Prevention of Catecholamine-Induced Cardiac Damage and Death with a Nucleoside Transport Inhibitor

H, Van Belle; Verheyen, Willy; K, Ver Donck; Pa, Janssen; Ji, Robertson

doi:10.1097/00005344-199208000-00001

Cited by 30 publications

(10 citation statements)

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“…In rabbits, R 75231 has shown to prevent death from catecholamine-induced cardiac toxicity (20) and to improve functional recovery after cardiac ischemia (21). In pigs, R 75231 reduces ischemia-induced arrhythmias (22).…”

Section: Introductionmentioning

confidence: 99%

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

Rongen¹,

Smits²,

Donck³

et al. 1995

J. Clin. Invest.

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In 12 healthy male volunteers (27-53 yr), a placebo-controlled randomized double blind cross-over trial was performed to study the effect of the intravenous injection of 0.25, 0.5, 1, 2, 4, and 6 mg draflazine (a selective nucleoside transport inhibitor) on hemodynamic and neurohumoral parameters and ex vivo nucleoside transport inhibition. We hypothesized that an intravenous draflazine dosage without effect on hemodynamic and neurohumoral parameters would still be able to augment the forearm vasodilator response to intraarterially infused adenosine. Heart rate (electrocardiography), systolic blood pressure (Dinamap 1846 SX; Critikon, Portanje Electronica BV, Utrecht, The Netherlands) plasma norepinephrine and epinephrine increased dose-dependently and could almost totally be abolished by caffeine pretreatment indicating the involvement of adenosine receptors. Draflazine did not affect forearm blood flow (venous occlusion plethysmography). Intravenous injection of 0.5 mg draflazine did not affect any of the measured hemodynamic parameters but still induced a significant ex vivo nucleoside-transport inhibition of 31.5±4.1% (P < 0.05 vs placebo). In a subgroup of 10 subjects the brachial artery was cannulated to infuse adenosine (0.15, 0.5, 1.5, 5, 15, and 50 ,ug/100 ml forearm per min) before and after intravenous injection of 0.5 mg draflazine. Forearm blood flow amounted 1.9+0.3 ml/100 ml forearm per min for placebo and 1.8±0.2, 2.0±0.3, 3.8±0.9, 6.3±1.2, 11.3±2.2, and 19.3±3.9 ml/100 ml forearm per min for the six incremental adenosine dosages, respectively. After the intravenous draflazine infusion, these values were 1.6±0.2 ml/100 ml forearm per min for placebo and 2.1±0.3, 3.3±0.6, 5.8±1.1, 6.9±1.4, 14.4±2.9, and 23.5±4.0 ml/100 ml forearm per min, respectively (Friedman ANOVA: P < 0.05 before vs after draflazine infusion). In conclusion, a 30-50% inhibition of adenosine transport significantly augments the fore- arm vasodilator response to adenosine without significant systemic effects. These results suggest that draflazine is a feasible tool to potentiate adenosine-mediated cardioprotection in man. (J. Clin. Invest. 1995. 95:658-668.)

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Section: Introductionmentioning

confidence: 99%

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

Rongen¹,

Smits²,

Donck³

et al. 1995

J. Clin. Invest.

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“…With the same treatment I h post-challenge only I out of 32 animals died. Myocardial lactate dehydrogenase isoenzyme levels in plasma were significantly lower than in the controls in both groups [71].…”

Section: In Vivo Modelsmentioning

confidence: 71%

Purine metabolism in the heart

Donck

1994

Pharm World Sci

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Adenosine has recently received much attention for the protection it provides against the deleterious effects of ischaemia reperfusion. Whenever the demand for oxygen exceeds its supply, adenosine triphosphate in myocytes is rapidly dephosphorylated to adenosine. Adenosine may then protect the myocardium against ischaemia-reperfusion damage. However, the accumulation of adenosine is limited by its rapid uptake and catabolism in the endothelium and in red blood cells. The strict compartmentalization of the enzyme pathways involved in the metabolism of adenosine, e.g. adenosine production by myocytes, its pharmacological action in the interstitium, its catabolism in the endothelium and in red blood cells, and its carrier-mediated transport across membranes, provides a unique target for pharmacological interventions. Blockade of adenosine uptake may indeed result in prolonged adenosine accumulation specifically in those regions of the heart where it is produced. In recent years considerable evidence has been gathered on the adenosine-mediated cardioprotective actions of nucleoside transport inhibitors.

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“…On the other hand, the enhancement of the action of adenosine by nucleoside transporter inhibitors is attributable to an inhibition of the influx of adenosine via a nucleoside transport pathway, thereby increasing the extracellular concentration of adenosine and enhancing the action of adenosine via the adenosine A1 receptor [10,11]. Previous studies [10,11,13] have demonstrated that nucleoside transport inhibitors prevent cardiac damage and contractile depression via the action of adenosine which protects reperfusion-induced injury in the myocardium. Further, other studies [14,15] have suggested that allopurinol (xanthine oxidase inhibitor) protects reperfusion-induced injury in the myocardium by inhibiting the action of xanthine oxidase and, thus, the generation of oxygen peroxide as well as the oxidation of hypoxanthine to uric acid via xanthine, although controversy exists [16].…”

Section: Discussionmentioning

confidence: 99%

Effect of TEI-6720, a Xanthine Oxidase Inhibitor, on the Nucleoside Transport in the Lung Cancer Cell Line A549

Yamamoto

Moriwaki²,

Fujimura³

et al. 2000

Pharmacology

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To examine the effect of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (TEI-6720), an inhibitor of xanthine oxidase, on purine metabolism in the lung cancer cell line A549, the activities of adenosine deaminase, purine nucleoside phosphorylase, adenine phosphoribosyltransferase, hypoxanthine guanine phosphoribosyltransferase, xanthine oxidase, and guanase together with pyrimidine nucleoside phosphorylase were measured with or without the addition of TEI-6720, and the extracellular concentrations of hypoxanthine, xanthine, inosine, uracil, and uridine were measured after the addition of inosine or uridine to the incubation medium with or without TEI-6720. Moreover, the Na-indepenent nucleoside transport was determined in A549 cells with or without TEI-6720. TEI-6720 inhibited the activity of xanthine oxidase in A549 cells, but did not affect other enzymes. During incubation, TEI-6720 not only prevented a decrease in the inosine concentration in inosine-containing medium, but also a decrease in the uridine concentration in uridine-containing medium. Furthermore, the Na-independent transport of uridine was inhibited by TEI-6720 with a K_i value of 4.1 μmol/l. These results indicate that TEI-6720 is an inhibitor of the Na-independent nucleoside transport of uridine and inosine, as well as xanthine oxidase.

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Prevention of Catecholamine-Induced Cardiac Damage and Death with a Nucleoside Transport Inhibitor

Cited by 30 publications

References 0 publications

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

Purine metabolism in the heart

Effect of TEI-6720, a Xanthine Oxidase Inhibitor, on the Nucleoside Transport in the Lung Cancer Cell Line A549

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