Effects of Nitrovasodilators, Endothelium-dependent Vasodilators, and Atrial Peptides on cGMP

Murad, Ferid; Leitman, Dale C.; Chang, Chih-Hung; Hirata, Masato; Kohse, Klaus P.

doi:10.1101/sqb.1988.053.01.115

Cited by 32 publications

(16 citation statements)

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“…37 Peroxynitrite has been shown to interact with proteins and produce nitrotyrosine residues. 15 Through the use of a nitrotyrosine antibody, we are able to clearly show that CsA treatment significantly increases the amount of nitrotyrosine (see Figure 7). Our data also show that the formation of nitrotyrosine is inhibited by the addition of the NADPH oxidase inhibitor DPI, the antioxidant NAC, as well as the oxygen radical scavenger Tiron and the peroxynitrite scavenger uric acid.…”

Section: Discussionmentioning

confidence: 87%

“…NO has such a high affinity for the superoxide anion that it has been shown to compete with SOD for binding of O 2 Ϫ . 15 It has even recently been shown that CsA treatment can induce the formation of peroxynitrite, dependent on the concentration of superoxide anion. 37 Peroxynitrite has been shown to interact with proteins and produce nitrotyrosine residues.…”

Section: Discussionmentioning

confidence: 99%

“…NO then binds to the heme group of soluble guanylate cyclase (sGC), thereby activating the enzyme to produce cGMP. 13,14 The NO synthase family and the NO radical have been shown to play an important role in many biological processes including maintaining cardiovascular tone 15 and ion balance. 16 Several studies have attempted to link NO 17,18 and the bradykinin pathway 11,12 to CsA-induced hypertension, but no clear answer regarding the involvement of either has been reached.…”

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confidence: 99%

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Cyclosporin A Disrupts Bradykinin Signaling Through Superoxide

Vetter

Chen²,

Chang³

et al. 2003

Hypertension

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Abstract-Cyclosporin A (CsA) is used to reduce transplant rejection rates. Chronic use, however, has a destructive toxic effect on the kidney, resulting in hypertension. In this study, we investigated the effects of CsA treatment on the bradykinin/soluble guanylate cyclase signaling cascade and the involvement of superoxide in LLC-PK1 porcine kidney proximal tubule cells. Treatment with 1 mol/L CsA for 24 hours increased basal cGMP levels by 41%, whereas CsA inhibited bradykinin-stimulated cGMP production by 26%. Western blotting showed increased expression of eNOS, but no other protein in the bradykinin/soluble guanylate cyclase (sGC) pathway was affected. Using lucigenin-dependent chemiluminescence, we found that CsA treatment significantly increased superoxide production. Production of O 2 Ϫ was not significantly reduced by 10 mol/L oxypurinol or 30 mol/L ketoconazole. However, it was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium chloride (10 mol/L) as well as the O 2 Ϫ scavenger superoxide dismutase (SOD) (100 U). On treatment with 50 mol/L quercetin, 10 mmol/L N-acetyl-cysteine, both antioxidants, as well as the O 2 Ϫ scavenger Tiron (10 mmol/L), concomitant with 1 mol/L CsA for 24 hours the activation of cGMP production, was restored in combination with a reduction in O 2 Ϫ . Incubation with 100 mol/L menadione, a reactive oxygen generator, and 10 nmol/L bradykinin showed similar effects on the level of cGMP as with CsA. CsA treatment was found to increase nitrotyrosine levels. Key Words: cyclosporin Ⅲ bradykinin Ⅲ nitric oxide Ⅲ cyclic GMP Ⅲ antioxidants C yclosporin (CsA) is an important immunosuppressant used in improving the chances of whole organ transplant and graft survival. 1,2 However, cyclosporin treatment has been linked to several significant nephrotoxic side effects. The side effects range from afferent arteriolar constriction 3 and a reduction in glomerular filtration rate 4 to interstitial fibrosis 5 and ultimately hypertension. Although the toxic effects are well established, the exact mechanisms that lead to the pathology and hypertension are not agreed on. The proposed mechanisms for the development of hypertension focus on induction of vasoconstrictive pathways as well as obstruction of vasodilative pathways examined in patients, rat models, and endothelial cells. The pathways examined as possibly affected by CsA include the renal sensory nerve endings, 6 the renin-angiotensin system, 7 endothelin-1, 8,9 thromboxane, 9,10 and the renal kallikrein-kinin system. 11,12 Bradykinin is an important vasodilating peptide involved in the renal kallikrein-kinin system. The bradykinin peptide exerts its effects by binding to its receptor, activating a heterotrimeric G protein complex, phospholipase C, and then nitric oxide synthase (eNOS), which generates nitric oxide (NO). NO then binds to the heme group of soluble guanylate cyclase (sGC), thereby activating the enzyme to produce cGMP. 13,14 The NO synthase family and the NO radical have been shown to play an important role in many ...

