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)

We tested whether dilation of outer medullary descending vasa recta (OMDVR) is mediated by cAMP, nitric oxide (NO), and cyclooxygenase (COX). Adenosine (A; 10(-6) M)-induced vasodilation of ANG II (10(-9) M)-preconstricted OMDVR was mimicked by the cAMP analog 8-bromoadenosine 3',5'-cyclic monophosphate (10(-10) to 10(-4) M) and reversed by the adenylate cyclase inhibitor SQ-22536. Adenosine (10(-4) M) stimulated OMDVR cAMP production greater than threefold. NO synthase blockade with N(G)-nitro-L-arginine methyl ester and N(G)-monomethyl-L-arginine (10(-4) M) did not affect adenosine vasodilation. Adenosine induced endothelial cytoplasmic calcium transients that were small. Indomethacin (10(-6) M) reversed adenonsine-induced dilation of OMDVR preconstricted with ANG II, endothelin, 4-bromo-calcium ionophore A23187, or carbocyclic thromboxane A(2). In contrast, selective A(2)-receptor activation dilated endothelin-preconstricted OMDVR even in the presence of indomethacin. We conclude that OMDVR vasodilation by adenosine involves cAMP and COX but not NO. COX blockade does not fully inhibit selective A(2) receptor-mediated OMDVR dilation.
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PMID:Adenosine signaling in outer medullary descending vasa recta. 1117 66

Short-circuit current (I(sc)) technique was used to investigate the role of testosterone in the regulation of chloride secretion in cultured rat efferent duct epithelia. Among the steroids tested, only testosterone, and to a lesser extent, 5alpha-dihydrotestosterone (5alpha-DHT), reduced the basal and forskolin-induced I(sc) in cultured rat efferent duct epithelia when added to the apical bathing solution. Indomethacin, a 3alpha-hydroxysteroid dehydrogenase, did not affect the inhibitory effect of 5alpha-DHT. The effect of testosterone occurred within 10-20 s upon application and was dose dependent with apparent IC(50) value of 1 microM. The effect was abolished by removal of Cl(-) but not HCO from the normal Krebs-Henseleit solution, suggesting that testosterone mainly inhibited Cl(-) secretion. The efferent duct was found to be most sensitive to testosterone, while the caput and the cauda epididymidis were only mildly sensitive. Cyproterone acetate, a steroidal antiandrogen, or flutamide, a nonsteroidal antiandrogen, did not block the effect of testosterone on the forskolin-induced I(sc), nor did protein synthesis inhibitors, cycloheximide, or actinomycin D. However, pertussis toxin, a G(i) protein inhibitor, attenuated the inhibition of forskolin-induced I(sc) by testosterone. Testosterone caused a dose-dependent inhibition of forskolin-induced rise in cAMP in efferent duct cells. It is suggested that the rapid effect of testosterone was mediated through a membrane receptor that is negatively coupled to adenylate cyclase via G(i) protein. The role of nongenomic action of testosterone in the regulation of electrolyte and fluid transport in the efferent duct is discussed.
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PMID:Nongenomic effect of testosterone on chloride secretion in cultured rat efferent duct epithelia. 1128 29

Nimesulide, a selective inhibitor of cyclooxygenase-2, has been reported to cause less gastric damage, compared to other NSAIDs. We investigated the effect of nimesulide on basal gastric acid secretion, a contributing factor in NSAID-induced gastric damage, and histamine, pentagastrin, 5-methylfurmethide, isobutyl methylxanthine or high K(+) stimulated acid secretion in the isolated mouse stomach. The stomachs, removed from mice, were transferred into an organ bath and continuously perfused. Changes in pH following the addition of secretagogues were measured by a pH electrode system. The effects of nimesulide on basal and secretagogues-stimulated acid secretion were compared to those of indomethacin. Nimesulide (1 microM to 100 microM) produced a rightward concentration-dependent shift and reduction of maximum acid secretion of all the agonist-stimulated acid secretion curves. Indomethacin was only effective at the higher concentration of 100 microM. Compared to their effects singly, nimesulide (20 microM) and famotidine (0.15 microM) together caused a further shift without further reduction in maximum acid output of the histamine-stimulated curve, suggesting that nimesulide was not acting at the histamine H(2)-receptor. Nimesulide concentration-dependent reduction of stimulated acid secretion in the isolated mouse stomach was not by antagonism of the histamine H(2) receptor and is probably beyond the level of adenylate cyclase stimulation. A direct effect on the calcium channel is demonstrated.
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PMID:Effect of nimesulide on gastric acid secretion in the mouse stomach in vitro. 1249 69

