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)

Adenylate and guanylate cyclase activities were measured in rat small intestinal villus and crypt cells to determine possible correlations with cellular differentiation. Isolated intestinal cells were prepared by a method which effectively separates differentiated villus cells from undifferentiated crypt cells (J Biol Chem 248:2542, 1973). Crypt cells were found to have a significantly lower guanylate cyclase activity than villus cells. Adenylate cyclase activity was higher in crypt cells than villus cells, although the difference was less striking than the reverse gradient observed for guanylate cyclase. There was no gradient of activity for cyclic guanosine 3':5'-monophosphate phosphodiesterase. However, cyclic adenosine 3':5'-monophosphate phosphodiesterase activity was lower in villus cells. No villus to crypt gradient of cyclic adenosine 3':5'-monophosphate concentration was detected in mucosa frozen rapidly in liquid nitrogen. The properties and subcellular localization of the cyclases were also evaluated, and of particular interest was the localization of guanylate cyclase to the microvillus membrane and the confirmation of adenylate cyclase activity in the lateral-basal membrane. The villus to crypt gradient of guanylate cyclase suggests that this enzyme has a specialized role in the differentiated villus cell. The contrasting subcellular localization of the cyclases suggests that the cyclases may be interrelated, possibly reflecting the epithelial cell polarity for absorption and secretion.
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PMID:Adenylate and guanylate cyclase activities and cellular differentiation in rat small intestine. 23 99

The distribution of guanylate cyclase, phosphodiesterase, and NADPH-diaphorase [nitric oxide (NO) synthase] was studied in rat brain both at the light and electron microscopic level with special emphasis on the vascular system. We showed that the cGMP-generating enzyme is located in cells (glial cells and pericytes) surrounding cerebral vessels, but not in the endothelium. For NO synthase, a dual localization was observed. The enzyme is present in parts of the endothelium and in nerve endings apparently innervating larger brain vessels. We propose, therefore, that NO acts on guanylate cyclase both from a "synaptic" and endothelial source.
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PMID:Histochemistry of guanylate cyclase, phosphodiesterase, and NADPH-diaphorase (nitric oxide synthase) in rat brain vasculature. 128 93

The present studies were performed in order to examine the possible role of cyclic GMP-stimulated phosphodiesterase (cGMP-PDE) activity in the inhibitory action of the inflammatory peptide bradykinin on cyclic AMP (cAMP) accumulation in D384 cells. Bradykinin decreased the forskolin-stimulated cAMP accumulation in the presence of the phosphodiesterase inhibitor rolipram, and caused a transient 50% rise in cellular cGMP in the presence of the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). Both basal and bradykinin-stimulated cGMP accumulation were about 8 times higher in the presence of IBMX than in the presence of rolipram. Sodium nitroprusside, which caused a 20-70-fold increase in cGMP levels reduced forskolin stimulated cAMP accumulation, whereas hydroxylamine, which maximally caused a 16-fold increase in cGMP, did not. 8-bromo-cGMP or dibutyryl cGMP had no effect on cAMP accumulation induced by forskolin. The inhibitory effect of nitroprusside was totally reversed by blocking the soluble guanylate cyclase activity by methylene blue treatment; however, the inhibitory action of bradykinin on cAMP accumulation was not changed by this treatment. Additionally, inhibition of nitric oxide synthesis, which is known to be regulated by Ca2+ and in turn stimulates cGMP production, by N omega-nitro-L-arginine (L-NAME) treatment did not alter the inhibitory effect of bradykinin on forskolin-induced cAMP accumulation. These results indicate that large increases in cGMP may regulate cAMP via cGMP-PDE whereas the small increase induced by bradykinin is insufficient and that cGMP is not involved in the inhibitory action of bradykinin on cAMP levels in D384 cells.
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PMID:Bradykinin inhibition of cyclic AMP accumulation in D384 astrocytoma cells. Evidence against a role of cyclic GMP. 128 20

