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)

Cimetidine, a recently developed histamine H2-receptor blocking agent has been shown to be a potent inhibitor of histamine-stimulated gastric acid secretion in rat, cat, dog and man. To study the mode of action of cimetidine the modification of stimulatory effects of histamine, sodium flouride and 5'-guanylylimidodiphosphate by cimetidine on the adenylate cyclase activity of guinea pig gastric mucosa was studied. The effect of cimetidine was also compared to that of metiamide, an older histamine H2-receptor antagonist. The effect of cimetidine was qualitatively similar to that of metiamide, i.e. a selective blockade of histamine H2-receptors. Quantitatively cimetidine was about 10-fold more potent than metiamide.
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PMID:Effects of cimetidine on adenylate cyclase activity of guinea pig gastric mucosa stimulated by histamine, sodium fluoride and 5'-guanylylimidodiphosphate. 1 13

Adenylate cyclase activity of human fundic mucosa is log-normally distributed and equally stimulated by pentagastrin and histamine. Cimetidine inhibits the histamine, but not the pentagastrin effect, which is even intensified by H2-receptor blockade. The results indicate that pentagastrin and histamine activate adenylate cyclase via distinct receptors.
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PMID:Pentagastrin activation of adenylate cyclase in human gastric biopsy specimens. 46 87

It has been found that TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), in rats, endoperitoneally or orally administered at dose of 1-10 mcg/kg, provokes irritability, aggressivity and restlessness (increase of spontaneous crossings in the shuttle box). The TCDD does not modify the conditioned avoidance (C.A.) or the conflictual situation. In "vitro" the TCDD stimulates directly the striatal and hypothalamic adenylate cyclase of rat. The TCDD increases the stimulation produced by dopamine on striatal adenylate cyclase. Haloperidol (dopamine antagonist) inhibits the stimulation produced by TCDD. TCDD does not significantly modify the stimulation by hystamine on hypothalamic adenylate cyclase. Cimetidine (H2) antagonist) causes a remarkable increase of the TCDD stimulating effect.
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PMID:[Neuropsychopharmacological effects of TCDD]. 74 17

The H2 subclass of histamine receptors mediates gastric acid secretion, and antagonists for this receptor have proven to be effective therapy for acid peptic disorders of the gastrointestinal tract. The physiological action of histamine has been shown to be mediated via a guanine nucleotide-binding protein linked to adenylate cyclase activation and cellular cAMP generation. We capitalized on the technique of polymerase chain reaction, using degenerate oligonucleotide primers based on the known homology between cellular receptors linked to guanine nucleotide-binding proteins to obtain a partial-length clone from canine gastric parietal cell cDNA. This clone was used to obtain a full-length receptor gene from a canine genomic library. Histamine increased in a dose-dependent manner cellular cAMP content in L cells permanently transfected with this gene, and preincubation of the cells with the H2-selective antagonist cimetidine shifted the dose-response curve to the right. Cimetidine inhibited the binding of the radiolabeled H2 receptor-selective ligand [methyl-3H]tiotidine to the transfected cells in a dose-dependent fashion, but the H1-selective antagonist diphenhydramine did not. These data indicate that we have cloned a gene that encodes the H2 subclass of histamine receptors.
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PMID:Molecular cloning of a gene encoding the histamine H2 receptor. 206 72

There are two means of reducing acid secretion. The best studied is inhibition of stimulation of the parietal cell. There are three major types of receptors that activate secretion by this cell and two classes of receptor antagonists, as well as at least two intracellular messenger pathways. The receptors are for histamine (H2 subtype), acetyl choline (M2 subtype) and gastrin. Antagonists of these receptors include the H2-antagonist class (Tagamet, Zantac and Pepcid), the M1 muscarinic antagonists (pirenzepine, telenzepine) and the gastrin antagonist, proglumide. The major pathway for stimulation appears to be the H2-receptor, since this is the only receptor that stimulates adenylate cyclase, and both acetyl choline and gastrin release histamine locally within the gastric mucosa. However, these agonists elevate intracellular calcium, which has a partially independent action on acid secretion. Accordingly, the most efficacious type of receptor antagonist will be of the H2 class, which is borne out by clinical experience. Prostaglandins of the E type prevent adenylate cyclase stimulation by histamine and are also effective antisecretory agents. It will be difficult to abolish acid secretion entirely by a single receptor antagonist, although longer-acting H2-antagonists should show clinical superiority to short-acting antagonists of this type. An alternative approach to acid suppression is to block the terminal step of acid secretion, the gastric proton pump (H+, K(+)-ATPase). This enzyme is virtually unique to the parietal cell and, when active, forms a very acidic space within the parietal cell called the secretory canaliculus. Activation of acid secretion involves several steps. The enzyme is present in cytosolic membranes when the cell is at rest and moves to the membrane of the secretory canaliculus when stimulated. Simultaneously, there is an increased permeability of potassium chloride (KCl), which allows presentation of K+ to the luminal surface of the pump and H+ for K+ exchange. The result is the secretion of HCl into the canaliculus, and hence into the gland lumen and then the stomach. There are two classes of pump inhibitors. One class is K+ competitive and relatively selective for the H+, K(+)-ATPase, as exemplified by SCH28080. This class has not yet been used in man. The other class is specific to the functioning H+, K(+)-ATPase in the stomach. It is exemplified by omeprazole (Losec). This compound is a weak base with a pKa of 4. In the unprotonated, uncharged form it will penetrate cell membranes and, at pH less than 4, it becomes protonated and therefore charged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biological basis of omeprazole therapy. 256 65