In the present study, we examined the effect of prostaglandin (PG) E2 on interleukin (IL) -12 production in monocytes stimulated with a combination of lipopolysaccharide (LPS) from Actinobacillus actinomycetemcomitans and interferon-gamma (A. actinomycetemcomitans-LPS/IFN-gamma). Indomethacin, a cyclooxygenase inhibitor, enhanced IL-12 production, but inhibited PGE2 generation in A. actinomycetemcomitans-LPS/IFN-gamma-stimulated monocytes. Exogenous PGE2 inhibited IL-12 release in the cells. EP2, EP3 and EP4 receptor mRNA expression was detected in monocytes by reverse transcription-polymerase chain reaction. 11-deoxy-PGE1 (an EP2/EP4 agonist) inhibited IL-12 production in A. actinomycetemcomitans-LPS/IFN-gamma-challenged monocytes, whereas butaprost (an EP2 agonist) or ONO-AP-324 (an EP3 agonist) had no effect on IL-12 production. Dibutyryl cAMP, a cAMP analogue, and forskolin, an adenylate cyclase activator, mimicked depression of IL-12 production by PGE2. From these results, we suggest that PGE2 inhibits IL-12 production via EP4 receptors by cAMP-dependent pathways in A. actinomycetemcomitans-LPS/IFN-gamma-challenged monocytes.
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PMID:Prostaglandin E2 downregulates interleukin-12 production through EP4 receptors in human monocytes stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans and interferon-gamma. 1275 65

The human ileocaecal adenocarcinoma cell line HCT-8 was characterized for its potential as an in vitro organ-specific model for gastro-intestinal toxicity. HCT-8 cells showed typical epithelial cell morphology, with microvilli and intercellular junctional complexes, and formed domes, consistent with transepithelial fluid secretion. The cells express three intestinal brush-border enzyme activities (alkaline phosphatase, leucine aminopeptidase and alpha-glucosidase), and adenylate cyclase can be stimulated with vasoactive intestinal peptide. The toxicity of eight non-steroidal anti-inflammatory drugs (NSAID; indomethacin, mefenamic acid, ketoprofen, ibuprofen, sulindac, aspirin, phenylbutazone and naproxen) were assessed using the MTT and neutral red uptake assays. The MTT assay was consistently a more sensitive measure of NSAID-induced toxicity, which suggests that perturbation of mitochondrial function may be an early event in NSAID-induced cellular damage. Comparing the rankings observed in acute studies in the rat in vivo with those observed with HCT-8 cells, there are some general agreements. Indomethacin, a potent ulcerogen in vivo, was consistently among the most toxic in vitro, while aspirin and phenylbutazone have comparatively low rankings in vitro and in vivo. In man, with chronic administration, indomethacin is again ranked as a potent ulcerogen, as is aspirin, in contrast to the in vitro data with HCT-8. Therefore, NSAID-induced toxicity in HCT-8 cells assessed by the MTT or neutral red assays, can only partially predict toxicity in vivo, which suggests that local gastro-intestinal environmental factors, such as luminal acidity, may play a role in vivo. The ability of HCT-8 cells to reconstitute intact epithelial layers, thereby allowing such environmental factors to be mimicked, allows further development of these cells as a model for the in vitro prediction of in vivo gastro-intestinal toxicity.
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PMID:Toxic effects of non-steroidal anti-inflammatory drugs in a human intestinal epithelial cell line (HCT-8), as assessed by the MTT and neutral red assays. 2073 14


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