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)

Vero cell cytotoxins and cytotonic enterotoxins produced by E. coli are toxic proteins, which have been implicated in a number of specific diseases in humans and animals. Nomenclature for these toxins is complicated by the existence of different names for the same toxin. The Vero cell cytotoxins are called verotoxins because they are lethal for Vero cells in culture; they are also known as Shiga-like toxins (SLTs) because they are clearly related to Shiga toxin in structure, amino acid sequence, mechanism of action, and biological activity. SLTs belong to two classes. SLT-I is identical with Shiga toxin and is in a class by itself (class I). The other SLTs are closely related to each other and form a second class (class II). Class II SLTs include SLT-II, SLT-IIv, SLT-IIvha, SLT-IIvhb, and SLT-IIva. All SLTs that have been investigated are A-B subunit protein toxins, whose A subunits possess N-glycosidase activity against 28S rRNA and cause inhibition of protein synthesis in eukaryotic cells. These toxins are enterotoxic as well as cytotoxic. SLTs produced in the intestine are absorbed into the blood stream and affect vascular endothelial cells in target organs. They may also have a direct toxic effect on enterocytes. Diseases in which E. coli SLTs have been implicated include diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome in humans and edema disease in pigs. Variation in receptor specificities among SLTs may be the reason for different disease syndromes in different host species. The E. coli enterotoxins belong to three distinct classes: heat-labile enterotoxin (LT), heat-stable enterotoxin type I or type a (STI, STa), and heat-stable enterotoxin type II or type b (STII, STb). There is clear evidence that these cytotonic enterotoxins play an essential role in diarrheal disease. LT is an A-B subunit protein toxin, closely related to cholera toxin. Following binding of LT to receptors in enterocytes the A subunit is internalized. The enzymatically active A subunit transfers ADP-ribose from NAD to a GTP-dependent adenylate cyclase regulatory protein, thereby elevating intracellular levels of adenylate cyclase. The increased levels of cyclic AMP cause stimulation of A kinase and lead to hypersecretion of electrolytes and fluid. STI is a small peptide of 18 or 19 amino acids. It binds to receptors in enterocytes and stimulates particulate guanyl cyclase. Elevated intracellular cyclic GMP stimulates G kinase, resulting in increased Cl- secretion and impaired absorption of Na+Cl-. STII is a peptide toxin whose mechanism of action is unknown.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Escherichia coli cytotoxins and enterotoxins. 139 38

This experiment was designed to investigate whether chronic hypoxia could reduce pulmonary artery relaxation induced by acetylcholine and sodium nitroprusside (endothelium-dependent and endothelium-independent vasodilator, respectively). Male Wistar rats were divided into 3 groups: control, kept in air; CH4, in hypobaric chamber (8000 m above sea level) for 4 days; CH20, in hypobaric chamber (5000 m above sea level) for 20 days. All the hypoxic rats developed pulmonary hypertension. Rings of extra- (EPPA) or intra- (IPPA) pulmonary artery were suspended in an organ bath containing oxygenated Kreb's solution at 37 degrees C for relaxation/inhibition studies. The results showed that chronic hypoxia, CH4 and CH20, inhibited the relaxation response of both IPPA and EPPA to both acetylcholine and sodium nitroprusside. It is suggested that chronic hypoxia might attenuate the sensitivity and reactivity of the pulmonary artery to both acetylcholine and sodium nitroprusside through the inhibition of guanyl cyclase activity in smooth muscle.
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PMID:[The inhibition of acetylcholine- and sodium nitroprusside-induced pulmonary artery relaxation by chronic hypoxia]. 183 57

NO is obviously identical with the relaxation factor produced by the vascular endothelium (EDRF) and is also the substance responsible for some other biological activities. It is formed in the organism from L-arginine by the action of the enzyme NO synthetase. The main mechanism of action is the activation of the enzyme guanyl cyclase and the result is an increase of the intracellular level of cyclic guanyl monophosphate. Depending on the type of effector cell, either vasodilatation occurs and adhesion is inhibited and the blood platelets coagulate or the cytotoxicity of macrophages increases. With the development of new, more effective inhibitors of NO synthetase there is also the possibility to study the physiological importance of NO in more detail. These new discoveries provide a more profound biochemical and pharmacological basis and perhaps also new indications or preventive possibilities of the known treatment of vascular spasms by nitroderivatives; moreover, there is the possibility to seek new ways in the anti-tumourous and antimicrobial treatment and elsewhere.
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PMID:[Nitric oxide--a new and nontraditional transmitter]. 197 39

