Identification of an N‐hydroxyguanidine reducing activity of xanthine oxidase

Dambrova, Maija; Uhlén, Staffan; Welch, Christopher J.; Wikberg, Jarl E. S.

doi:10.1046/j.1432-1327.1998.2570178.x

Cited by 19 publications

(11 citation statements)

References 29 publications

(26 reference statements)

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“…In a previous study we showed that the hydroxyguanidine guanoxabenz was capable of supporting the oxidation of xanthine to uric acid both during anaerobic and aerobic conditions (Dambrova et al ., 1998). In subsequent studies we synthesized a novel series of hydroxyguanidines and found that PR5 showed a higher capacity than guanoxabenz to support the anaerobic oxidation of xanthine by xanthine oxidase (Dambrova et al .…”

Section: Discussionmentioning

confidence: 99%

“…In the present study we have evaluated a new possibility to protect the heart in ischaemia and reperfusion. The approach originates from our recent finding that an N‐hydroxyguanidine, guanoxabenz (1‐(2,6‐dichlorobenzylideneamino)‐3‐hydroxyguanidine), an α 2 ‐adrenoceptor active antihypertensive drug (Ledoux et al ., 1981), could also act as an alternative electron acceptor in xanthine oxidase catalyzed oxidation of xanthine (Dambrova et al ., 1998). In the continuation of these studies we synthesized a novel series of N‐hydroxyguanidines and evaluated their capacity to function as electron acceptors in bovine milk xanthine oxidase catalyzed oxidation of xanthine.…”

Section: Introductionmentioning

confidence: 99%

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Cardioprotective effects of N‐hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats

Veveris

Dambrova

Cirule

et al. 1999

British J Pharmacology

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1 The potential for the N-hydroxyguanidine compound PR5 (N-(3,4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. 2 Administration of 1 ± 10 mg kg 71 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular ®brillation incidence 93 vs 43% (P50.05); mortality 47 vs 0% (P50.05), for controls and for 3 mg kg 71 of PR5, respectively). 3 Administration of 3 mg kg 71 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most e ective in reducing arrhythmias and decreasing mortality (43 vs 0%, P50.05), but e ects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. 4 Coronary occlusion/reperfusion (10 ± 20 min) increased malondialdehyde (MDA) of rat hearts (0.88+0.13 for sham vs 1.45+0.12 nmol mg 71 protein for ischaemic; P50.05). In rats where 3 mg kg 71 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04+0.12; P50.05 vs ischaemic). 5 PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326+32 mg for controls vs 137+21 mg for animals treated with 363 mg kg 71 of PR5 (P50.01). 6 PR5 reduced the elevation of the ST-segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. 7 We conclude that the N-hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias. These e ects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardioprotective effects of N‐hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats

Veveris

Dambrova

Cirule

et al. 1999

British J Pharmacology

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“…In a recent study we even purified the spleen cytosolic guanoxabenz converting activity to homogeneity and showed it to reside in xanthine oxidase (Dambrova et al 1998b). The data of fig.…”

Section: Discussionmentioning

confidence: 97%

“…In our previous studies we showed that the guanoxabenz activating mechanism in the spleen was potently inhibited by the xanthine oxidoreductase inhibitor, allopurinol (Mas-sey et al 1970), and we suggested that the activation is mediated by xanthine oxidase (Uhlen et al 1998;Dambrova et al 1998a). In a recent study we even purified the spleen cytosolic guanoxabenz converting activity to homogeneity and showed it to reside in xanthine oxidase (Dambrova et al 1998b). The data of fig.…”

Section: Discussionmentioning

confidence: 97%

Characterization of Guanoxabenz Reducing Activity in Rat Brain

Dambrova

Uhlén

Wikberg

1998

Pharmacology & Toxicology

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Guanoxabenz (1 -(2,6-dichlorobenzylidene-amino)-3-hydroxy~uanidine) and guanabenz (1 -(2,6-dichlorobenzylidene-amino)-3-guanidine) are both known as centrally active antihypertensive drugs. We have previously shown that enzymatic activity in the rat spleen can induce N-reduction of guanoxabenz, leading to high affinity az-adrenoceptor binding, due to the formation of the a,-adrenoceptor active drug, guanabenz. The spleen activity appears to reside in xanthine oxidase as it is activated by xanthine and blocked by allopurinol. We report that high affinity guanoxabenz binding is also induced in rat brain membranes after addition of NADH or NADPH cofactors. However, the brain process was clearly different from that of the spleen, as the formation of high affinity binding in the brain was not blocked by allopurinol. Moreover the NADHNADPH activated mechanism of the brain membranes was not blocked by carbon monoxide and SKF525A, thus the activity appears not to reside in cytochrome P450 enzymes. Instead the activity was blocked by menadione and dicumarol. We conclude that the rat cerebral cortex contains an enzymatic activity that may activate guanoxabenz leading to formation of a metabolite showing high affinity for az-adrenoceptors. We also conclude that the rat brain activity is clearly distinct from that of the rat spleen.

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“…The reduction of nitrogen-containing groups like aromatic nitro compounds, hydroxamic acids, oximes, tertiary Noxides, azo compounds, and N-hydroxyguanidines by the molybdenum hydroxylases aldehyde oxidase and xanthine oxidase have been described previously (Dambrova et al, 1998;Kitamura et al, 2006). However, the activities were often only described for in vitro investigations under the exclusion of oxygen.…”

Section: Introductionmentioning

confidence: 99%