Xanthine oxidase is not a source of free radicals in the ischemic rabbit heart

Downey, James M.; Miura, Tetsuji; Eddy, Lynne J.; Chambers, David; Mellert, Tuesday K.; Hearse, David J.; Yellon, Derek M.

doi:10.1016/s0022-2828(87)80350-4

Cited by 119 publications

(32 citation statements)

References 16 publications

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“…To substantiate this cardioprotective activity we have monitored an attenuation of the ST-segment elevation, an accepted indicator of ischaemic injury (Kjekshus et al, 1972;Ross, 1976). The degree of cardioprotection exhibited by cloricromene is similar to that reported for iloprost (Chiariello et al, 1988), defibrotide (Thiemermann et al, 1989) and superoxide dismutase/catalase (Downey et al, 1987) using occlusion of the same branch of the coronary artery in the rabbit. Collectively, these results indicate that a reduction in infarct size of about 50% may represent the maximum protection achievable in this experimental model of severe myocardial ischaemia.…”

Section: Discussionsupporting

confidence: 79%

Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity

Lidbury

Cirillo

Vane

1993

British J Pharmacology

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1 Cloricromene is a non-anticoagulant coumarin derivative with anti-platelet and anti-leukocyte properties, which has beneficial effects in various models of ischaemia and shock. 2 We have assessed the effects of cloricromene on (a) ex vivo platelet aggregation, and (b) infarct size using a model of myocardial ischaemia in the anaesthetized rabbit.3 Cloricromene (1-1000 tgkg' min'I for 15min) induced a dose-dependent inhibition of ex vivo platelet aggregation, causing only a minimal increase in heart rate and no change in mean arterial blood pressure. The inhibitory activity was considerably stronger when platelet aggregation was induced by collagen than by ADP. 4 Cloricromene inhibited ex vivo platelet aggregation in rabbits pretreated with indomethacin (5 mg kg-') and this inhibition persisted for 30-60 min.5 The model of myocardial ischaemia involved 1 h occlusion of the first antero-lateral branch of the left coronary artery followed by 2 h of reperfusion. Infusion of cloricromene (30 or 300 gg kg-' min-'), ibuprofen (80 iLg kg-' min') or vehicle began 15 min prior to occlusion, and continued throughout the experiment.6 While area at risk was similar for all groups studied, cloricromene (30 or 300 ftg kg' min-') or ibuprofen caused a reduction in infarct size, and decreased myeloperoxidase activity in the tissue of the infarcted myocardium.7 Cloricromene at 300 pg kg-' min-' also reduced the occlusion-induced elevation of the ST-segment of the rabbit electrocardiogram, and inhibited platelet aggregation ex vivo. Ibuprofen or cloricromene at 30 fg kg-' min'-had no effect on either the ST-elevation or platelet reactivity.8 Thus, cloricromene exhibits a cardioprotective activity via an inhibition of leukocyte infiltration, in the presence (300 tLg kg-l min-') or absence (30 ltg kg'-min-') of inhibition of platelet activity ex vivo.The anti-aggregatory activity of cloricromene acts via a mechanism that is either different from, or in addition to, inhibition of cyclo-oxygenase, and is of long duration.

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Section: Discussionsupporting

confidence: 79%

Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity

Lidbury

Cirillo

Vane

1993

British J Pharmacology

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“…However, previous studies using spin-trapping techniques have demonstrated that free radicals are generated in porcine myocardium reperfused after 15 min of regional ischemia (19) as well as after 90 min of global hypothermic ischemia (53). Free radical generation after brief ischemia followed by reperfusion has also been documented in the rabbit heart (21,(54)(55)(56), which, like the porcine heart, lacks xanthine oxidase (57). There are a number of pathways that could lead to formation of reactive oxygen species in xanthine oxidasedeficient tissues, including activation of the arachidonate cascade, autoxidation of catecholamines and other compounds, accumulation of reducing equivalents, and mitochondrial respiration (36).…”

Section: Discussionmentioning

confidence: 99%

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Sun¹,

Tang²,

Park³

et al. 1996

J. Clin. Invest.

223

137

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Conscious pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, for three consecutive days (days 1, 2, and 3). On day 1, pigs received an i.v. infusion of a combination of antioxidants (superoxide dismutase, catalase, and N -2 mercaptopropionyl glycine; group II, n ϭ 9), nisoldipine (group III, n ϭ 6), or vehicle (group I [controls], n ϭ 9). In the control group, systolic wall thickening (WTh) in the ischemic-reperfused region on day 1 remained significantly depressed for 4 h after the 10th reperfusion, indicating myocardial "stunning." On days 2 and 3, however, the recovery of WTh improved markedly, so that the total deficit of WTh decreased by 53% on day 2 and 56% on day 3 compared with day 1 ( P Ͻ 0.01), indicating the development of a powerful cardioprotective response (late preconditioning against stunning). In the antioxidant-treated group, the total deficit of WTh on day 1 was 54% less than in the control group ( P Ͻ 0.01). On day 2, the total deficit of WTh was 85% greater than that observed on day 1 and similar to that observed on day 1 in the control group. On day 3, the total deficit of WTh was 58% less than that noted on day 2 ( P Ͻ 0.01). In the nisoldipine-treated group, the total deficit of WTh on day 1 was 53% less than that noted in controls ( P Ͻ 0.01). On days 2 and 3, the total deficit of WTh was similar to the corresponding values in the control group. These results demonstrate that: ( a ) in the conscious pig, antioxidant therapy completely blocks the development of late preconditioning against stunning, indicating that the production of reactive oxygen species (ROS) on day 1 is the mechanism whereby ischemia induces the protective response observed on day 2; ( b ) antioxidant therapy markedly attenuates myocardial stunning on day 1, indicating that ROS play an important pathogenetic role in postischemic dysfunction in the porcine heart despite the lack of xanthine oxidase; ( c ) although the administration of a calcium-channel antagonist (nisoldipine) is as effective as antioxidant therapy in attenuating myocardial stunning on day 1, it has no effect on late preconditioning on day 2, indicating that the ability of antioxidants to block late preconditioning is not a nonspecific result of the mitigation of postischemic dysfunction on day 1. Generation of ROS during reperfusion is generally viewed as a deleterious process. Our finding that ROS contribute to the genesis of myocardial stunning but, at the same time, trigger the development of late preconditioning against stunning supports a complex pathophysiological paradigm, in which ROS play an immediate injurious role (as mediators of stunning) followed by a useful function (as mediators of subsequent preconditioning). (

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“…Another, related question that arose was the following: Is there XO or an increase in XO in the reperfused heart? With respect to the specificity of allopurinol, Das and colleagues reported in 1987 that both allopurinol and oxypurinol exerted direct free radical scavenging effects in isolated hearts, and exerted cardioprotective effects despite no detectable XO activities in the preparations used (Das et al, 1987;Downey et al, 1987;Hopson et al, 1995). These findings were in stark contrast with other studies demonstrating detectable XO activities in reperfused hearts and its inhibition by allopurinol Brown et al, 1988;Terada et al, 1991;Werns et al, 1991;Ashraf and Samra 1993).…”

Section: Xanthine Oxidase and Myocardial Ischemia-reperfusion Injurymentioning

confidence: 99%

Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol

2006

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Xanthine oxidase is not a source of free radicals in the ischemic rabbit heart

Cited by 119 publications

References 16 publications

Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity

Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol

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