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)

The physiology, the pharmacology and the biochemistry of the atrial natriuretique factor (ANF) have been investigated and documented by numerous studies and works since its discovery and cloning ten years ago. More recently, the physiopathological aspect of ANF biosynthesis and secretion by the whole heart during overload and congestive heart failure was reported in experimental models and in human patients. Moreover the cyclic GMP which is the ANF second messenger, egressed from endothelial cells, was correlated with the production of ANF. Therefore the activation of heart endocrine function from ANF gene over-expression to peripheral cyclic GMP appeared as an independent prognosis indicator in congestive heart failure. Two types of ANF receptors have been recently cloned. One is the particulate guanylate cyclase, the second is a clearance receptor involved in the endocytosis and lysozomial degradation of ANF in target cells. Neutral endopeptidase, an ectoenzyme present in different tissues and particularly in the kidney is also capable to cleave ANF in unefficient peptide. The blockade of ANF metabolism by clearance receptor antagonists and neutral endopeptidase inhibitor potentializes the biological effect of exogenous and endogenous ANF particularly on the renal function. This approach of ANF metabolism-inhibition opens new ways on the future of ANF in cardiovascular therapeutic.
Arch Mal Coeur Vaiss 1990 Dec
PMID:[Atrial natriuretic factor. Current data and future perspectives]. 217 42

Small amounts of bacterial lipopolysaccharide (LPS) greatly increase cGMP levels in short term cultures of rat fetal liver and spleen cells in a dose and time dependent manner. To determine the role of guanylate cyclase in this response, a series of experiments was undertaken using either intact or broken fetal spleen cells, the most sensitive tissue evaluated to date. The phosphodiesterase inhibitor, 1-methyl-3-isobutyl-xanthine, potentiated the LPS-cGMP effect in cultures of these cells even at maximal doses of LPS. Moreover, after incubation of intact cells with LPS for 4 h, soluble guanylate cyclase (EC 4.6.1.2) activity was increased 2-fold, whereas particulate activity was unchanged. This increase in soluble activity was proportional to the dose of LPS, was synchronous with the elevation of cGMP levels, and was not associated with any change in cGMP-phosphodiesterase (EC 3.1.4.17) activity. In contrast to intact cells, neither total nor soluble guanylate cyclase activity was increased by the addition of LPS to spleen cell whole sonicate or cytosol for various times from 10 min to 3.5 h. These results suggest that the LPS-cGMP response is due to a persistent indirect stimulation of soluble guanylate cyclase activity that is both dose and time dependent.
Biochim Biophys Acta 1988 Dec 09
PMID:A novel mechanism of soluble guanylate cyclase stimulation: time-dependent activation by bacterial lipopolysaccharide in rat fetal spleen cells. 246 43

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.
J Cardiovasc Pharmacol 1988 Dec
PMID:Release of endothelium-derived relaxing factor is inhibited by 8-bromo-cyclic guanosine monophosphate. 246 85

1. Rabbit retinas were isolated and subjected in vitro to shifts between light and darkness in the presence or absence of four concentrations of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Changes in the rate of cyclic GMP hydrolysis (determined by 18O labelling of guanine nucleotide alpha-phosphoryls) and in total cyclic GMP content (determined by radioimmunoassay) were compared with the changes in the electrical potential across the retina. The experiments were designed so that the changes in potential would reflect changes in the light-sensitive conductance of the photoreceptors. 2. IBMX at 27-730 microM caused dose-related reductions in cyclic GMP hydrolysis in both light and darkness. The reductions in hydrolysis were associated with almost equal reductions in synthesis, so that there was little increase in the total content of cyclic GMP despite large changes in its metabolic flux. 3. Shifting from light (2.3 x 10(3) photons microns-2 s-1) to darkness also caused large reductions in the metabolic flux of cyclic GMP, with little increase in its total content. 4. Reductions in cyclic GMP flux were always associated with increases in the vitreous-positive transretinal potential, which was used as a measure of photoreceptor outer segment conductance, and the inverse correlation between flux and potential was closely maintained (r = 0.98) under all conditions examined. The correlation between total cyclic GMP content and transretinal potential was much less close. 5. Since IBMX and darkness acted similarly and additively, the combination of IBMX and darkness caused large decreases, of up to 21-fold, in cyclic GMP flux and large increases, of up to 23-fold, in the transretinal potential. 6. Kinetic analysis of the data indicated that the great majority (about 95%) of the light-sensitive conductance was closed under physiological conditions in darkness. 7. The data appear to be consistent with a system in which much of the cyclic GMP is bound, in which the binding is increased by light, and in which the free cyclic GMP acts co-operatively with a Hill coefficient of 3 to open outer segment conductance and to inhibit guanylate cyclase.
J Physiol 1988 Dec
PMID:Metabolic flux of cyclic GMP and phototransduction in rabbit retina. 247 68

