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)

Octimibate inhibited ADP- and collagen-induced platelet aggregation in human, rabbit and rat platelet-rich plasma. Washed human platelets treated with octimibate had elevated cyclic AMP (cAMP) levels and cAMP-dependent protein kinase activity. When whole platelets were incubated with radiolabeled phosphate, octimibate produced an increase in the phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. This pattern of protein phosphorylation is identical to that observed when the platelets were treated with forskolin, phosphodiesterase inhibitors or other compounds that elevate platelet cAMP levels. Octimibate also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets, which is consistent with octimibate's ability to elevate platelet cAMP levels. When isolated platelet plasma membranes were treated with octimibate, adenylate cyclase activity was stimulated, reaching maximal activation at 1 microM octimibate. (The maximal activation of adenylate cyclase observed with octimibate is 70-75% of that observed with 10 microM PGE1.) This stimulation of platelet adenylate cyclase activity was enhanced by GTP. Octimibate competed for radiolabeled prostaglandin E1 and lloprost binding to isolated platelet membranes at submicromolar concentrations, but did not compete with radiolabeled prostaglandin D2 binding. These studies suggest that octimibate inhibits platelet aggregation by activating platelet adenylate cyclase through stimulation of platelet prostacyclin receptors.
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PMID:Octimibate inhibition of platelet aggregation: stimulation of adenylate cyclase through prostacyclin receptor activation. 217 92

Using selective media and complement-mediated lysis of primary cultures of a fetal rat calvarial cell population, we have developed a cell line (OBCK6) that exhibits osteoblastic characteristics. OBCK6 cells demonstrated enhanced parathyroid hormone (PTH)-stimulated adenylate cyclase activity relative to the primary calvarial population, production of alkaline phosphatase activity and type 1 collagen, and the capacity to form mineralized nodules in unsupplemented medium after prolonged (22-26 day) culture. Two sublines, CFK1 and CFK2, which were isolated by dilution cloning, differed morphologically and with respect to growth rate. CFK1 cells demonstrated high PTH and prostaglandin E2-stimulated adenylate cyclase activity, whereas only low PTH-stimulated activity was observed in CFK2 cells. Retinoic acid and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] each reduced PTH-stimulated adenylate cyclase activity in both the cell types. Retinoic acid and dexamethasone reduced and 1,25(OH)2D3 enhanced alkaline phosphatase activity in these cells. PTH significantly augmented alkaline phosphatase activity to a much greater extent in CFK1 than in CFK2 cells. Both CFK1 and CFK2 cells expressed type I but type III collagen, and neither expressed osteocalcin. Strong Alcian blue staining of CFK2 cells was suggestive of a cartilaginous phenotype. These three cell lines, therefore, demonstrated discrete characteristics of skeletal cell function and should provide important models for evaluation of mechanisms of mineralization and for control of skeletal cell growth and mesenchymal differentiation in vitro.
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PMID:Establishment of an osseous cell line from fetal rat calvaria using an immunocytolytic method of cell selection: characterization of the cell line and of derived clones. 224 27

ADP is known to induce platelet shape change, aggregation, and exposure of fibrinogen binding sites as well as inhibit stimulated adenylate cyclase. The platelet is unique in that its purinergic receptor prefers ADP over ATP, which functions as a competitive antagonist. The affinity reagent, 5'-p-fluorosulfonylbenzoyl adenosine (FSBA), has been used to covalently label a single membrane protein, aggregin, on the external platelet surface with mol wt of 100 kDa. Concomitant with incorporation of FSBA, ADP-induced shape change, aggregation, and fibrinogen binding is inhibited. FSBA is also a weak agonist at short times and high concentration, which suggests that prior noncovalent binding to aggregin takes place before covalent modification. Aggregin differs from platelet glycoprotein IIIa in its physical and immunochemical properties. Aggregin is distinct from the receptor coupled to adenylate cyclase. Using FSBA as a probe, platelet aggregation by thromboxane A2 analogs and collagen was shown to be dependent on ADP but not the shape change induced by these agonists. Binding to aggregin is required for epinephrine-induced aggregation. In turn, epinephrine increases the affinity of ADP for its receptor. Thrombin at concentrations greater than 2 nM (0.2 units/ml) stimulates platelet aggregation independent of ADP, but by raising cytoplasmic Ca2+ it activates platelet calpain, which in turn cleaves aggregin. Thus aggregin, in addition to serving as the ADP receptor linked to shape change and aggregation, plays a role in fibrinogen receptor latency that is relieved entirely by ADP binding to or proteolysis of aggregin.
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PMID:Aggregin: a platelet ADP receptor that mediates activation. 240 87

