Effect of a Xanthine Oxidase Inhibitor on Adenine Nucleotide Degradation in Hemorrhagic Shock

Cunningham, S. K.; Keaveny, T. V.

doi:10.1159/000128020

Cited by 38 publications

(20 citation statements)

References 10 publications

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“…The lack of change in myocardial adenine nucleotides, in response to these procedures does, however, contrast with that of other tissues. Although no other measurements of nonmyocardial adenine nucleotides were made in the studies described in this paper, in the liver, kidney and intestine, under similar conditions, the adenine nucleotide content is markedly reduced, and this is prevented by allopurinol pretreatment (Chaudry et al, 1974;Hopkins et al, 1975;Cunningham & Keaveny, 1978). It therefore appears that there is some heterogeneity in the response of different tissues to haemorrhagic shock and reperfusion, and in the myocardium, at least, this does not involve changes in adenine nucleotide.…”

Section: Discussionmentioning

confidence: 65%

The protective action of allopurinol in an experimental model of haemorrhagic shock and reperfusion

Allan

Cambridge²,

Lee-Tsang-Tan

et al. 1986

British J Pharmacology

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Haemorrhagic shock was induced in anaesthetized, open‐chest dogs by controlled arterial bleeding, sufficient to reduce and maintain mean arterial blood pressure at 40 mmHg for 30 min. The blood volume was then restored to the pre‐shock level by rapid, intravenous reinfusion of the blood shed during the shock period. Haemorrhagic shock produced significant haemodynamic changes, characterized by a marked depression of myocardial function. Cardiac output (1226 ± 57 ml min−1), peak aortic blood flow (6030 ± 383 ml min−1) and maximum rate of rise of left ventricular pressure (2708 ± 264 mmHg s−1) were all reduced by more than 50%. The haemodynamic profile was markedly improved by reinfusion of shed blood but this improvement was not sustained. There was a gradual decline such that 50% of the untreated animals suffered complete circulatory collapse and death between 60 and 120 min following reinfusion. Neither haemorrhagic shock, nor reinfusion of shed blood produced any consistent or significant changes in the myocardial adenine nucleotide pool. The ATP, ADP and AMP levels were, respectively, 25.9 ± 4.2; 15.6 ± 1.0; 4.3 ± 1.9 nmol g−1 protein, before haemorrhagic shock; 21.6 ± 3.4; 21.5 ± 2.5; 10.2 ± 2.7 nmolg−1 protein, after 30min haemorrhagic shock; and 29.9 ± 3.9; 16.5 ±1.2; 4.2 ± 1.1 nmolg−1 protein, 60 min following reinfusion of shed blood. Pretreatment with allopurinol (50.0 mg kg−1 i.v.), 60 min before inducing haemorrhagic shock, had no significant effect upon the haemodynamic response to shock, but did prevent the gradual decline seen following reinfusion in the untreated animals. All of the allopurinol‐treated animals displayed significantly better haemodynamic profiles than the untreated animals, furthermore, there was a 100% survival rate in this group. Allopurinol had no significant effect upon the myocardial adenine nucleotide pool either during haemorrhagic shock or following reinfusion of shed blood.

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Section: Discussionmentioning

confidence: 65%

The protective action of allopurinol in an experimental model of haemorrhagic shock and reperfusion

Allan

Cambridge²,

Lee-Tsang-Tan

et al. 1986

British J Pharmacology

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“…Accordingly, it would be anticipated that the content of cellular high energy phosphates might decrease, leading to an increase in the serum concentration of hypoxanthine -a degradation product of intracellular nucleotides. The concentration of serum hypoxanthine is known to correlate inversely with the cellular energy state (the cellular high energy phosphate content) [23][24][25]. A similar ATP-depletion theory for the pathogenic mechanism of rhabdomyolysis in severely phosphate depleted patients has previously been proposed by Rowland [26].…”

