Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The muscarinic agonist oxotremorine produced a linear dose-dependent increase in membrane fluidity of intact and viable human lymphocytes in vitro. This effect proved to be receptor-mediated because preincubation with 10(-5)M atropine shifted the dose-response curve one order of magnitude rightward. Pirenzepine preincubation did not affect membrane fluidity variation. A cGMP increase was also found after oxotremorine treatment. The results are discussed in terms of possible modulation of guanyl cyclase and adenyl cyclase through membrane fluidity variations.
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PMID:Intact human lymphocyte membranes respond to muscarinic receptor stimulation by oxotremorine with marked changes in microviscosity and an increase in cyclic GMP. 299 66

Acute bacterial diarrheal disease is a worldwide problem of enormous magnitude. In recent years a number of bacteria have been added to the list of recognized etiologic agents causing acute diarrheal disease. This was made possible by our increased understanding of the mechanisms by which such bacteria cause diarrhea and by the development of methods to detect these bacterial enteropathogens. We are now able to define an etiologic agent in 50-80% of cases of acute diarrhea, depending on the particular population. The bacterial agents recently incriminated as important causes of diarrhea include E coli Y. enterocolitica, B. cereus, C. fetus, V. parahemolyticus, and many other coliform organisms. Establishment of an enteric infection depends upon a complex interplay between host defense mechanisms and bacterial virulence factors adapted to overcome these defenses. Bacterial enteropathogens cause diarrhea primarily by elaborating enterotoxins (which also requires the organisms to adhere to the surface of the intestinal cell) and by invading the intestinal mucosa. The number of known bacterial enterotoxins has rapidly increased. Enterotoxins cause intestinal secretion and diarrhea by stimulating the adenyl cyclase system or the guanyl cyclase system and by other mechanisms yet to be defined. The ability of enterotoxigenic bacteria to adhere to the intestine involves a specific binding interaction between bacterial structures called pili or fimbriae and specific receptors on the surface of intestinal cells. Both bacterial pili and the intestinal receptors are under genetic control. A variety of other bacteria, Salmonellae, Shigellae, Y. enterocolitica etc, must invade the mucosa to cause diarrheal disease. The ability to invade is essential to the pathogenesis of disease and requires particular surface characteristics of the bacterium as well as the active participation of both the bacterium and the host cell. The bacteria probably elaborate substances that signal the host cell to initiate the invasive process, i.e. endocytosis. The mechanism by which invasive bacteria evoke intestinal secretion is uncertain but is probably a multifactorial process involving products elaborated by the mucosal acute inflammatory reaction and enterotoxins elaborated by the bacteria.
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PMID:Pathogenesis of acute bacterial diarrheal disorders. 701 73

Somatostatin and its analogue octreotide have been used for two decades to treat oesophageal variceal haemorrhage. The drug was introduced because of its capacity to decrease portal venous pressure without major side effects. In clinical trials assessing the efficacy of somatostatin and long-acting analogues in arresting variceal haemorrhage, conflicting results have been obtained. Furthermore, in haemodynamic studies evaluating the effects of somatostatin and analogues in patients with cirrhosis, divergent effects were observed. The main reason for these differences is probably related to different affinities of the drugs for different somatostatin receptor subtypes. The effects of somatostatin and analogues are mediated via five different G-protein coupled receptors (somatostatin receptor subtypes 1-5), which regulate the activity of ion channels (Ca2+, K+, Na+ and Cl-) and enzymes (adenyl cyclase, phospholipase C, phospholipase A2, phosphoinositide 3-kinase and guanylate cyclase) responsible for the synthesis or degradation of intracellular second messengers including cyclic AMP, inositol 1,4,5-trisphosphate, diacylglycerol and cyclic GMP. Despite universal use of somatostatin, the cellular and biochemical mechanisms of its effects in portal hypertension are relatively poorly studied and remain incompletely understood. In this review, we summarize relevant signal transduction of somatostatin and analogues, the haemodynamic effects of the drugs and the possible mechanisms by which these effects are mediated.
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PMID:Pharmacological rationale for the use of somatostatin and analogues in portal hypertension. 1294 Sep 22

The methanolic extract of leaves of Michelia figo Spreng. (Magnoliaceae), as well as several purified fractions, showed a concentration-dependent vasorelaxing effect on aortic rings endothelium-deprived and pre-contracted by norepinephrine (NE). For further pharmacological investigation on the mechanism of action, the fraction S4 was selected, since it showed the best vasodilator properties. The pharmacological effect was not produced through the stimulation of cyclooxygenase, adenyl cyclase, or guanylyl cyclase, since selective inhibitors did not prevent the fraction S4-induced effects. Moreover, the vasorelaxing effect of the fraction was resistant to the block of nifedipine-sensitive Ca(2+) channels. The fraction S4 (10(-4) g/ml) produced a shift towards the right of the concentration-contractile response curve to NE, in normal conditions, and the shift was more evident in Ca(2+)-free Tyrode solution, suggesting an action on intracellular Ca(2+)-channels. The vasodilator action of fraction S4 on NE pre-contracted rings was not prevented by cyclopiazonic acid (blocker of Ca(2+)/ATPase), which excludes a role for mechanisms involving the storage of Ca(2+) in the sarcoplasmic reticulum. The reduction of the contraction elicited by caffeine, an opener of ryanodine-sensitive receptors, suggests that the fraction S4 of Michelia figo leaves could produce the vasorelaxing response by the blockade of ryanodine-sensitive Ca(2+) channels of the sarcoplasmic reticulum.
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PMID:Vasodilator activity of Michelia figo Spreng. (Magnoliaceae) by in vitro functional study. 1512 Apr 49

