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)

Ethionine-induced hepatomas are characterized by high adenylate cyclase activity and cyclic adenosine 3',5'-monophosphate content relative to those of surrounding liver or liver from pair-fed control rats. The present study examined the properties of the guanylate cyclase-cyclic guanosine 3',5'-monophosphate (cGMP) system of these tissues. cGMP levels of the ethionine-induced hepatomas, determined in both specimens quick-forzen in situ and after in vitro incubation of tissue slices, were approximately 2 times higher than those of surrounding liver or controls. Higher cGMP in the tumors was associated with an increase in whole homogenate, soluble, and particulate guanylate cyclase activities, as well as an increase in soluble cGMP-phosphodiesterase activity. 3-Isobutyl-1-methylxanthine, a potent inhibitor of cGMP-phosphodiesterase activity, potentiated the differences in cGMP between slices of the hepatomas and surrounding liver or control, suggesting that the higher steady-state cGMP content of the tumors reflected enhanced basal cGMP synthesis which was partially offset by increased nucleotide degradation. In the hepatomas, a greater proportion of the total guanylate cyclase activity was located in the particulate cell fraction (31%) as compared to the subcellular distribution of enzyme activity in either surrounding liver or controls (15% of total in the particulate fraction). Carbamylcholine, which increased cGMP 3-fold in surrounding liver and controls, failed to alter cGMP levels inslices of hepatoma. Further, the relative changes in both cGMP accumulation and guanylate cyclase activity of the tumors in response to NaN3, NH2OH, and NaNO2 were blunted compared to surrounding liver or controls, although in each instance a response was clearly evident. Ethionine-induced hepatomas are thus characterized by: (a) significant increases in cGMP content and in guanylate cyclase and cGMP-phosphodiesterase activities, (b) a change in the subcellular distribution of guanylate cyclase, and (c) altered responsiveness of the guanylate cyclase-cGMP system to several agonists.
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PMID:Increased guanylate cyclase activity and guanosine 3',5'-monophosphate content in ethionine-induced hepatomas. 1 87

In adult male Sprague-Dawley rats contralateral nephrectomy was followed by an initial fall of the concentration of cGMP in renal cortical tissue followed by a rise to a peak level of 300 percent of the initial concentration within two hours. cGMP concentration in the remaining renal cortex remained at about 300 percent of the initial value during the subsequent 72 hours and slowly declined to 150-200 percent in the following two weeks. The changes in cGMP concentration were due to exactly parallel changes in the soluble fraction of renal cortical guanylate cyclase activity, while cGMP-phosphodiesterase activity remained unchanged. cAMP concentration after contralateral nephrectomy fell significantly by about 25 percent within two hours and remained below baseline level for up to eight hours. In the kidneys of newborn rats the concentration of cAMP was approximately one-half that found in adult kidneys: it slightly fell between the fourth and the seventh day after birth and subsequently continuously rose to reach adult values approximately two weeks after birth. The concentration of cGMP was significantly greater four days after birth than in adult rats, further rose between the fourth and the seventh day after birth and subsequently gradually declined to adult levels. The increased cGMP concentration appears to be due to an increase of guanylate cyclase activity in total kidney homogenates which, in turn, was mainly due to an increase of the particulate (membrane-bound) fraction of the enzyme. cGMP-phosphodiesterase activity, however, was also increased in respect to adult levels, one or three weeks after birth. Renal growth from the seventh day after birth to adulthood is accompanied by a continuous increase of the ratio cAMP/cGMP. Removal of one kidney four to seven days after birth resulted in a slower increase of this ratio. The data suggest that cGMP may trigger renal growth and that increases of cGMP concentration in the kidneys are the result of a primary increase in the activity of guanylate cyclase.
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PMID:Evidence for altered cyclic nucleotide metabolism during compensatory renal hypertrophy and neonatal kidney growth. 3 65

Tolerance to glyceryl-trinitrate (GTN) in arteries and veins was studied in different in vitro and in vivo models. The development of GTN tolerance was associated with a down-regulation of the cGMP system, i.e. an impairment of the nitrocompound-dependent activation of guanylate cyclase and an increase of the cGMP-phosphodiesterase activity. We suggest that a decreased function of the cGMP system might cause an impairment of the negative feedback loop involving cGMP in blood vessels, and a concomitant supersensitivity to contractile stimuli.
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PMID:Experimental studies on the mechanism of glyceryl trinitrate-tolerance and dependence. 302 3

