels. To explore the possible benefits of cAMP analogs/agonists in organ preservation, we used a rat heterotopic cardiac transplant model; dibutyryl cAMP added to preservation solutions was associated with a time- and dose-dependent increase in the duration of cold storage associated with successful graft function. Preservation was also enhanced by 8-bromo-cAMP, the Sp isomer of adenosine 3',5'monophosphorothioate, and types III (indolidan) and IV (rolipram) phosphodiesterase inhibitors. Neither butyrate alone nor 8-bromoadenosine were effective, and the cAMP-dependent protein kinase antagonist Rp isomer of adenosine 3',5'monophosphorothioate prevented preservation enhancement induced by 8-bromo-cAMP. Grafts stored with dibutyryl cAMP demonstrated a 5.5-fold increase in blood flow and a 3.2-fold decreased neutrophil infiltration after transplantation. To explore the role of cAMP in another cell type critical for vascular homeostasis, vascular smooth muscle cells were subjected to hypoxia, causing a time-dependent decline in cAMP levels. Although adenylate cyclase activity was unchanged, diminished oxygen tensions were associated with enhanced phosphodiesterase activity (59 and 30% increase in soluble types III and IV activity, respectively). These data suggest that hypoxia or graft ischemia disrupt vascular homeostasis, at least in part, by perturbing the cAMP second messenger pathway. Supplementation of this pathway provides a new approach for enhancing cardiac preservation, promoting myocardial function, and maintaining vascular homeostatic properties.
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PMID:Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model. 825 53


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