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)

Glomerular mesangial cells are believed to contribute to regulation of glomerular filtration rate through their contractility, which is regulated by various vasoactive hormones such as angiotensin II (A II), and atrial natriuretic peptide (ANP). A II has been recently reported to inhibit ANP-induced cyclic GMP (cGMP) accumulation in vascular smooth muscle cells, and other types of cells, but the mechanism of this inhibitory effect of A II is still unclear. In order to know the interaction between A II and ANP in glomerular mesangial cells and to know the mechanism of the interaction, I examined the effects of A II on ANP-induced cGMP accumulation in cultured rat glomerular mesangial cells. ANP produced rapid increase in cellular cGMP in cultured rat glomerular mesangial cells, which was significantly inhibited by co-incubation with A II. A II also inhibited cGMP accumulation produced by sodium nitroprusside, soluble guanylate cyclase activator. This inhibitory effect of A II was completely blocked by 1 mM of 3-isobutyl-1-methylxanthine (IBMX), a cyclic nucleotide phosphodiesterase inhibitor. Thus, it seems that A II inhibits ANP-induced cGMP accumulation by activating phosphodiesterase rather than by inhibiting guanylate cyclase. Since the action of A II has been reported to be mediated by increase of cytosolic free Ca2+ secondary to inositol 1,4,5-trisphosphate (IP3) generation and activation of protein kinase C secondary to diacylglycerol (DG) generation, I investigated the effects of Ca ionophore (A23187), and 12-O-tetradecanoyl phorbol-13-acetate (TPA), protein kinase C activator, on ANP-induced cGMP accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Angiotensin II decreases atrial natriuretic peptide-induced cyclic GMP accumulation in rat glomerular mesangial cells]. 216 60

The newly identified peptide C-type natriuretic peptide (CNP) caused only a slight elevation of cGMP in rat renal glomeruli. In contrast, CNP potently increased cGMP levels in cultured rat vascular smooth muscle cells (VSMC) and stimulated guanylate cyclase activity in the particulate fraction of the cells. The extent of maximum activation of the enzyme induced by CNP was 4-fold higher than that by human atrial natriuretic peptide (alpha-hANP) while CNP was 4- and 16-fold weaker than alpha-hANP in binding affinity for the putative receptors on VSMC and vasorelaxant activity for rat aorta, respectively. These results indicate that CNP is a potent stimulator of cGMP formation in VSMC but not in glomeruli and pharmacological feature of CNP is distinct from that of ANP.
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PMID:Novel natriuretic peptide, CNP, potently stimulates cyclic GMP production in rat cultured vascular smooth muscle cells. 216 3

We evaluated the relationship between cell pH and cGMP production in cultured rat renal inner medullary collecting duct cells. The cGMP level, 21 +/- 6, was not different in control vs. alkalinized cells, 49 +/- 17 fmol/mg protein (p greater than 0.5). 10(-11) M atrial natriuretic peptide (ANF) enhanced cGMP production in alkalinized cells, 426 +/- 34 vs. 141 +/- 9*. Conversely, alkalinization inhibited 10(-4)M nitroprusside (SNP) induced cGMP formation, 29 +/- 9 vs. 332 +/- 67*. Phosphodiesterase inhibition abolished the difference in cGMP production by ANF but did not reverse the inhibitory effect of alkalinization on SNP induced cGMP production. In rat renal inner medullary collecting duct cells, cellular alkalinization plays a significant role in the regulation of guanylate cyclase mediated cGMP production. * = p less than 0.05).
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PMID:Regulation of cGMP production by intracellular alkalinization in cultured rat inner medullary collecting duct cells. 216 12

A collection of analogues of atrial natriuretic peptide (ANP) were screened for their ability to inhibit ANP-induced cGMP stimulation. The antagonists revealed through this screen are structurally related; almost all are substituted at either aspartate-13 or phenylalanine-26. This tendency is consistent throughout several families of small ANP analogues, suggesting that these two amino acid residues are involved in the process of ANP/cGMP signal transduction. One compound, A74186, was studied in some detail. A74186 is a potent inhibitor of the activation of guanylate cyclase by ANP; it acts with a pA2 of 7.12 in rat vascular smooth muscle cells and shifts the ANP/cGMP dose-response curve by 3 orders of magnitude at a 10 microM concentration. It also inhibits cGMP release in vivo, and at an infusion rate of 10 micrograms/kg-min it completely abolishes ANP-induced natriuresis and diuresis. A74186 does not, however, antagonize the hypotensive or vasorelaxant effects of ANP; in fact it acts as an agonist in these assays. It thus appears that cGMP, although it may mediate the renal responses to ANP, is not responsible for the vascular and hemodynamic effects that result from the action of the hormone.
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PMID:Atrial natriuretic peptide antagonists: biological evaluation and structural correlations. 217

