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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular ATP, N6-(L-2-phenylisopropyl)adenosine (PIA) and other purinergic agonists inhibited atrial natriuretic peptide (ANP)-induced cGMP accumulation in FRTL-5 thyroid cells. These agonists were functionally classified into three groups. Group 1 agonists represented by ATP inhibited the ANP action in association with phospholipase C activation in a partially islet-activating protein (IAP, pertussis toxin)-sensitive manner. Group 2 including GTP and 8-bromoadenosine 5'-triphosphate acted similarly to Group 1 except for total insensitivity of the former to IAP. The IAP-insensitive portion of Group 1 actions and the actions of Group 2 as well as of A23187, a Ca2+ ionophore which mimicked the Group 2 agonist actions, were almost completely inhibited by phosphodiesterase inhibitors such as M & B 22948 (2-O-propoxyphenyl-8-azapurin-6-one) and 3-isobutyl-1-methylxanthine. Group 3 including PIA and AMP did not affect phospholipase C, but inhibited the ANP performance in an IAP-sensitive fashion. This action of Group 3 and the IAP-sensitive portion of Group 1 actions were insensitive to the phosphodiesterase inhibitors. We conclude that ATP and other Group 1 agonists attenuated the ANP-induced cGMP accumulation by at least two mechanisms: 1) stimulation of cGMP hydrolysis via a phospholipase C-Ca2(+)-phosphodiesterase system and 2) inhibition of cGMP generation, probably by an IAP-sensitive G-protein-mediated inactivation of the ANP-receptor-coupled guanylate cyclase. Group 2 agonists stimulate only the first mechanisms, whereas Group 3 agonists prefer the second one.
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PMID:Inhibition of atrial natriuretic peptide-induced cGMP accumulation by purinergic agonists in FRTL-5 thyroid cells. Involvement of both pertussis toxin-sensitive and insensitive mechanisms. 217 85

Cytidylate cyclase was demonstrated to be distributed in various tissues of rat, with the highest activity in brain, and it was shown to be a membrane-bound type enzyme. The enzyme was effectively dispersed from the membrane fraction of rat brain with 0.3% (w/v) Triton X-100. The dispersed cytidylate cyclase had an optimal pH of 9.4 and the activity at a physiological pH of 7.5 was less than 20% of the maximum value. This enzyme completely lost its activity in the absence of divalent cation such as Mn2+ and Mg2+. The Km value for CTP was calculated as 0.0156 mM, by Lineweaver-Burk analysis. It was also found that activity of dispersed enzyme was inhibited by ATP, but not GTP. Both forskolin and lanthanum chloride, which affect adenylate cyclase, showed no effect on cytidylate cyclase. These results indicate that cytidylate cyclase is a unique membrane-bound enzyme distinct from purine nucleotide cyclases, adenylate cyclase and guanylate cyclase.
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PMID:Characterization of detergent dispersed cytidylate cyclase of rat brain. 228 31

Atrial natriuretic factor (ANF) produced rapid increases in cyclic GMP (cGMP) in cultured aortic smooth muscle cells. Angiotensin II (ANG II) markedly decreased the accumulation of cGMP that was evoked by ANF. Arginine vasopressin and ATP, which evoke transient increases in free Ca2+ similarly to ANG II, also inhibited cGMP accumulation. The effect of the calcium mobilizing neurohormones was mimicked by the divalent cation ionophore, A23187. The cyclic nucleotide phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, prevented ANG II from inhibiting ANF-evoked cGMP accumulation. ANG II also inhibited cGMP accumulation induced by nitroprusside, a compound that activates cytosolic guanylate cyclase. These findings support the hypothesis that ANG II decreases cGMP accumulation by stimulating cGMP hydrolysis, apparently via a Ca2+-activated cGMP phosphodiesterase.
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PMID:Angiotensin decreases cyclic GMP accumulation produced by atrial natriuretic factor. 244 Mar 11