1) Eicosanoids are a family of polyunsaturated 20-carbon fatty acids and their metabolites. The metabolites are produced by three enzymatic pathways: the cyclooxygenase pathway, giving prostaglandins (PGs), the lipoxygenases and the epoxygenases pathways. Arachidonic acid (C20:4) is the most common fatty acid precursor in mammalian cells, where it is incorporated, as an ester, into the membrane lipid complex. 2) The eicosanoids have a variety of effects on several cell activities, including secretion, muscle contraction, cell growth and differentiation. The type of effect--stimulation or inhibition--depends on the metabolite, its concentration, the metabolic activity of the cell and the involvement of other humoral factors. 3) The message may be transmitted via a specific membrane receptor to a specific transduction system: the adenyl or guanyl cyclase system and mobilization of free cytosolic Ca2+, or via the participation of membrane ion channels. Depending on which is involved, the eicosanoid message applies to the cell in which it was synthesized or to neighboring cells (autocrine or paracrine action). 4) The eicosanoids, especially the PGs, take part in many reproductive processes; in the hypothalamic-pituitary axis, particularly through the synaptic modulation by PGE2 (stimulation of LHRH secretion and inhibition of noradrenaline secretion); in the ovary: follicle maturation and luteolysis; in the oviducts: gamete migration; in the uterus: ovum implantation and parturition. 5) PGs seem to have a variety of species-dependent effects on the normal onset of labor. In sheep there is an increase in fetal cortisol, a drop in the progesterone/estradiol ratio and increased PG synthesis. In women, there is an increase of phospholipase A2 activity in amnios and uterus with an increase of PGE2 in the first tissue and of PGF2 alpha in the second one. 6) The PGs from the seminal fluid have several actions. They effect fertility by acting on the female genital tract or on the spermatozoa. PGE1 and PGE2 influence the fertilization capacity. PGs also effect the process of ejaculation (inhibition of the stimulatory effect of noradrenaline). Finally, they effect the immune responses: PGEs and 19 hydroxy PGEs immuno-suppressive characteristics.
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PMID:[Prostaglandins and reproduction. I. Physiological aspects]. 201 23

The present study, addressed to understand the mechanism behind the cholesterol-induced proliferative and collagen secretory activity of smooth muscle cells, revealed that cholesterol-induced smooth muscle cellular DNA synthesis and collagen secretion was mediated through its ability to amplify the intracellular cGMP signal because of the fact that Trifluoperazine (an anticalmodulin and blocker of phospholipase A2) and colchicine (an antitubulin and inhibitor of guanyl cyclase) inhibited DNA synthesis and collagen-secretory activity of smooth muscle cells by their ability to decrease the cGMP levels within smooth muscle cells. From these results we suggest that membrane cholesterol modulated phospholipase 'A2' activity may be the basic mechanism involved in cholesterol-induced proliferative and collagen-secretory activity of smooth muscle cells in vitro.
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PMID:Effect of trifluoperazine and colchicine on smooth muscle cellular proliferative and secretory activity induced by hypercholesterolemic medium in vitro. 216 85

Nicorandil, a compound having structural similarities to some of the organic nitrates, was studied for its mechanism of vasodilation. Nicorandil is thought to be a K+ channel opening agent. However, little is known about its receptor activation profile, its endothelial dependence, and its effects in atherosclerotic vessels. Nicorandil, at 0.2 to 5 x 10(-6) M, relaxed norepinephrine precontracted rabbit aortic rings in a concentration-dependent manner. Moreover, nicorandil relaxed aortic rings to the same extent in the presence and absence of an intact endothelium. However, nicorandil's effect was diminished in aortic rings from atherosclerotic rabbits. The vasorelaxation action of nicorandil was unaffected by the cyclooxygenase inhibitor ibuprofen or the lipoxygenase inhibitor propyl gallate, suggesting that nicorandil does not act via the release of a vasodilator eicosanoid. Although the nicorandil effect was not influenced by atropine, a muscarinic receptor antagonist, it was significantly attenuated by methylene blue, a guanyl cyclase inhibitor. Thus, nicorandil has some properties in common with organic nitrates and with K+ channel activators but appears to be a unique type of vasodilator.
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PMID:Studies on the mechanism of the vasodilator action of nicorandil. 245 46