Strips of bovine mesenteric arteries brought to sustained contraction by the addition of 3.0 microM phenylephrine relaxed when exposed to ultraviolet radiation (366 nm). The relaxation was reversible and associated with a rapid increase in the cGMP content. After termination of the radiation the cGMP level rapidly decreased below the basal level. The crude soluble guanylate cyclase from the artery was stimulated about 8-fold by ultraviolet radiation (366 nm). Neither the cGMP-phosphodiesterase activity nor the cAMP level were found to be changed during irradiation. The ultraviolet light-induced relaxation was not dependent on an intact intimal surface. Furthermore, the relaxing effect was found to be enhanced and accompanied by a larger increase of the cGMP level in nitroglycerin-tolerant arteries. The present results show that the ultraviolet light-induced relaxation in bovine mesenteric arteries is associated with a rapid increase in the cGMP content and that ultraviolet light and nitrocompounds may exert their relaxing actions through a common substance.
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PMID:Effects of ultraviolet radiation on the tension and the cyclic GMP level of bovine mesenteric arteries. 614 30

Bovine mesenteric arteries (BMA) were made tolerant to nitroglycerin (GTN) by incubation with high concentrations of GTN at elevated pH. This treatment has previously been shown to reduce the relaxant and cGMP-elevating action of a challenging dose of GTN. The stimulatory action of nitroprusside (NP) or GTN/cysteine on guanylate cyclase (GC) was reduced by 50-60% in GTN-tolerant vessels as compared to control vessels. The stimulatory action of GTN and NP on GC has been suggested to occur through formation of S-nitrosothiols, probably with a previous denitration step required for GTN. However, tolerance induction to GTN was not found to change the rate of nitrite formation from GTN, and exogenous addition of thiols in the GC assay, in order to increase S-nitrosothiol formation, did not restore the GC activity in tolerant vessels back to control level. This is suggested to indicate a direct effect of GTN tolerance on GC. Since the cGMP-phosphodiesterase activity was not affected in GTN-tolerant vessels, the reduced GC activity may be of a crucial importance for the reduced cGMP response in GTN-tolerant BMA as found earlier (Axelsson et al. 1982).
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PMID:Nitroglycerin tolerance in vitro: effect on cGMP turnover in vascular smooth muscle. 615 May 99

In Dictyostelium discoideum extracellular cyclic AMP (cAMP), as shown by previous studies, induces a transient accumulation of intracellular cyclic guanosine-5'-monophosphate (cGMP), which peaks at 10 s and recovers basal levels at 30 s after stimulation, even with persistent cAMP stimulation. Additional investigations have shown that the cAMP-mediated cGMP response is built up from surface cAMP receptor-mediated activation of guanylyl cyclase and hydrolysis of cGMP by phosphodiesterase. The regulation of these activities was measured in detail on a seconds time-scale, demonstrating complex adaptation of the receptor, allosteric activation of cGMP-phosphodiesterase by cGMP, and potent inhibition of guanylyl cyclase by Ca2+. In this paper we present a computer model that combines all experimental data on the cGMP response. The model is used to investigate the contribution of each structural and regulatory component in the final cGMP response. Four models for the activation and adaptation of the receptor are compared with experimental observations. Only one model describes the magnitude and kinetics of the response accurately. The effect of Ca2+ on the cGMP response is simulated by changing the Ca2+ concentrations outside the cell (Ca2+ influx) and in stores (IP3-mediated release) and changing phospholipase C activity. The simulations show that Ca2+ mainly determines the magnitude of the cGMP accumulation; simulations are in good agreement with experiments on the effect of Ca2+ in electropermeabilized cells. Finally, when cGMP-phosphodiesterase activity is deleted from the model, the simulated cGMP response is elevated and prolonged, which is in close agreement with the experimental observations in mutant stmF that lacks this enzyme activity. We conclude that the computer model provides a good description of the observed response, suggesting that the main structural and regulatory components have been identified.
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PMID:A model for cAMP-mediated cGMP response in Dictyostelium discoideum. 791 38

We have used the truncated outer segment preparation to measure rod cGMP-phosphodiesterase activity, as well as its modulation by Ca2+, in darkness and in light. The basal enzyme activity in darkness was approximately 0-3 s-1, and was largely independent of Ca2+ concentration from 10 nM to 10 microM. The steady state activity elicited by a step of light (lambda = 520 nm) was strongly enhanced by Ca2+, increasing from approximately 0.005 s-1/(h nu micron-2 s-1) at 10 nM Ca2+ to approximately 0.16 s-1/h nu micron-2 s-1) at 10 microM Ca2+. Based on these measurements, as well as previous measurements on the effects of Ca2+ on rod guanylate cyclase and the cGMP-gated channel, we have calculated the step response-intensity relation for the rod cell in steady state. This relation agrees reasonably well with the relation directly measured from intact rods. We have also evaluated the relative contributions from the three Ca2+ effects to rod sensitivity. At low background light intensities, the Ca2+ modulation of the guanylate cyclase appears to be the most important for sensitivity regulation. At higher light intensities, especially above half-saturation of the response, the Ca2+ modulation of the light-stimulated phosphodiesterase shows a progressively important influence on the light response; it also extends the Weber-Fechner behavior of the cell to higher intensities. The contribution of the Ca2+ modulation of the cGMP-gated channel is slight throughout.
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PMID:The cGMP-phosphodiesterase and its contribution to sensitivity regulation in retinal rods. 864 97

