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)

This first article of a 2-part series examined the epidemiology, therapy, and prospects for immunoprophylaxis of diarrheal infections in infants. 3 main strains of Escherichia coli can be identifiied with the etiology of infantile diarrhea: enterotoxigenic E. coli, invasive E. coli, and enteropathogenic E. coli. Viral agents may also be the etiological agents. Specific pathogens can be identified in 55-85% of cases of infantile diarrhea today; in the 1960s, only 25-34% of cases could be identified by specific etiology. Rotavirus, the usual viral etiological agent, and shigella, salmonella, campylobacter, and yersinia occur less commonly in summer diarrhea syndrome than does E. coli. Possible mechanisms of infection for each specific pathogen are discussed. For example, enterotoxigenic E. coli infection is thought to proceed by a mechanism similar to that of cholera, where a toxin is released by the organism and attaches to intestinal epithelial cells. Then, part of the toxin molecule migrates to the inner plasma membrane where, by stimulating the adenylate cyclase-cyclic adenosine monophosphate system, it evokes active fluid and electrolyte transport and blockade of sodium and chloride reabsorption, resulting in copius diarrhea. Studies showing the existence of antibody to rotavirus in exposed populations indicate that immunoprophylaxis is conceivable.
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PMID:Acute diarrheal infections in infants I. Bacterial and viral causes. 624 8

The effect of colchicine on jejunal adenylate cyclase activity, prostaglandin E2 (PGE2) and cAMP contents, the enzyme and mediators involved in intestinal fluid secretion was tested in rats. Four h after the intraperitoneal injection of colchicine (0.5 mg/100 g body wt.) mucosal PGE2 content, adenylate cyclase activity and mucosal cAMP content were almost doubled. Pretreatment with indomethacin (4 mg/kg body wt., s.c./day x 2) or methyl prednisolone (3.0 mg/kg body wt.) decreased both the increase in mucosal PGE2 content and the stimulation of adenylate cyclase activity induced by colchicine. These results suggest that the stimulation of adenylate cyclase activity and an increase in mucosal PGE2 and cAMP contents might be among the mechanisms whereby colchicine induces a net accumulation of water manifested clinically as diarrhea. It is also suggested that the stimulation of adenylate cyclase activity is mediated by the increase in mucosal PGE2 content.
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PMID:Effect of colchicine on jejunal adenylate cyclase activity, PGE2 and cAMP contents. 625 30

Assays for (Na+-K+)-ATPase and basal, fluoride stimulated and percentage of activation of adenylate cyclase have been established for small portions of human jejunal biopsies. Control means and ranges have been established for each activity in a group of children with failure to thrive but no gastrointestinal disease. Activities of (Na+-K+)-ATPase and percentage of activation and basal activity of adenylate cyclase are increased in children with toddler diarrhea. (Na+-K+)-ATPase activity is reduced in children with active postenteritis syndrome, and recovery from this syndrome is associated with an increase in this activity and of percentage of activation and basal activity of adenylate cyclase.
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PMID:Mucosal (Na+-K+)-ATPase and adenylate cyclase activities in children with toddler diarrhea and the postenteritis syndrome. 625 79

The effect of membrane-stabilizing and sedative drugs on enterotoxic diarrhoea was studied in mice. Fluid secretion was induced in ligated loops of the small intestine by challenge with cholera toxin (CT), heat-labile enterotoxin (LT) from Escherichia coli or dibuturyl-cyclic AMP (dB-cAMP). Chlorpromazine, melperone, diazepam, mebumal, ketamine and ethanol all inhibited CT-induced hypersecretion. ED50 being 1.5, 4, 4, 35, 70 and 1500 mg/kg, respectively. The drugs also blocked CT-stimulation of adenylate cyclase, which mediates the action of CT. Concomitant with the antisecretory effect a sedative effect was induced, as judged by the motility and righting reflex of the animals. Hypersecretion by E. coli and LT was also totally blocked by chlorpromazine, diazepam, ketamine and ethanol. In contrast, the secretion by dB-cAMP which bypasses adenylate cyclase in its action, was not affected by diazepam and was only partly reversed by chlorpromazine, ketamine and ethanol. The reversal of dB-cAMP-secretion is probably due to enhanced absorption, rather than inhibition of adenylate-cyclase. The use of membrane-stabilizing drugs may represent a new principle for pharmacological treatment of diarrhoea.
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PMID:Reversal of enterotoxic diarrhoea by anaesthetic and membrane-stabilizing agents. 629 65