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

Cultured human skin fibroblasts possessed the high-affinity and low-capacity binding sites for [125I]alpha-human atrial natriuretic peptide (hANP), in which the dissociation constant and maximal binding capacity were computed to 68.7 +/- 11.3 pM and 7.3 +/- 1.2 fmols/mg protein, respectively, from Scatchard plot analysis. The specific [125I] alpha-hANP binding sites of cultured human fibroblast were displaced by unlabeled atriopeptin I, a truncated analogue, to the same extent as the case of alpha-hANP. In human adrenal membrane fractions, [125I] alpha-hANP binding sites were suppressed only by unlabeled alpha-hANP, while the high concentrations of atriopeptin I could slightly inhibit the binding sites for alpha-hANP. As it was reported that atriopeptin I had more significant affinity to the low-molecular weight ANP receptor (60-70 KD) than that to the high-molecular weight form (130-140 KD), the specific bindings may be attributed by the low-molecular weight ANP receptor in cultured human fibroblasts. Furthermore, alpha-hANP up to 10(-8)M failed to induce the significant cGMP formation in cultured human skin fibroblasts. The molecular weight of [125I]alpha-hANP binding sites of human fibroblasts was identified only at the region of 67 KD and no radioactive band was visualized around the region of large molecular weight ANP receptor in the SDS gel electrophoresis of a crosslinked [125I]alpha-hANP-receptor complex. In contrast, the affinity labeling of [125I]alpha-hANP to the human adrenal membrane fractions showed that 135 KD binding sites were responsible to the human adrenal ANP receptor. In conclusion, cultured human skin fibroblasts have a high-affinity low-capacity receptor for ANP. The molecular weight of ANP receptor is approximately 67 KD, and ANP-specific guanylate cyclase may not be linked to the receptor, suggestive that so-called C receptor may be localized in cultured human fibroblasts.
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PMID:[Structure and function of the receptor for human atrial natriuretic peptide in cultured human skin fibroblasts]. 217 31

L-arginine has been proposed to be the precursor of the endothelium-derived relaxing factor. In this study, we evaluated the pulmonary vascular effects of L-arginine-HCl and its benzoyl derivative N-alpha-benzoyl-L-arginine ethyl ester (BAEE) in the rat, in comparison with other vasodilators such as acetylcholine and sodium nitroprusside. In isolated pulmonary artery rings incubated with indomethacin (10 microM) and precontracted with phenylephrine (2 microM), BAEE (10(-6)-10(-5) M) significantly (P less than .05) relaxed the rings more than L-arginine. This effect was potentiated by the endothelium (P less than .05). The relaxing effect of BAEE (ED50 = 2.1 X 10(-6) M) and acetylcholine (ED50 = 2.4 X 10(-7) M) was significantly less potent than that of sodium nitroprusside (ED50 = 1.1 X 10(-8) M). Moreover, pretreatment with the soluble guanylate cyclase inhibitors methylene blue (10(-5) M) and hemoglobin (10(-5) M) antagonized BAEE-induced relaxation in intact pulmonary rings but had no effect on the relaxation elicited with atrial natriuretic peptide. In the isolated lung preparations perfused with the endoperoxide analog U46619 (5-10 nmol/min), sodium nitroprusside (10(-10)-10(-8) M) elicited potent vasodilation (ED50 = 2.8 X 10(-9) mol) whereas no vasodilation was observed with acetylcholine (10(-8)-10(-5) mol). BAEE (10(-6)-10(-5) M) decreased in a dose-dependent manner pulmonary perfusion pressure, and similar doses of L-arginine showed only a mild vasodilating effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vasodilatory property of N-alpha benzoyl-L-arginine ethyl ester in the rat isolated pulmonary artery and perfused lung. 236 85