The formation of nitric oxide (NO) by an L-arginine:NO synthase and its stimulation of the soluble guanylate cyclase was studied in rat whole adrenal and bovine cortex and medulla cytosol. In the presence of L-arginine, the stimulation of soluble guanylate cyclase was accompanied by the formation of citrulline and NO2-, formed from NO. The NO synthase was NADPH- and Ca(2+)-dependent and was inhibited by several L-arginine analogues. These results indicate that rat and bovine adrenal cytosol contains an L-arginine:NO synthase.
Biochem Biophys Res Commun 1989 Dec 15
PMID:Nitric oxide from L-arginine stimulates the soluble guanylate cyclase in adrenal glands. 248 Jul 84

In slices of young rat cerebellum, the glutamate analogue kainate induced a large accumulation of cyclic GMP, which was inhibited by non-N-methyl-D-aspartate antagonists. Quisqualate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate evoked only small cyclic GMP responses and inhibited the effect of kainate. When tested in cerebellar cell suspensions, glutamate was also a potent antagonist of the cyclic GMP response to kainate. Superoxide dismutase enhanced the response in the isolated cells, whereas haemoglobin and methylene blue were inhibitory. The response in slices was Ca2+ dependent, augmented by arginine, and inhibited by L-NG-monomethylarginine in a manner that could be reversed by additional arginine. It is concluded that stimulation of kainate receptors leads to activation of the enzyme that synthesizes nitric oxide from arginine and that activation of soluble guanylate cyclase by the released nitric oxide accounts for the cyclic GMP generation.
J Neurochem 1989 Dec
PMID:A kainate receptor linked to nitric oxide synthesis from arginine. 255 70

A linear decapeptide, [cyclohexylalanine 106]ANP-(105-114)NH2 (1), where ANP is atrial natriuretic peptide, was prepared by solid phase synthesis and purified by reverse-phase liquid chromatography. This novel peptide was found to bind to ANP receptors in rabbit lung membranes, to stimulate cGMP production in various tissues, and to fully relax precontracted rabbit aorta in a dose-dependent fashion. The potency of 1 in the various in vitro assays varies between one-twentieth and one-eightieth of the potency of the reference peptide, the 24-mer rat ANP-(103-126). The linear decapeptide 1, which encompasses amino acid residues from the rat ANP sequence (105-114), features a cyclohexylalanine residue instead of the phenylalanine 106 residue in the hormone sequence, a free sulfhydryl function at the N-terminal cysteine 105, and a carboxamide C terminus. Its disulfide dimer 6 was active in the rabbit aorta assay while the S-methyl cysteine 7 analogue was not active in the same assay at similar concentrations. The decapeptide 1 is of particular significance because it is the shortest analogue reported to date endowed with agonistic activity at the guanylate cyclase-coupled ANP receptor. In particular, it is interesting to compare its structure to the structures of other short linear analogues of ANP which are totally devoid of the ability to stimulate particulate guanylate cyclase activity.
J Biol Chem 1989 Dec 05
PMID:A synthetic linear decapeptide binds to the atrial natriuretic peptide receptors and demonstrates cyclase activation and vasorelaxant activity. 255 53