To investigate the pathogenesis of diarrhea in ulcerative colitis, colonic adenylate cyclase activity was determined in patients and normal subjects. Basal adenylate cyclase activity in 19 patients with active disease [61.5 +/- 9.6 (mean +/- SE) pmol cyclic adenosine monophosphate/mg protein . 10 min] was two times higher (p less than 0.01) than its activity in colonic mucosa of 30 normal subjects or 10 ulcerative colitis patients in remission [31.4 +/- 2.0 and 23.6 +/- 1.9 pmol cyclic adenosine monophosphate/mg protein . 10 min, respectively]. The enzyme activity was stimulated to the same extent in all groups by sodium fluoride, vasoactive intestinal polypeptide, or by substitution in the assay mixture of guanosine triphosphate by its hydrolysis-resistant analogue--GTP gamma S. Prostaglandin E2 significantly stimulated the enzyme activity in tissue obtained from normal subjects, patients with shigellosis, and ulcerative colitis patients in remission while it had no effect on adenylate cyclase activity in colonic mucosa of patients with active ulcerative colitis. These results suggest that stimulation of colonic adenylate cyclase activity, possibly secondary to the reported enhanced colonic prostanoid synthesis, may contribute to the diarrhea in ulcerative colitis.
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PMID:Increased colonic adenylate cyclase activity in active ulcerative colitis. 630 87

The colonic cyclic AMP system is known to be involved in intestinal secretion and can be stimulated by a variety of gastrointestinal hormones including prostaglandins. We have investigated the effect of chronic ethanol ingestion on the activity of the key enzymes in cyclic AMP metabolism--adenylate cyclase and cyclic AMP phosphodiesterase--in the colonic mucosa of the rat. Chronic ethanol consumption by feeding a nutritionally adequate liquid diet enhanced basal colonic adenylate cyclase activity significantly by 168% (p less than 0.01), but had no effect on colonic low Km cyclic AMP phosphodiesterase activity. In addition, various hormonal secretagogues were used to stimulate colonic adenylate cyclase. Colonic adenylate cyclase exhibited a significantly greater sensitivity and efficacy to prostaglandins and vasoactive intestinal peptide after chronic ethanol ingestion. Since increased intestinal cyclic AMP production due to an increased activity of intestinal adenylate cyclase is known to promote intestinal secretion of water and electrolytes, the frequently observed diarrhea in alcoholics may be explained at least in part by an enhanced production of colonic cyclic AMP.
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PMID:Colonic cyclic AMP metabolism following chronic ethanol consumption in the rat: effect of hormonal secretagogues. 631 79

The beneficial effect of loperamide in some children with severe protracted diarrhoea which persisted when nil by mouth, made us suspect that loperamide may have an antisecretory action. Using a steady-state perfusion technique in rat jejunum we showed that loperamide inhibits cholera toxin induced secretion of water, sodium and chloride (p less than 0.001). This antisecretory action was blocked by naloxone and not mediated via an effect on tissue cyclic AMP level or adenylate cyclase activity. More recently we have studied the effect of loperamide on secretion of water in the rat jejunum induced by other agents with differing mechanisms of action. The first set of observations suggest that loperamide's antisecretory effect is mediated via opiate receptors either distal to, or separate from the adenylate cyclase/cyclic AMP pathway. Our more recent studies support the notion that loperamide has an effect on specific transport systems rather than non-specific passive diffusional processes.
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PMID:Mechanisms of action of loperamide. 631 91