Subcultured bovine corneal fibroblasts accumulated cyclic AMP intracellularly and in the culture media in response to incubation with 3-isobutyl-1-methylxanthine, isoproterenol, cholera toxin or forskolin. The duration of the intracellular cyclic AMP effect was rather short using isoproterenol (less than three hours) but cholera toxin and forskolin maintained cyclic AMP stimulations for 24 hours at greater than 3-fold and 27-fold over control, respectively. Agents which stimulated adenylate cyclase by different mechanisms or mimicked the action of cyclic AMP decreased collagen secretion by these cells. In general, the degree of inhibition of collagen production was consistent with the magnitude and duration of each drug's cyclic AMP response.
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PMID:Effect of cyclic AMP on collagen production by corneal fibroblasts. 242 78

Although many drugs have inhibitory effects on platelet function, none of them inhibits all of the mechanisms that may be involved in the various forms of thrombosis. Choice of suitable drugs is hampered by lack of full knowledge concerning the reactions that make the major contributions to the formation of arterial thrombi at sites of repeated vessel wall injury or on atherosclerotic lesions. Drugs such as aspirin that inhibit the arachidonate pathway in platelets can only be expected to be effective against thromboembolic events in which the generation of thromboxane A2 plays a major part. If thrombin and fibrin formation are dominant, oral anticoagulant agents or heparin should be beneficial; thus, experimental evidence indicates that with repeated vessel wall injury, the formation of platelet fibrin thrombi on the vessel wall is probably influenced more by inhibitors of thrombin generation than by the subendothelial constituents such as collagen. Agents like prostacyclin that raise platelet cyclic adenosine monophosphate (AMP) levels in platelets by stimulating adenylate cyclase are potent inhibitors of the reaction of platelets to all aggregating and release-inducing stimuli, but these agents are not suitable for long-term administration. The effect of dipyridamole on platelet cyclic AMP levels is weak, and this drug may act through other effects on platelets or on other cells. Indeed, several of the drugs that have been tested in clinical trials may exert their effects through unrecognized mechanisms. Many combinations of drugs have been used to affect platelets or platelets and coagulation. This practice has been based on the theory that because several mechanisms may be involved in thrombus formation, combinations of drugs that inhibit different mechanisms may be beneficial.
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PMID:Pharmacology of platelet inhibitors. 243 Oct 20

Human polycystic kidney disease (PKD) epithelia were successfully grown in culture and expressed abnormal characteristics. Cysts lining epithelia of superficial and deep cysts were microdissected and compared to individual normal human proximal straight tubules (PST) and cortical collecting tubules (CCT) grown in defined media. PKD cyst epithelia differed from normal renal tubular epithelia in growth patterns and structural and functional properties. PKD epithelia grew more rapidly and showed cyst-like areas in otherwise confluent monolayers. Polygonal and elongate cells contained an epithelial-specific cytokeratin antigen and had polarized morphology. An extremely abnormal basement membrane morphology was seen and consisted of some banded collagen and numerous unique blebs or spheroids. These blebs were apparently extruded from intracellular vacuoles and stained with ruthenium red, suggesting a proteoglycan component. Cytochemistry of marker enzymes demonstrated the presence of NaK-ATPase and alkaline phosphatase, but a lack of gamma-glutamyl transpeptidase. The response of adenylate cyclase activity to vasopressin, parathyroid hormone, and forskolin was significantly diminished in PKD cells as compared to PST and CCT. These studies suggest a defect in cell growth and basement membrane synthesis in human PKD. Cultured PKD epithelia provide a new tool for the study of the pathogenesis of this disease.
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PMID:A new method for studying human polycystic kidney disease epithelia in culture. 243 Nov 89

Effect of collagen soluble forms of the I and III types on biosynthesis of DNA, RNA on activity of adenylate and guanylate cyclase as well as on activity of several key enzymes of energy metabolism was studied in bioptic samples of wound granulation tissue and in homogenates of intact rat liver tissue in vitro. Effects of the collagen soluble forms were shown to depend on their type and the step of wounds healing. Collagen of the III type stimulated DNA and RNA biosynthesis inhibited adenylate cyclase and activated guanylate cyclase within 3 days after the operation. Activities of lactate-, malate-, glucose-6-phosphate dehydrogenases and creatine phosphokinase were also dissimilarly altered in presence of collagens of the I and III types. The data obtained suggest that collagens of the I and III types affected dissimilarly the metabolic processes in wound tissues within various steps of their healing.
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PMID:[Differences between collagens of the the interstitial type and their effect on the biosynthesis of DNA and RNA and activity of various enzymes in biopsy specimens of wound tissues in rats]. 245 54