Section: Discussionmentioning

confidence: 95%

Nontraumatic rhabdomyolysis during diabetic ketoacidosis

Møller-Petersen

Pt²,

Hjörne

et al. 1986

Diabetologia

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Summary. The frequency of nontraumatic rhabdomyolysis in diabetic ketoacidosis was investigated by serial measurements of the serum levels of myoglobin and the serum activity of creatine kinase isoenzyme MM in 12 consecutively admitted ketoacidotic patients. In 5 patients (Group 1) we found hypermyoglobinaemia and elevated activity of creatine kinase isoenzyme MM on admission to hospital, whereas these two variables were normal in 7 patients (Group 2). On admission significantly higher median blood glucose levels and higher median serum osmolality were found in Group 1 than in Group 2 (for blood glucose: 49.6 mmol/1 versus 19.0 mmol/1, p<0.02; for serum osmolality: 360mosm/kg H20 versus 315 mosm/kg H20, p <0.05). Decreased renal function was found in Group 1 as reflected by significantly higher betarmicroglobulin serum concentrations in Group 1 compared with Group 2 on admission (median values 4.1 mg/1 versus 1.7 mg/1, p < 0.01) and during the first 3 days of therapy. The serum concentration of hypoxanthine (an indicator of the cellular energy state) was elevated in all patients on admission, with no difference between patients with or without hypermyoglobinaemia. In conclusion, our findings suggest that nontraumatic rhabdomyolysis with hypermyoglobinaemia and elevated serum activity of creatine kinase isoenzyme MM may be a hitherto unrecognized common feature of diabetic ketoacidosis.

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“…This aberrant metabolic process damages the cell either through the generation of cytotoxic radicals (2 7 and H202) from xanthine oxidase, or through a depletion of cellular purine stores, which impairs the ability of the cells to maintain sufficient phosphate compounds for cell membrane integrity. Allopurinol, a xanthine oxidase inhibitor, has been repeatedly shown to increase the survival period in haemorrhagic shock in dogs (Crowell et al, 1969;Cunningham & Keaveny, 1978;Chambers et al, 1985) and rats (Cederna et al, 1990), and superoxide dismutase has been found to ameliorate splanchnic artery occlusion shock in rats (Bitterman et al, 1988). Favourable results have also been obtained with the spin-trapping agent PBN in a traumatic model of shock in rats (Novelli, 1992).…”

Section: Discussionmentioning

confidence: 99%

Influence of ACTH‐(1–24) on free radical levels in the blood of haemorrhage‐shocked rats: direct ex vivo detection by electron spin resonance spectrometry

Guarini

Bazzani

Ricigliano

et al. 1996

British J Pharmacology

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The influence of ACTH‐(1–24) on the blood levels of highly reactive free radicals in haemorrhagic shock was studied in rats. Volume‐controlled haemorrhagic shock was produced in adult rats under general anaesthesia (urethane, 1.25 g kg−1 intraperitoneally) by stepwise bleeding until mean arterial pressure stabilized at 20–23 mmHg. Rats were intravenously (i.v.) treated with either ACTH‐(1–24) (160 μg kg−1 in a volume of 1 ml kg−1) or equivolume saline. Free radicals were measured in arterial blood by electron spin resonance spectrometry using an ex vivo method that avoids injection of the spin‐trapping agent (α‐phenyl‐N‐tert‐butylnitrone). Blood levels of free radicals were 6490 ± 273 [arbitrary units (a.u.) ml−1 whole blood, before starting bleeding, and 30762 ± 2650 after bleeding termination (means ± s.e.mean of the values obtained in all experimental groups). All rats treated with saline died within 30 min, their blood levels of free radicals being 35450 ± 5450 a.u. ml−1 blood, 15 min after treatment. Treatment with ACTH‐(1–24) produced a rapid and sustained restoration of arterial pressure, pulse pressure, heart rate and respiratory function, with 100% survival at the end of the observation period (2 h); this was associated with an impressive reduction in the blood levels of free radicals, that were 12807 ± 2995, 10462 ± 2850, 12294 ± 4120, and 10360 ± 2080 a.u. ml−1 blood, 15, 30, 60 and 120 min after ACTH‐(1–24) administration, respectively. These results provide a direct demonstration that (i) in haemorrhagic shock there is a rapid and massive production of highly reactive free radicals, and that (ii) the sustained restoration of cardiovascular and respiratory functions induced by the i.v. injection of ACTH‐(1–24) is associated with a substantial reduction of free radical blood levels. It is suggested that ACTH‐(1–24) prevents the burst of free radical generation during blood mobilisation and subsequent tissue reperfusion, and this may be an important component of its mechanism of action in effectively preventing death for haemorrhagic shock.

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Effect of a Xanthine Oxidase Inhibitor on Adenine Nucleotide Degradation in Hemorrhagic Shock

Cited by 38 publications

References 10 publications

The protective action of allopurinol in an experimental model of haemorrhagic shock and reperfusion

The protective action of allopurinol in an experimental model of haemorrhagic shock and reperfusion

Nontraumatic rhabdomyolysis during diabetic ketoacidosis

Influence of ACTH‐(1–24) on free radical levels in the blood of haemorrhage‐shocked rats: direct ex vivo detection by electron spin resonance spectrometry

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