The diterpene, forskolin, direct activator of the catalytic subunit of the adenylate cyclase from various tissues, also stimulates gastric acid secretion: in vitro, with an isolated parietal cell preparation, forskolin dose-dependently stimulated acid secretion (EC50: 1 microM) (measured by accumulation in the acidic spaces of the weak base [14C]-aminopyrine) and the maximal acid secretory value at 0.1 mM was 4 times higher than that obtained with histamine. Forskolin dramatically increased the production of intracellular cyclic-AMP at a level 4 times higher than that obtained with histamine at the same concentration. In vivo, gastric acid secretion of the rat is dose-dependently increased. The doses required to get a significant response (100 nmol/kg) were 1,000 times higher than those required for gastrin and 100 times lower than those for histamine, but the same maximal value was obtained. Cimetidine did not significantly modified this response. These results demonstrate that, both in vitro and in vivo, forskolin is a potent stimulant for gastric acid secretion.
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PMID:[Is forskolin a stimulant of gastric secretion?]. 285 29

The metabolism of cyclic AMP and HCl secretion has been studied in eight healthy volunteers, in eight duodenal ulcer (DU) patients, and in four pernicious anaemia patients. Pentagastrin showed a tendency to increase adenylate cyclase and cyclic nucleotide phosphodiesterase activities in the fundal mucosa and caused a significant increase in cyclic AMP output into the gastric juice in healthy volunteers and in DU patients. Cimetidine inhibited all these events but had no effect on basal cyclic AMP output. Vagotomy significantly inhibited basal cyclic AMP output. We conclude that cyclic AMP is involved both in basal and in pentagastrin-stimulated gastric secretion in man. Basal secretion is mainly controlled by vagal tone. The main pathway for this stimulus at the parietal cell may be via other than H2-receptors, probably through acetylcholinergic receptors. However, a significant part of the pentagastrin stimulation of the human parietal cell is via H2-receptors.
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PMID:Cyclic AMP and gastric secretion in man. An in vivo study in healthy volunteers, duodenal ulcer patients, and pernicious anaemia patients. 285 60

Cimetidine is widely used as a ligand for the classification of histamine H2-receptors in peripheral and central tissues. It demonstrates apparently simple competitive antagonism in isolated tissue assays and in brain adenylate cyclase assays. In this study its action in a cardiac adenylate cyclase assay was compared with its effects in the isolated guinea pig right atrial preparation. Using either histamine or impromidine, cimetidine expressed similar affinity (pKB = 6.1) in the intact tissue assay. In washed homogenates of guinea pig ventricle cimetidine appeared to antagonize competitively the stimulation by histamine of adenylate cyclase but the estimated pKB was 6.7. In contrast, the pKB for tiotidine was similar in both assays (7.7). Application of a recently developed concentration-ratios method indicated that cimetidine expressed a resultant action in the cyclase assay consisting of competitive H2-receptor antagonism and an additional inhibitory property involving a postreceptor action. The concentration-ratios analysis allowed the purely competitive component of cimetidine action to be quantified in the cyclase assay giving a pKB of 6.0.
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PMID:Resultant action of cimetidine in a cardiac adenylate cyclase assay: its elucidation by concentration-ratios analysis. 369 25

The aim of this study was to demonstrate histamine-H2 receptors in glomeruli isolated from rat renal cortex and to correlate binding to stimulation by histamine of glomerular cyclic AMP concentration. Binding studies were performed at 10-12 degrees C using [3H]cimetidine as a tracer. Specificity of binding relies on the following: inhibition of [3H]cimetidine binding by the unlabelled drug, other H2-antagonists and agonists in contrast with the very weak inhibitory effects of H1 agonists and antagonists; reversibility of steady-state binding after addition of unlabelled drug; half inhibition of the glomerular cyclic AMP response to histamine at concentrations of cimetidine close to the KD value derived from the binding studies (3 microM); calculated KD value in agreement with the therapeutical concentration of cimetidine and the physiological concentration of histamine. [3H]Cimetidine binding concentration of cimetidine and the physiological concentration of histamine. [3H]Cimetidine binding strikingly increased in the presence of copper chloride (20-300 microM) due to an increase both in number of sites and affinity. However this greater binding did not influence either the inhibitory effect of cimetidine on histamine-induced glomerular cyclic AMP concentration or the stimulatory effect of histamine itself. [3H]Cimetidine binding was temperature-dependent since it progressively diminished from 0 to 37 degrees. This was not due to [3H]cimetidine degradation as shown by thin layer chromatography but rather to a change in drug-receptor interaction at higher temperatures. Glumerular concentration of cyclic AMP increased progressively in the presence of histamine (0.1-1000 microM). This stimulatory effect was markedly inhibited by H2 antagonists. These data demonstrate the presence in rat glomeruli of H2 receptors linked to adenylate cyclase.
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PMID:Histamine H2 receptors in rat renal glomeruli. 628 Jul 28

Recent evidence suggests that the histamine receptor blocking agent cimetidine can decrease parathyroid hormone release from human parathyroids. To determine the mechanism for inhibition we examined the ability of histamine 1 X 10(-5) moles/liter to stimulate adenylate cyclase in a particulate membrane preparation from 13 human parathyroid glands. Histamine significantly increased adenylate cyclase activity as compared to control; however, the degree of stimulation was variable among the individual tissue samples. Enzyme stimulation was dose dependent over the concentration range of 1 X 10(-7) to 1 X 10(-4) moles/liter. Cimetidine at 1 X 10(-4) moles/liter completely abolished the histamine mediated increase in activity, but did not block the epinephrine-induced stimulation. The identification of an adenylate cyclase system in certain human parathyroid adenomas that is stimulated by histamine and blocked by cimetidine may offer a basis for the pharmacologic alteration of parathyroid hormone secretion.
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PMID:Human parathyroid adenoma adenylate cyclase: stimulation by histamine that is blocked by cimetidine. 724 69


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