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

Alterations in endothelium-derived relaxing factor (EDRF) production or mechanism of action may be involved in the responses of the developing pulmonary vasculature to changes in oxygenation. In this study the effects of acute changes in in vitro oxygen tension on EDRF production were determined in isolated segments of ovine fetal intrapulmonary arteries (4th generation) obtained at 125-135 days of gestation (term 144 +/- 4 days). EDRF production was assessed by measuring segment guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in the presence of a phosphodiesterase inhibitor. Basal (nonstimulated) cGMP production and cGMP production with acetylcholine (ACh) stimulation were dependent on the presence of the endothelium, on the availability of L-arginine, and on soluble guanylate cyclase activity, confirming that they were indicative of EDRF production. cGMP production with sodium nitroprusside (SNP) was used to discriminate changes in the sensitivity of soluble guanylate cyclase with varying conditions. With decreasing oxygen tension, basal and ACh-stimulated cGMP production were attenuated, whereas cGMP production with SNP was not, indicating oxygen modulation of EDRF production. Studies of endothelium-dependent relaxation yielded comparable findings in that the response to ACh was attenuated, but that to SNP was not altered by decreased oxygenation. In addition, the decline in endothelium-dependent relaxation with decreased oxygen tension was rapidly reversed when oxygenation was increased. Parallel experiments examining cGMP production in similarly sized mesenteric arteries revealed that the effect of oxygen on pulmonary artery EDRF production may be specific to that vascular bed. These findings indicate that oxygen selectively modulates EDRF production and endothelium-dependent relaxation in ovine fetal pulmonary arteries. Direct effects of oxygen on EDRF production may at least partially underlie the responses of the developing pulmonary circulation to changes in oxygenation.
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PMID:Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries. 131 28

We have demonstrated previously that in response to hypoxia, isolated rat pulmonary arteries show an initial endothelium-dependent relaxation followed by an endothelium-independent transient contraction. In the presence of increased extracellular Ca2+, both of these responses were enhanced in endothelium-intact arteries. Nitro-L-arginine, a blocker of the biosynthesis of endothelium-derived relaxing factor (EDRF), abolished the initial endothelium-dependent relaxation and Ca(2+)-induced enhancement of hypoxic contraction in endothelium-intact arteries but did not alter responses in endothelium-denuded vessels. Inhibition of prostaglandin formation with indomethacin had no effect on the hypoxia-elicited responses. Preincubation with LY 83583, an inhibitor of guanylate cyclase activation, abolished the initial hypoxia-elicited relaxation and subsequent contraction. M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor, decreased tone under O2 but not under N2, causing an apparent enhancement of the contraction to hypoxia. Thus the modulation of hypoxic responses by the endothelium is dependent on changes in EDRF production, and a decrease in smooth muscle cGMP not involving an EDRF mechanism appears to mediate the endothelium-independent hypoxic contraction observed in the isolated rat pulmonary artery.
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PMID:Role of cGMP mechanisms in response of rat pulmonary arteries to hypoxia. 132 58

1. The present study has examined the influence of alpha-human atrial natriuretic peptide (alpha-hANP) on the synthesis of dopamine and its deamination into 3,4-dihydroxyphenylacetic acid (DOPAC) in rat kidney slices loaded with exogenous L-dihydroxyphenylalanine (L-DOPA). 2. alpha-hANP (3.3 and 330 nM) was found to produce a marked reduction (63-78% reduction) in the time-dependent accumulation of newly-formed dopamine and of its deaminated metabolite DOPAC in kidney slices loaded with 10 microM L-DOPA. alpha-hANP (330 nM) was also found to decrease the accumulation of newly-formed dopamine (45-66% reduction) and DOPAC (38-61% reduction) in experiments in which increasing concentrations (1-100 microM) of L-DOPA were used. This inhibitory effect was found to be potentiated by zaprinast (M&B 22,948; 10 microM), a guanosine cyclic 3',5'-monophosphate (cyclic GMP) phosphodiesterase inhibitor. Alone, zaprinast also decreased the accumulation of both dopamine (54-71% reduction) and DOPAC (73-92% reduction). 3. In kidney homogenates, alpha-hANP (330 nM) was found to affect neither the formation of dopamine nor its deamination to DOPAC. 4. Both alpha-hANP (330 nM) and zaprinast (10 microM) were found not to affect the formation of dopamine and DOPAC in kidney slices obtained from rats on a high salt diet during the previous 6 weeks. A similar situation was also found to occur when kidney slices obtained from 24-months old rats were used.5. The results obtained suggest that the inhibitory effect of alpha-hANP on the renal synthesis of dopamine is dependent on the activation of a membrane-operated mechanism, coupled to the enzyme guanylate cyclase, controlling the entry of L-DOPA into the cells.
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PMID:Effect of alpha-human atrial natriuretic peptide on the synthesis of dopamine in the rat kidney. 132 52