Effect of a synthetic atrial natriuretic peptide, rat atriopeptin II (rAP-II) on the formation of cyclic nucleotides and progesterone production in Percoll-purified rat luteal cells was investigated. Incubation of luteal cells with varying concentrations of rAP-II resulted in a dose-related stimulation of intracellular cyclic GMP content; maximum stimulation being achieved with 10 nM rAP-II. The increase in cyclic GMP formation was extremely rapid and a 12-fold increase in the cyclic GMP content over basal level was attained within 5 min of incubation of the cells with 10 nM rAP-II. In the presence of phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine, both basal and rAP-II-stimulated levels of cyclic GMP were increased approximately 10 times, but the magnitude of stimulation remained similar in the presence or absence of the inhibitor. The atrial peptide at the concentration of 1-100 nM, however, had no effect on either basal or gonadotropin-stimulated progesterone production and cyclic AMP formation by the luteal cells. Furthermore, the increase in the level of cellular cyclic GMP content of rAP-II was demonstrated to result from a selective activation of particulate guanylate cyclase.
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PMID:Atrial natriuretic factor stimulates luteal guanylate cyclase. 244 51

Receptors for atrial natriuretic peptide (ANP) have been demonstrated in renal mesangial cells as well as other cell types in the glomerulus. The biochemical basis for the effects of ANP on glomerular hemodynamics remains undefined. Using cultured rat glomerular mesangial cells, we demonstrated a concentration-dependent stimulation of cGMP production in intact cells, and of guanylate cyclase in membranes. Despite the presence of a guanylate cyclase response, ANP had no inhibitory effect on basal inositol trisphosphate production nor on basal cytosolic calcium. Arginine vasopressin stimulated IP3 production, caused a rise in cytosolic calcium as measured using the calcium-sensitive fluorescent probe Indo-1, and caused mesangial cell contraction. ANP caused a slight but significant enhancement of vasopressin-stimulated IP3 production, but had no effect on the cytosolic calcium response nor on the contractile response. 8-Bromo-cGMP likewise had no effect on the generation of the calcium signal. These results indicate that the effects of ANP on glomerular hemodynamics are not mediated by an alteration in the generation of the calcium signal in mesangial cells. In contrast, addition of calcium inhibited ANP stimulated guanylate cyclase activity.
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PMID:Interaction of atrial natriuretic peptide-stimulated guanylate cyclase and vasopressin-stimulated calcium signaling pathways in the glomerular mesangial cell. 244 31

Cultured rat lung fibroblasts were used to explore desensitization of guanylate cyclase to nitrovasodilators. The effect of pretreatment with glyceryl trinitrate (GTN) on the concentration-response curves of GTN and sodium nitroprusside (SNP) for cyclic GMP accumulation in intact cells and activation of guanylate cyclase in broken cell preparations was measured. Pretreatment of cells with 1 microM GTN for 3 h decreased cyclic GMP accumulation induced by GTN but had no effect on SNP-induced cyclic GMP accumulation. Pretreatment of cells with 100 microM GTN decreased the efficacy of GTN and SNP for cyclic GMP elevation by 89% and 40%, respectively. In contrast to results obtained with GTN, SNP slightly desensitized cyclic GMP accumulation induced by GTN and SNP. Pretreatment of cells with 100 nM atrial natriuretic peptide resulted in a 44% decrease in cyclic GMP accumulation induced by subsequent exposure to 10 nM atrial natriuretic peptide but had no effect on cyclic GMP elevation induced by nitrovasodilators. In experiments with crude preparations of soluble guanylate cyclase from cells pretreated with 1 mM GTN, activation of the enzyme by GTN and SNP was inhibited almost completely. Tolerance to GTN in intact cells could not be reversed by subsequent incubation with thiols such as cysteine, N-acetylcysteine or glutathione. However, overnight incubation of GTN-tolerant cells in media without added thiols resulted in complete recovery of responsiveness to GTN. Recovery of GTN-induced cyclic GMP accumulation was inhibited in a concentration-dependent manner by cycloheximide, suggesting that reversal of organic nitrate tolerance requires de novo synthesis of gyanylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glyceryl trinitrate-induced desensitization of guanylate cyclase in cultured rat lung fibroblasts. 245 70


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