Guanylate Cyclase C (GCC) serves as a receptor for the endogenous ligands, guanylin and uroguanylin, as well as the family of bacterial heat-stable enterotoxins (ST), which are one of the major causes of diarrhoea the world over. We had earlier provided evidence that GCC, present in the human colonic T84 cell line, is desensitized on prolonged exposure to ST, and this desensitization was reflected in a reduced ST-stimulated guanylate cyclase activity of GCC [Bakre, M.M. & Visweswariah, S.S. (1997) FEBS Lett. 408, 345-349]. In this study, we have investigated the mechanisms that underlie this cellular desensitization process. Desensitization of T84 cells was not a result of reduction in GCC present in membranes prepared from desensitized T84 cells, nor due to increased cGMP-phosphodiesterase activity associated with the membrane fraction. The decrease in ST-stimulatable guanylate cyclase activity of GCC was due to a dramatic reduction in the Vmax of the cyclase, which was also seen when MnGTP was used as the substrate. GCC undergoes ligand-induced inactivation in vitro, which is alleviated in the presence of ATP. In vivo desensitized GCC could be further inactivated in vitro when preincubated with ST, indicating that the two mechanisms of GCC inactivation are distinct. Cellular refractoriness as reflected by a reduced responsiveness to further ST-stimulation following prior exposure to IST, coupled with GCC desensitization was also observed in another colonic cell line, Caco2. However, HEK293 cells, stably transfected with GCC cDNA, when exposed to ST for prolonged periods, did not result in GCC desensitization, indicating that desensitization of GCC appeared to be a cell specific phenomenon. GCC expressed in HEK293-GCC cells, however, showed in vitro ligand induced inactivation, suggesting that there are two independent means of ligand-induced desensitization of GCC, perhaps distinct from the mechanisms that have been described earlier for other members of the guanylate cyclase receptor family.
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PMID:Homologous desensitization of the human guanylate cyclase C receptor. Cell-specific regulation of catalytic activity. 1060 65

Cyclic guanosine-3',5'-monophosphate (cGMP)-mediated mechanisms play an important role in vasodilation and blood pressure regulation. We investigated basal activity of the nitric oxide (NO)-cGMP signal transduction pathway in corpus cavernosum from both middle-aged and young rats, and the electrical field stimulation-induced relaxation in the organ was also evaluated. In middle-aged rats, nitric oxide synthase (NOS) and cGMP-phosphodiesterase activities were significantly decreased; however, guanylate cyclase activity was similar. cGMP concentration, a secondary messenger of NO, remained almost the same level as compared with young rats. These results suggest that decrease in cGMP-phosphodiesterase activity is likely to account for the maintenance of cGMP concentration. In isolated corpus cavernosum from middle-aged rats, electrical field stimulation-induced relaxation was partially impaired. These results suggest that downregulation of the NOS and cGMP-phosphodiesterase activities are early events in the pathogenesis of erectile dysfunction.
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PMID:Enzyme activities of the nitric oxide-cGMP pathway in corpus cavernosum isolated from middle-aged rats. 1287 39

Our recent study suggests that there is a reciprocal mechanism to maintain cGMP content, via both a decrease in cGMP degradation (decrease in cGMP-phosphodiesterase activity) and an increase in synthesis of cGMP (increase in guanylate cyclase activity) in the kidney of cyclosporin A-treated rats. We undertook this study to clarify the role of cGMP-phosphodiesterase in cyclosporin A nephrotoxicity by evaluating N-(3,4-dimethoxybenzyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitrobenzamide (FR226807), a phosphodiesterase type 5 inhibitor, in an animal model. Male spontaneous hypertensive rats (SHR) were treated with cyclosporin A (50 mg/kg) for 2 weeks or with cyclosporin A and FR226807 (3.2 mg/kg or 10 mg/kg) for 2 weeks. Cyclosporin A-treated rats showed renal dysfunction and histological change compared with vehicle-treated rats. Administration of FR226807 improved the renal dysfunction (increase in serum creatinine and fractional excretion of sodium, and decrease in creatinine clearance) as well as the pathological changes (tubular vacuolization) induced by cyclosporin A in SHR. At the molecular level, administration of FR226807 resulted in a further increase in cGMP content in the kidney, aorta and platelets from cyclosporin A-treated rats. Our present study demonstrates that cGMP-phosphodiesterase plays an important role in the cyclosporin A nephrotoxicity and also suggests that further inhibition of cGMP-phosphodiesterase is a potential pharmacological target for preventing cyclosporin A nephrotoxicity.
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PMID:Phosphodiesterase type 5 inhibition ameliorates nephrotoxicity induced by cyclosporin A in spontaneous hypertensive rats. 1451 21


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