The enzymatic properties of adenylate and guanylate cyclases were examined in sonicates of trypsinized guinea pig epidermal cells as enzyme source. Adenylate cyclase was found to be membrane-bound, while guanylate cyclase activity was detected in both membrane and cytosolic fractions. The maximal activities of the enzymes were obtained in the presence of Mn++ in the pH range 7.8-8.8. The apparent Km values of adenylate cyclase for Mn++- and Mg++-ATP were 20.5 and 38.6 microM, respectively, while the value of guanylate cyclase for Mn++-GTP was 500 microM. Examinations of cells separated by velocity sedimentation at unit gravity revealed that the basal activity of adenylate and guanylate cyclases was maximal in the germinative cells, falling gradually to the low level as cells differentiated. We assume that in the epidermis, the control and coordination of proliferation require higher concentrations of adenylate and guanylate cyclases as compared with events occurring during terminal differentiation.
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PMID:Adenylate and guanylate cyclase activities in isolated guinea pig epidermal cells at various stages of differentiation. 244 8

Endothelial cells are known to contain both soluble and particulate guanylate cyclase, but the functional role of cyclic guanosine monophosphate (cGMP) in endothelial cells remains unknown. We have investigated the effects of 8-bromo-cGMP on endothelium-dependent relaxations to acetylcholine, substance P, ATP, and the calcium ionophore A23187, and on endothelium-independent relaxations to sodium nitroprusside and glyceryl trinitrate (GTN). The ability of each of these agents to relax phenylephrine-preconstricted rings of rabbit aorta was tested in the absence and presence of 8-bromo-cGMP. In the presence of 8-bromo-cGMP, a greater concentration of phenylephrine had to be used to produce a similar level of tone and then endothelium-dependent relaxations to acetylcholine and substance P were inhibited, whereas endothelium-dependent relaxations to ATP and A23187 were unaffected. Endothelium-independent relaxations to sodium nitroprusside and GTN were only inhibited at the highest concentrations of nitroprusside and GTN. These results suggest that: (a) increasing GMP levels in endothelial cells inhibit agonist-induced release of endothelium-derived relaxing factor (EDRF); (b) a negative feedback mechanism may exist whereby EDRF stimulates soluble guanylate cyclase in endothelial cells to inhibit its own release; and (c) ATP does not induce EDRF release via phosphoinositol hydrolysis.
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PMID:Release of endothelium-derived relaxing factor is inhibited by 8-bromo-cyclic guanosine monophosphate. 246 85

Pharmacological probes were used to assess the possible roles of guanosine 3',5'-cyclic monophosphate (cGMP)-associated endothelium-derived relaxing factor (EDRF) in mediating microvascular responses to endogenous and exogenous agents in vivo. Pentobarbital-anesthetized rats (Wistar, 6 wk old) were prepared for in vivo microscopic observation and quantification of changes in diameter of third-order arterioles (15-25 microns) in the cremaster muscle to topical application of all agents. In indomethacin-pretreated preparations, cremasteric arteriolar dilator responses to acetylcholine, bradykinin, or ATP, but not to adenosine, histamine, or prostaglandin E2, were inhibited by hydroquinone (50 microM). Vasodilation to acetylcholine was also inhibited by methylene blue (5 microM), a blocker of guanylate cyclase activation. Constrictor responses to norepinephrine were not affected by hydroquinone or methylene blue. The inhibition of acetylcholine-induced vasodilation by hydroquinone and methylene blue was reversed by superoxide dismutase, suggesting that superoxide anion antagonized the response. On the other hand, basal arteriolar diameters or responses to acetylcholine were not affected by oxygen metabolite scavengers. Unlike in isolated arteries, vasodilator responses to the calcium ionophore A23187 or arachidonic acid were completely antagonized by cyclooxygenase inhibition. These data suggest that EDRF could be involved in the control of microvascular tone; however, significant differences exist in the stimuli that elicit dilation through this mediator in small and large blood vessels.
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PMID:Endothelium-associated vasodilators in rat skeletal muscle microcirculation. 249 47