The chloroformic crude extract of roots of Bupleurum fruticosum L. (Umbelliferae) showed a concentration-dependent vasorelaxing effect on aortic rings endothelium-deprived and pre-contracted by norepinephrine (NE). The pharmacological effect was not produced through the stimulation of cyclooxygenase, adenyl cyclase, or guanylyl cyclase, since selective inhibitors did not prevent the extract-induced responses. The incubation of the aortic rings with the chloroformic extract (10(-4) g/ml) produced a depression of the concentration-contractile response curve to NE, in normal conditions, and this effect was more evident in Ca2+-free Tyrode solution, suggesting an action on the intracellular mobilization of Ca2+ ions. Moreover, the vasodilator action of Bupleurum fruticosum extract was resistant to the pre-treatment with nifedipine and to the pre-treatment with cyclopiazonic acid (blocker of Ca2+/ATPase). Finally, the chloroformic extract of Bupleurum fruticosum produced a reduction of the contraction obtained by caffeine, an opener of ryanodine-sensitive receptors, suggesting that the plant could elicit the vasorelaxing response by the blockade of ryanodine-sensitive Ca2+ channels of the sarcoplasmic reticulum.
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PMID:Vasorelaxant effects of the chloroformic crude extract of Bupleurum fruticosum L. (Umbelliferae) roots on rat thoracic aorta. 1558 55

Intracellular levels of the second messengers cAMP and cGMP are maintained through a balance between production, carried out by adenyl cyclase (AC) and guanylyl cyclase (GC), and degradation, carried out by phosphodiesterases (PDEs). Recently, PDEs have gained increased attention as potential new targets for cognition enhancement, with particular reference to phosphodiesterase type 5 (PDE5A). It is accepted that once consolidation is completed memory becomes permanent, but it has also been suggested that reactivation (memory retrieval) of the original memory makes it sensitive to the same treatments that affect memory consolidation when given after training. This new period of sensitivity coined the term reconsolidation. Sildenafil (1, 3, and 10mg/kg, ip), a cGMP-PDE5 inhibitor, facilitated retention performance of a one-trial step-through inhibitory avoidance task, when administered to CF-1 male mice immediately after retrieval. The effects of sildenafil (1mg/kg, ip) were time-dependent, long-lasting and inversely correlated with memory age. The administration of sildenafil (1mg/kg, ip) 30 min prior to the 2nd retention test did not affect retention of mice given post-retrieval injections of either vehicle or sildenafil (1mg/kg, ip). Finally, an enhancement of retention was also observed in CF-1 female mice receiving sildenafil (1mg/kg, ip) immediately, but not 180 min after retrieval. In the present paper we reported for the first time that systemic administration of sildenafil after memory reactivation enhances retention performance of the original learning. Our results indirectly point out cGMP, a component of the NO/cGMP/PKG pathway, as a necessary factor for memory reconsolidation.
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PMID:Sildenafil, a selective phosphodiesterase type 5 inhibitor, enhances memory reconsolidation of an inhibitory avoidance task in mice. 2133 92

Foods rich in polyphenols such as procyanidins (PC) have been proposed to have anti-inflammatory properties, and we have previously reported inhibition of lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in human dendritic cells (DCs) by PC derived from cocoa. To explore the mechanistic basis of this inhibition, here we conducted transcriptomic analysis on DCs cultured with either LPS or LPS combined with oligomeric cocoa PC. Procyanidins suppressed a number of genes encoding cytokines and chemokines such as CXCL1, but also genes involved in the cGMP pathway such as GUCY1A3 (encoding guanylate cyclase soluble subunit alpha-3). Upregulated genes were involved in diverse metabolic pathways, but notably two of the four most upregulated genes (NMB, encoding neuromedin B and ADCY3, encoding adenyl cyclase type 3) were involved in the cAMP signalling pathway. Gene-set enrichment analysis demonstrated that upregulated gene pathways were primarily involved in nutrient transport, carbohydrate metabolism and lysosome function, whereas down-regulated gene pathways involved cell cycle, signal transduction and gene transcription, as well as immune function. qPCR analysis verified differential expression of GUCY1A3, ADCY3, NMB as well as a number of other genes, and marked suppression of LPS-induced CXCL1 and IL-23 protein secretion was also observed. Thus, our results confirm a marked anti-inflammatory effect of PC in human DCs, which may be related mechanistically to second-messenger function and metabolic activity. Our results provide a foundation to further investigate metabolic pathways altered by PC during intestinal inflammation, and further encourage investigation of the health-promoting potential of PC-rich functional foods.
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PMID:Cocoa procyanidins modulate transcriptional pathways linked to inflammation and metabolism in human dendritic cells. 2971 95