ANF did not prevent the formation of [3H] inositol trisphosphate in response to AII but inhibited aldosterone secretion in calf adrenal glomerulosa cells. 8-bromo cGMP did not affect either inositol phosphate formation or aldosterone secretion. Changes in cytosolic Ca++ concentration induced by AII, as measured by Quin 2 fluorescence, were also unaffected by ANF. No difference in adrenal cell protein phosphorylation with AII or AII + ANF was observed. The results suggest that ANF may inhibit aldosterone secretion through a non-guanyl cyclase linked receptor system not involving the formation of phosphoinositide-derived second messengers. Interference with protein kinase C activity cannot be ruled out.
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PMID:Atrial natriuretic factor inhibits angiotensin-induced aldosterone secretion: not through cGMP or interference with phospholipase C. 253 17

The influence of cyclic 3',5'-guanosine monophosphate (cGMP) on the lipolytic and antilipolytic (inhibition of glucagon-stimulated lipolysis) responses to GH (1 microgram/ml) was examined in chicken adipose tissue in vitro. Both 8-bromo-cGMP (0.1 mM) and sodium nitroprusside (1 mM) (a guanyl cyclase stimulator) completely inhibited the lipolytic effect of GH. A cGMP-lowering agent, LY83583 (10 microM), reversed the inhibitory effect of sodium nitroprusside on GH-stimulated lipolysis. Furthermore, the suppressive effects of insulin (100 ng/ml), insulin-like growth factor I (IGF-I) (100 ng/ml), or insulin-like growth factor II (IGF-II/MSA) (100 ng/ml), but not somatostatin (1 ng/ml), on GH-stimulated lipolysis were prevented by LY83583 addition. Neither 8-bromo-cGMP, sodium nitroprusside, nor LY83583 altered GH-induced inhibition of glucagon (1 ng/ml)-stimulated lipolysis. It is proposed that cGMP may mediate inhibitory control of GH-stimulated lipolysis by insulin, IGF-I, and IGF-II in chicken adipose tissue.
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PMID:Inhibition of growth hormone-induced lipolysis by 3',5'-guanosine monophosphate in chicken adipose tissue in vitro. 284 72

Taking their lead from studies which have shown that endothelium-derived relaxing factor(s) (EDRF) mediates vasorelaxation by activating smooth muscle guanyl cyclase, the authors of the current article have examined the role of the endothelium in relation to the effects of the alpha-adrenoceptor antagonist prazosin. Prazosin acted as a non-competitive antagonist of norepinephrine- (NE-) induced contraction in rat aortic preparations with intact endothelium, but as a competitive antagonist in endothelium-denuded preparations. The affinity of NE for its smooth muscle receptor was the same in the presence or absence of endothelium, but its efficacy was 7 times lower in the presence than in the absence of endothelium. Other experiments showed that inhibition of guanyl cyclase by methylene blue in the presence of endothelium (like endothelium removal) led to competitive antagonism of NE responses by prazosin, and that increasing the tissue content of cyclic GMP by pre-incubating de-endothelialized preparations with 8-Br-cyclic GMP (as in intact preparations) led to non-competitive antagonism of NE responses by prazosin. The authors concluded that EDRF, by increasing the cyclic GMP content of vascular smooth muscle of rat aorta, can modify the efficacy of NE, and thereby alter the mode of antagonism of prazosin.
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PMID:Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta. 285 49

The action of a synthetic 'atrial natriuretic factor' (sANF) on induced tone in isolated rat renal resistance vessels (lumen diameter about 200 microns) was examined and compared with the effects of sANF on resistance vessels of similar size taken from the cerebral, mesenteric and femoral vasculature. Synthetic ANF caused a relaxation of the renal vessels when these were submaximally activated with noradrenaline or serotonin, but had no effect on the responses of the other vessels to these agonists. In contrast to previous reports concerning rabbit aortic vessels, methylene blue (which is thought to cause inhibition of guanyl cyclase) did not reduce the dilator response to sANF in the renal vessels. The results demonstrate that sANF has a specific relaxing effect on renal resistance vessels, and are consistent with its effect being mediated through specific receptors. The mechanism of this relaxant effect remains unknown.
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PMID:Synthetic atrial natriuretic factor is a specific dilator of noradrenaline and serotonin activated renal resistance vessels. 285 24


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