Although most enteropathogenic Escherichia coli strains do not produce recognized enterotoxins, we wished to examine whether they produce any factors like heat-stable enterotoxin b or cholera toxin active subunits that might be missed by conventional assay methods. E. coli strains E851 (O142) and E2348 (O127) that had caused diarrhea in volunteers were negative for heat-labile enterotoxin and heat-stable enterotoxin a in Chinese hamster ovary cell and suckling mouse assays, failed to cause secretion in ligated small bowel loops from 6- to 8-week-old pigs after 4 to 5 h (used to show heat-stable enterotoxin b), and did not activate adenylate cyclase in pigeon erythrocyte lysates (used to demonstrate cholera toxin A subunit). We conclude that crude, unconcentrated culture filtrates and sonicates do not mimic heat-labile or heat-stable enterotoxins or cholera toxin or its A subunit and that enteropathogenic strains of E. coli probably have yet another mechanism or group of mechanisms by which they cause diarrhea.
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PMID:Does enteropathogenic Escherichia coli produce heat-labile enterotoxin, heat-stable enterotoxins a or b, or cholera toxin A subunits? 638 54

The immunogenicity and safety of procholeragenoid, a minimally toxic, heat-induced aggregate of cholera toxin (CT), were studied in enterically immunized rats and dogs. Although 99% less toxic than CT, procholeragenoid was only slightly less efficient in causing jejunal anti-CT responses in rats; in contrast, choleragenoid, the nontoxic B subunit pentamer of CT, was much less effective. The immunogenicity of procholeragenoid was due almost entirely to its large-molecular-weight components (MW = 10(6) to 10(7)) and was markedly reduced by preincubation with GM1 ganglioside or treatment with Formalin to eliminate residual toxicity. These findings suggest that molecular aggregation, binding to GM1 receptors on cell membranes, and stimulation of cellular adenylate cyclase each contributed to the effectiveness of procholeragenoid as a mucosal immunogen. In dogs, oral immunization with five 500-micrograms doses of procholeragenoid evoked vigorous anti-CT responses in jejunal mucosa without causing significant diarrhea. When subsequently challenged with virulent Vibrio cholerae, immunized dogs showed 83% protection against the development of severe or lethal diarrhea compared with non-immunized controls. These results confirm a protective role for mucosal antitoxin in experimental cholera and show that procholeragenoid is both safe and effective as an oral immunogen. Procholeragenoid, combined with other antigens of V. cholerae, may constitute a simple, safe, and effective oral vaccine for cholera.
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PMID:Procholeragenoid: a safe and effective antigen for oral immunization against experimental cholera. 660 94

Indomethacin, a rapid and intense inhibitor of prostaglandin synthesis, was used with a view to find out similarity in secretory mechanism of heat-labile enterotoxins of three diarrhoea producing enteric bacteria viz., Salmonella weltevreden, Escherichia coli and Vibrio cholerae in rabbits. A significant inhibition (90% to 94%) of biological activity of indomethacin pretreated Salmonella enterotoxin was evident in indomethacin treated rabbits, whereas the biological activity was found comparatively low (28% to 76%) in the untreated enterotoxin preparations. In contrast, the skin permeability reaction to cholera toxin remained unaltered in the absence of pretreatment of cholera toxin with indomethacin and it dropped to 55% in pre-treated toxin preparations. There was complete inhibition of biological activity of E. coli enterotoxin which did not receive indomethacin pretreatment. Based on these observations it may be inferred that indomethacin inhibits skin permeability response of heat labile enterotoxin of S. weltevreden both by blocking the effect of prostaglandins (Blocking mechanism) as well as by prostaglandin-adenyl cyclase pathway. The reduction in the biological activity of cholera toxin seems to be occurring through blocking of prostaglandins by indomethacin. In case of E. coli enterotoxin the inhibition mechanism seems operating through prostaglandin-adenyl cyclase system. These observations indicate that the Salmonella enterotoxin shares some similarity with enterotoxins of E. coli and Vibrio cholerae in respect of mechanism of action.
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PMID:Inhibitory effect of indomethacin on skin permeability reactions mediated by heat-labile enterotoxins of Salmonella weltevreden, Escherichia coli and Vibrio cholerae. 675 Sep 83


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