We have examined the interaction of zaprinast, a selective inhibitor of cGMP phosphodiesterase, with guanylate cyclase activators on vascular smooth muscle relaxation in vitro and in vivo. Isolated porcine coronary arterial rings precontracted with prostaglandin F2 alpha (PGF2 alpha) were relaxed dose dependently by the guanylate cyclase activators nitroglycerin and nitroprusside, the cGMP phosphodiesterase inhibitor zaprinast and the endothelium-dependent agent bradykinin. A 1 h pretreatment with 0.5 mM nitroglycerin shifted the dose-response curve to nitroglycerin to the right by a factor of 90, reflecting the development of tolerance. The dose-response curve to sodium nitroprusside was also affected, albeit to a much lesser degree (9-fold increase in IC50). Both zaprinast and bradykinin remained unaffected by nitroglycerin pretreatment. A 30 min pretreatment of rings with zaprinast (1 microM) had no effect on nitroglycerin- or nitroprusside-induced relaxation in control rings, but enhanced vasorelaxation to both nitrovasodilators 7- and 2-fold, respectively, in tolerant rings. Similarly, a 30 min pretreatment of rings with 0.1 microM nitroprusside enhanced zaprinast-induced vasorelaxation 4- and 8-fold, respectively, in control and tolerant rings. Similar observations were made in vivo in anesthetized spontaneously hypertensive rats where zaprinast (0.1-3.0 mg/kg i.v.), caused dose-dependent reductions in mean arterial pressure. This effect was enhanced when rats had been pretreated with nitroprusside (1 micrograms/kg per min). In comparison, in zaprinast-pretreated rats the magnitude of depressor responses to nitroprusside (0.5-5.0 micrograms/kg) was not altered, but the duration of hypotensive response to the highest dose of nitroprusside was enhanced by zaprinast. These data demonstrate an enhanced vasodilatory response of nitrocompounds in combination with peak I-selective phosphodiesterase inhibitors.
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PMID:In vitro and in vivo interactions of nitrovasodilators and zaprinast, a cGMP-selective phosphodiesterase inhibitor. 132 38

The phenolic preservative, methylparaben (MPB), has in the past been demonstrated to harbour definite pharmacological effects. In an attempt to examine the possible central effects of MPB, notably on cyclic nucleotides and cyclic nucleotide phosphodiesterase (PDE; EC 3.1.4.17), rats were orally treated with the drug (0.4% in rat food) for 3 weeks with cortex extracts being used for the various determinations. Three isozymes were identified by DEAE-cellulose anion exchange chromatography, namely the calmodulin/calcium-stimulated form or PDE I (peak I), the cGMP-stimulated form or PDE II (peak II), and an independent form not affected by either calmodulin or cGMP also known as PDE IV (peak III). The presence of MPB induced a significant decrease in cortical cAMP, as well as strongly stimulating the activity of PDE IV (peak III). In addition, a small, yet significant, increase in cGMP levels was observed. Since no increase in cGMP hydrolysis was observed, we conclude that chronic ingestion of MPB induces a preference for cAMP hydrolysis, which was confirmed by the increase in PDE IV (peak III) activity. PDE IV is a membrane-bound, low Km PDE exhibiting high selectivity for cAMP hydrolysis. While there was an increase in cGMP, we failed to observe an increase in the activity of the cGMP-stimulated PDE (PDE II). These data are discussed with reference to the possible membrane effects of MPB allowing it to alter both the kinetic properties of PDE IV with the resultant effects on cAMP, as well as a means whereby it may activate guanyl cyclase and increase cGMP.
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PMID:Central effects of the preservative, methylparaben. In vivo activation of cAMP-specific phosphodiesterase and reduction of cortical cAMP. 132 56

Phototransduction mechanisms have been so far investigated mostly in rods, whereas those in cones are much less known. In the present experiment, we investigated phototransduction mechanisms in inside-out patches excised from cone outer segments of the carp. Cyclic GMP-activated channels on the patch became light-sensitive when both GTP and Mg2+ were supplied by perfusion. When the channels were activated by a hydrolysis-resistant analogue of cGMP, activities were not suppressed by light even though both GTP and Mg2+ were present. Thus activation of transducin and phosphodiesterase (PDE) were involved in the transduction processes, indicating that phototransduction mechanisms in cones are qualitatively similar to those in rods. In cone patches, however, light responses fully terminated even though ATP was absent, opposing to the report that ATP was indispensable for light response termination in rods. The response termination in the cone patch might result from activation of guanylate cyclase and/or inactivation of PDE. Under the perfusion of GTP together with Mg2+ and 3-isobutyl-1-methyl xanthine, no channel activities were observed, indicating that no guanylate cyclase activity was present in cone patch preparations. Therefore, termination of the light response in the patch might be caused by inactivation of PDE which resulted from inactivation of photopigment and transducin. Based on these observations, differences in light response kinetics between the rod and cone are discussed.
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PMID:Phototransduction in cones as examined in excised membrane patch. 133 81


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