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cyclosporin A Disrupts Bradykinin Signaling Through Superoxide

Vetter

Chen²,

Chang³

et al. 2003

Hypertension

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“…Both within the same cell and in specific target cells, this NO-like factor (or group offactors) activates soluble guanylyl cyclase, thereby acting as an intra-and intercellular signal molecule to regulate the intracellular concentration of cGMP (11)(12)(13)(14). Earlier studies have demonstrated that L-arginine could activate guanylyl cyclase in brain and neuronal cells (15, 16); however, the mechanisms were not elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…The formation of GAF from L-arginine is catalyzed by an NADPH-dependent GAF synthase (6,(21)(22)(23)(24)(25). GAF synthase and its target enzyme, soluble guanylyl cyclase, represent the protein components of this signal-transduction pathway (13,14,17,18,26,27). In rat cerebellum, GAF synthase activity is due to a cytosolic Ca2+/calmodulin-regulated isoform of the enzyme.…”

mentioning

confidence: 99%

Purification of a soluble isoform of guanylyl cyclase-activating-factor synthase.

Schmidt

Pollock

Nakane

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

348

162

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The soluble form of guanylyl cyclase-activating-factor (GAF) synthase from rat cerebellum was purified to homogeneity by sequential affinity chromatographic steps on adenosine 2',5'-bisphosphate (2',5'-ADP)-Sepharose and calmodulin-agarose. Enzyme activity during purification was bioassayed by the L-arginine-, NADPH-, and with a molecular mass ofabout 155 ± 3 kDa. These data suggest that soluble GAF synthase purified from rat cerebellum is a homodimer of 155-kDa subunits and that enzyme activity is dependent upon the presence of calmodulin.In various mammalian cell types [e.g., macrophages (1), endothelial cells (2), polymorphonuclear neutrophils (3, 4), brain (5, 6), and neuronal cell lines (7, 8)], L-arginine is oxidized to yield the endothelium-derived relaxing factor with physicochemical and pharmacological properties similar to nitric oxide (NO) or a NO-containing compound (9, 10). Both within the same cell and in specific target cells, this NO-like factor (or group offactors) activates soluble guanylyl cyclase, thereby acting as an intra-and intercellular signal molecule to regulate the intracellular concentration of cGMP (11)(12)(13)(14). Earlier studies have demonstrated that L-arginine could activate guanylyl cyclase in brain and neuronal cells (15, 16); however, the mechanisms were not elucidated. This laboratory has proposed (17, 18) that hormonal regulation of cGMP accumulation could be mediated through such a signal transduction pathway. Since the exact chemical structure of this ubiquitous factor (or group of factors) remains to be clarified (19,20), we suggest the preliminary name of guanylyl cyclase-activating factor (GAF). The formation of GAF from L-arginine is catalyzed by an NADPH-dependent GAF synthase (6,(21)(22)(23)(24)(25). GAF synthase and its target enzyme, soluble guanylyl cyclase, represent the protein components of this signal-transduction pathway (13,14,17,18,26,27). In rat cerebellum, GAF synthase activity is due to a cytosolic Ca2+/calmodulin-regulated isoform of the enzyme. GAF synthase was found to catalyze the conversion of L-arginine to both L-citrulline and a labile NO-like activator of soluble guanylyl cyclase (i.e., GAF). The enzyme was purified by the sequential use of two affinity chromatography columns, ADP-Sepharose and calmodulin-agarose, from the crude supernatant fraction to homogeneity (8925-to 10,076-fold, assayed by citrulline and soluble guanylyl cyclase stimulation, respectively). Purified GAF synthase is a (homo)dimer of protein subunits of 155 ± 3 kDa. Some of these observations have been presented in abstract form (28-30).MATERIALS AND METHODS Materials. Calmodulin-agarose and Sepharose 4B were obtained from Sigma. All other column materials and standard marker proteins were purchased from Pharmacia. Glycine and Tris (Bio-Rad) and SDS (Boehringer Mannheim) were of electrophoresis grade. All other reagents were of analytical grade. Biotinylated calmodulin, biotinylated alkaline phosphatase, and avidin were kindly provided

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Die Entdeckung einiger biologischer Wirkungen von Stickstoffmonoxid und seiner Rolle für die Zellkommunikation (Nobel-Vortrag)

Murad

1999

Angewandte Chemie

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Ein einzigartig einfaches Molekül mit einer Vielzahl von Signalfunktionen: NO. Das freie Radikal Stickstoffmonoxid vermittelt nicht nur viele biologische Wirkungen, indem es die Guanylat‐Cyclase aktiviert und so die Synthese von cyclischem GMP aus GTP verstärkt, sondern es kann auch mit Übergangsmetallen wie Eisen, mit Thiolgruppen, anderen freien Radikalen, Sauerstoff, dem Superoxid‐Anion, ungesättigten Fettsäuren und anderen Molekülen reagieren. Außer als intrazellulärer Botenstoff kann NO auch als Autocoid, parakrine Substanz oder Neurotransmitter fungieren oder als ein Hormon, das an entfernte Wirkorte transportiert werden kann, um dort seine Funktion auszuüben.

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Effects of Nitrovasodilators, Endothelium-dependent Vasodilators, and Atrial Peptides on cGMP

Cited by 32 publications

References 0 publications

Cyclosporin A Disrupts Bradykinin Signaling Through Superoxide

Cyclosporin A Disrupts Bradykinin Signaling Through Superoxide

Purification of a soluble isoform of guanylyl cyclase-activating-factor synthase.

Die Entdeckung einiger biologischer Wirkungen von Stickstoffmonoxid und seiner Rolle für die Zellkommunikation (Nobel-Vortrag)

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