Buffered solutions (pH 5-pH 8) of glyceryl trinitrate (GTN), sodium nitroprusside (NaNP), S-nitroso-N-acetylpenicillamine (SNAP), molsidomine and its active metabolite (SIN-1) at concentrations of 30 microM were each tested at 37 degrees C for the release of nitric oxide (NO) by its co-oxidation to NO3 along with oxidation of oxyhaemoglobin to methaemoglobin. Apart from GTN and molsidomine, three other stimulators of guanylate cyclase released NO in a pH-dependent manner. Optimum for the release of NO by SIN-1 was at pH 7.4 and therefore this guanylate cyclase stimulator was chosen for studies on interaction with the adenylate cyclase stimulator iloprost, a stable prostacyclin analogue. Human platelets, neutrophils and strips of coronary arteries were used as targets to study this interaction. SIN-1 and iloprost synergized in the inhibition of collagen-induced platelet aggregation and protection of neutrophils against the release of lactate dehydrogenase, whereas no synergism between these drugs was observed in their vasorelaxant action. It is concluded that pharmacological synergism between adenylate and guanylate cyclase stimulators is not a general rule, but occurs only in certain types of cells.
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PMID:Interaction between stimulators of adenylate and guanylate cyclases in human leukocytes, platelets and arteries. 248 90

Baraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a.8b- tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6- 1H-cyclopenta[b]benzo-furan-5-butyrate, TRK-100) is a novel stable epoprostenol (prostaglandin I2, PGI2) analogue having antiplatelet and vasodilating actions. Its effect on platelet aggregation in whole blood ex vivo and platelet suspension in vitro, formation of cyclic AMP(cAMP), production of malondialdehyde(MDA), and 45Ca++-influx into platelets were studied in rats. Oral administration of TRK-100 (0.3-1 mg/kg) showed a dose-dependent inhibition of platelet aggregation induced by ADP and collagen in whole blood and also inhibited in vitro thrombin-induced aggregation of platelet suspension in the presence or absence of external Ca++. Oral TRK-100 (0.3-3 mg/kg) dose-dependently increased plasma cAMP levels and this action was confirmed in vitro with platelet rich plasma in the presence or absence of theophylline. 45Ca++-influx into platelets stimulated by thrombin was dose-dependently inhibited by TRK-100 (3-100 nmol/l). TRK-100 (3-100 nmol/l) also suppressed MDA production induced by thrombin in platelet suspension but not that induced by arachidonic acid. From these results, TRK-100 which is orally active was suggested to exert its antiplatelet action through the increase of cAMP in platelets by activation of adenylate cyclase, concomitantly followed by the inhibition of Ca++-influx and thromboxane A2 formation.
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PMID:Studies on the antiplatelet effect of the stable epoprostenol analogue beraprost sodium and its mechanism of action in rats. 254 30

We examined the effects of synthetic human atrial natriuretic factor (human ANF 99-126) on adenylate cyclase activity, cAMP and cyclic GMP (cGMP) levels, bone resorption, collagen and DNA synthesis, and prostaglandin E2 (PGE2) production in fetal rat bone organ cultures. ANF (100 nM) inhibited PTH- and PGE2-stimulated cAMP production but had no effect on basal cAMP production in 21-day fetal rat calvaria. ANF increased cGMP levels, and this was not affected by PTH. ANF (10 nM) partially inhibited bone resorption stimulated by PGE2 but had no effect on control or PTH-stimulated resorption in 19-day fetal rat long bones. ANF had no effect on collagen and DNA synthesis or PGE2 production and did not alter responses to PTH or PGE2 in the fetal rat calvaria. Thus, ANF has no major direct effect on bone resorption or formation, but it is possible that ANF modulates the local regulatory function of PGE2 in bone.
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PMID:Effects of atrial natriuretic factor on cyclic nucleotides, bone resorption, collagen and deoxyribonucleic acid synthesis, and prostaglandin E2 production in fetal rat bone cultures. 255 55


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