We report here on the effect of an endothelium-dependent vascular smooth muscle relaxant, lysophosphatidylcholine (LPC) on rabbit aortic strips and on hemodynamic changes by LPC in atherosclerotic animals. Cyclic GMP changes induced by LPC in atherosclerotic vessels were also determined. Atherosclerosis was produced by feeding a high cholesterol and saturated fatty acid diet. LPC was injected into the left atrium and coronary flow was measured by radioactive microspheres; in vitro, relaxation of precontracted aortic strips by lysophosphatidylcholine was also recorded. LPC failed to increase coronary flow in the presence of atherosclerosis. In isolated aortic strips, dose-response curves with acetylcholine and LPC showed diminished relaxation in atherosclerotic preparations, and cyclic GMP production following LPC was reduced. The results demonstrate that vascular relaxation by LPC, together with its ability to activate guanylate cyclase is dependent on the functional and morphological integrity of the vascular wall.
Atherosclerosis 1989 Dec
PMID:Effect of lysophosphatidylcholine on atherosclerotic rabbit arteries. 255 62

1. The inhibitory effects of the K+ channel activator, cromakalim, upon contractions to noradrenaline, histamine and caffeine were examined in rabbit isolated renal artery. For comparison, the effects of pinacidil, dazodipine and sodium nitroprusside were also studied in some experiments. 2. In normal Krebs solution, cromakalim (1 microM) produced a 39.1% reduction in area under the curve (AUC) of the noradrenaline concentration-response, and a 61.8% reduction in the histamine AUC. Ca2+ removal (with EGTA 0.1 mM) gave an 80.0% reduction in the noradrenaline AUC and a 74.5% reduction in the histamine AUC. The combination of Ca2+ removal and cromakalim (1 microM) had no further effect on the noradrenaline responses (a reduction of 78.4% in AUC), but produced a significantly greater reduction in the histamine AUC (86.2%). 3. LaCl3 (1 mM) reduced the noradrenaline AUC by 74.8% and gave an 81.8% reduction in the response to a single (EC90) histamine concentration. LaCl3 (1 mM) plus cromakalim (1 microM) produced no further reduction in the noradrenaline AUC (71.9%) but gave a significant further reduction of the histamine response (94.6%). 4. Pinacidil (3 microM) reduced the noradrenaline AUC by 35.5%. Pinacidil (3 microM) plus LaCl3 (1 mM) produced the same reduction in the noradrenaline AUC (80.9%) as LaCl3 alone (80.9%). 5. In both normal and Ca2+-free Krebs solution, cromakalim (0.1, 1.0 and 10 microM) produced concentration-related inhibition of the contraction to caffeine (10 mM). This inhibition was antagonised by the K+ channel blocker, glibenclamide (3 microM). Similarly, pinacidil (0.3, 3.0 and 30 microM) produced a glibenclamide-sensitive inhibition of the caffeine contraction. At equi-vasorelaxant concentrations, dazodipine (0.01, 0.1 and 1.O microM) and sodium nitroprusside (0.03, 0.3 and 3.0 microM) had no significant effect on caffeine contractions. 6. The data show that the K+ channel activators, cromakalim and pinacidil, unlike the Ca2+ channel blocker, dazodipine, or the guanylate cyclase activator, sodium nitroprusside, can inhibit the contraction which results from caffeine-induced Ca2+ release. Cromakalim and pinacidil, however, inhibit only the component of the noradrenaline response resulting from Ca2+ influx (tonic component) and not that resulting from Ca2 + release (phasic component). Cromakalim may affect both components of the histamine contraction.
Br J Pharmacol 1989 Dec
PMID:Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca2+. 257 15

We tested the ability of the following putative vasoactive agents to stimulate guanylate cyclase activity in isolated rat cerebral microvessels: angiotensin II, arginine vasopressin, atrial natriuretic peptide, bradykinin, carbachol and thrombin; at concentrations ranging between 10(-3) and 10(-9) M. The ability of cerebral microvessels to increase their cyclic GMP generation was ascertained in the presence of sodium nitroprusside. Of all the agents tested, only atrial natriuretic peptide stimulated cyclic GMP generation in isolated rat cerebral microvessels. Such stimulation was dose-dependent, reaching its maximum at 1 microM concentration. These results are consistent with the finding of atrial natriuretic peptide receptors in brain microvessels, and suggest that this peptide has an important role in modulating the function of brain capillaries, which constitute the blood-brain barrier. If receptors for the other vasoactive agents exist in brain microvessels, their action does not seem to be mediated by cyclic GMP as a second messenger.
Neurosci Lett 1989 Dec 15
PMID:Effect of several vasoactive agents on guanylate cyclase activity in isolated rat brain microvessels. 257 27


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