The effect of ethanol was studied on the endothelium-dependent vascular responses in isolated rat aortic strips. Ethanol depressed the endothelium-dependent relaxation induced by acetylcholine and ATP but not that induced by the calcium ionophore, A23187. Endothelium-independent relaxation in response to sodium nitroprusside, a soluble guanylate cyclase activator, was not depressed by ethanol. On the other hand, ethanol significantly enhanced the contractile response to clonidine, an alpha 2-adrenoceptor agonist, in endothelium-intact strips and depressed it in endothelium-denuded strips. These results suggest that ethanol can inhibit endothelium-dependent relaxation by acting on endothelial cells but not on smooth muscle cells, and can also suppress an inhibitory effect of the endothelium on alpha 2-adrenoceptor-mediated vasoconstriction.
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PMID:Inhibitory effect of ethanol on endothelium-dependent vascular responsiveness. 251 Oct 33

Changes in viscous drag acting upon the endothelial lining and a number of circulating agonists (ATP, ADP, serotonin, thrombin) stimulate the release of EDRF from intact endothelial cells. EDRF is probably identical with nitric oxide (NO), the vasoactive compound which is also formed in the metabolism of nitrovasodilators in the vasculature (some of them directly release NO without the essential foregoing bioconversion step). Albuminally released NO stimulates soluble guanylate cyclase (sGC) in the vasculature initiating vasodilation; luminally released NO stimulates, sGC in platelets and increases cyclic GMP inhibiting platelet activation and aggregation. Endothelial impairment brings about loss of dilator and antiaggregant capacity.
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PMID:[Inhibition of thrombocyte aggregation and adhesion by endothelium-derived relaxant factor (EDRF) and their pathophysiologic significance]. 251 72

The long-term patency of the internal mammary artery (IMA) graft is of considerable interest owing to its extensive use in myocardial revascularization. The aim of the present study was to elucidate the role of endothelium in modulating the responses of the porcine IMA to several vasoactive drugs. Isolated ring segments of porcine IMA contracted in a reproducible and dose dependent manner to phenylephrine, potassium chloride and the thromboxane mimic U46619, but the responses to serotonin, histamine and ATP were significantly less prominent. Both acetylcholine and bradykinin elicited endothelium-dependent relaxation which was not inhibited by indomethacin, but by methylene blue, an inhibitor of soluble guanylate cyclase. These two endothelium-dependent drugs and two endothelium-independent relaxing drugs, nitroprusside and nitroglycerin relaxed the IMA in a dose dependent manner which was associated with an elevation of cyclic GMP. The endothelium dependent vasodilator peptides such as bradykinin contain L-arginine in their sequence. Benzoyl derivatives of L-arginine but not L-arginine relaxed the IMA in a dose dependent manner. These data confirm and extend exploratory studies performed with a simpler vascular model which indicate that the precursor of endothelium derived relaxing factor (EDRF) is an arginine moiety.
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PMID:Role of the endothelium and arginine peptides on the vaso-motor response of porcine internal mammary artery. 254 72

Endothelium-dependent relaxation of blood vessels is produced by a large number of agents (e.g., acetylcholine, ATP and ADP, substance P, bradykinin, histamine, thrombin, serotonin). With some agents, relaxation may be limited to certain species and/or blood vessels. Relaxation results from release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) or factors. EDRF stimulates guanylate cyclase of the vascular smooth muscle, with the resulting increase in cyclic GMP activating relaxation. EDRF is rapidly inactivated by hemoglobin and superoxide. There is strong evidence that EDRF from many blood vessels and from cultured endothelial cells is nitric oxide (NO) and that its precursor is L-arginine. There is evidence for other relaxing factors, including an endothelium-derived hyperpolarizing factor in some vessels. Flow-induced shear stress also stimulates EDRF release. Endothelium-dependent relaxation occurs in resistance vessels as well as in larger arteries, and is generally more pronounced in arteries than veins. EDRF also inhibits platelet aggregation and adhesion to the blood vessel wall. Endothelium-derived contracting factors appear to be responsible for endothelium-dependent contractions produced by arachidonic acid and hypoxia in isolated systemic vessels and by certain agents and by rapid stretch in isolated cerebral vessels. In all such experiments, the endothelium-derived contracting factor appears to be some product or by-product of cyclooxygenase activity. Recently, endothelial cells in culture have been found to synthesize a peptide, endothelin, which is an extremely potent vasoconstrictor. The possible physiological roles and pathophysiological significance of endothelium-derived relaxing and contracting factors are briefly discussed.
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PMID:Endothelium-derived relaxing and contracting factors. 254 95


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