Effect of a new inhibitor of lipid peroxidation on kidney function after ischaemia-reperfusion. A study on rat and rabbit kidneys.

Lipid peroxidation of mitochondrial and cell membrane structures is the final step in the oxygen radical-induced damage observed at reperfusion of kidneys after ischaemia. We compared the ability of an indeno-indol compound (code name H290/51) with that of alpha-tocopherol to inhibit lipid peroxidation in reoxygenated isolated rat renal tissue in vitro measured as production of TBARS (thiobarbituric acid reactive substances). H290/51 was 100 times more efficient than alpha-tocopherol. Treatment of rats in vivo with H290/51 in a dosage giving a plasma concentration of 500 nmol L-1 inhibited TBARS production measured in vitro by 80%. Treatment of rabbits with H290/51 almost completely inhibited radical production at reperfusion after 60 min of ischaemia measured with spin trap technique using OXANOH (2-ethyl-3-hydroxy-2,4,4-trimethyloxazolidine) as a spin trap. Furthermore, such pretreatment significantly improved kidney function and survival of rabbits subjected to 60 min of ischaemia to the left kidney and contralateral nephrectomy. These studies stress the importance of inhibiting lipid peroxidation to prevent the ischaemia-reperfusion damage and furthermore suggest a role for treatment with antioxidants like H290/51 in clinical practice, e.g. at reconstructive renal surgery and transplantation.

A novel anti-oxidative agent improves recovery of the heart after cardiac arrest.

Experiments were designed to determine whether adding a synthetic anti-oxidative agent H 290/51 (cis-7methyl-9-methoxy-5,5 a,6,10 b-tetrahydroindeno [2,1-b] indole), to a crystalloid cardioplegic solution was beneficial for myocardial recovery and coronary reactivity in isolated rat hearts after six hours cold arrest. Two groups of hearts were single-flush perfused using the Langendorff technique (10 ml at 4 degrees C) with either Plegisol (St. Thomas' Hospital Solution) (n = 6) or Plegisol with H 290/51 (n = 6) added to a final concentration of 1 mummol/L. The heart were then stored for six hours in the respective solution at 4 degrees C. A third group of hearts (n = 6) were single-flush with Plegisol and reperfusion was immediately started (the 'non-stored' group). Before and after the arrest phase the hearts were perfused at constant pressure with Krebs-Henseleit bicarbonate buffer. To evaluate coronary vascular function, endothelium-dependent vasodilatation was induced with 5-hydroxy-tryptamine (5-HT) and smooth-muscle relaxation with nitroglycerin (GTN). Myocardial contractility after 30 min reperfusion, measured as left-ventricular developed pressure (LVDP), was significantly improved in hearts in the Plegisol+H 290/51 group compared to hearts in the Plegisol group (LVDP 89 +/- 8.5% vs 57.2 +/- 10.7% of prearrest values; p < 0.05). LVDP in hearts receiving Plegisol+H 290/51 was comparable to non-stored hearts (88.2 +/- 1.3%). The vasodilatory response to GTN was significantly reduced in hearts perfused with plain Plegisol (p < 0.05) but not in hearts receiving Plegisol+H 290/51 or in the non-stored hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute cobalt exposure and oxygen radical scavengers in the rat myocardium.

Excessive amounts of cobalt are cardiotoxic, although the mechanism for this toxicity remains unclear. We studied the effects of acute cobalt exposure on the activities of free radical scavengers in the myocardium in 5 groups of rats. Six rats served as a control group and were given a daily subcutaneous injection of 1 ml saline for 8 days. The other 4 groups of rats received a daily injection subcutaneously of cobalt chloride in doses of 1 mg/kg bw, 5 mg/kg bw, 20 mg/kg bw and 50 mg/kg bw, respectively for 8 days. There was a marked and dose-dependent accumulation of cobalt in the myocardium of the cobalt exposed rats. Creatine kinase, copper-zinc superoxide dismutase (CuZn-SOD) and alpha-tocopherol content did not differ between the control and the cobalt exposed groups. The activity of glutathione peroxidase increased, while the activity of manganese-superoxide dismutase (Mn-SOD) was significantly reduced in the cobalt exposed groups. There was an inverse relationship (r = 0.60, P < 0.0001) between the cobalt content and Mn-SOD activity in the myocardium. These results suggest that acute cobalt cardiotoxicity may involve a reduction of intrinsic scavengers resulting in an increased vulnerability to oxygen free radical toxicity.

Vascular bound recombinant extracellular superoxide dismutase type C protects against the detrimental effects of superoxide radicals on endothelium-dependent arterial relaxation.

Extracellular superoxide dismutase type C (EC-SOD C) is a secretory SOD isoenzyme that, in vivo, is bound to heparan sulfate proteoglycans in the glycocalyx of various cell types (e.g., endothelial cells) and in the connective tissue matrix. The aim of this study was to investigate the efficacy of vascular bound EC-SOD C in protecting arterial relaxation mediated by endothelium-derived relaxing factor (EDRF) against the inhibitory effects of superoxide radicals. For comparison, the effect of CuZn SOD was also studied. This SOD isoenzyme lacks affinity toward heparan sulfate and does not bind to cell surfaces. Rings from rabbit aorta were mounted in an organ bath and acetylcholine-induced endothelium-dependent relaxation was then studied in preparations precontracted with phenylephrine. Pyrogallol (10(-4) M), used to generate superoxide radicals, reduced the maximal relaxant effect of acetylcholine from about 65% to 25%. When present in the buffer throughout the experiment, CuZn SOD and EC-SOD C caused a concentration-dependent prevention of the pyrogallol effect on EDRF-mediated relaxation, with a half-maximal effect at about 100 units/ml (KO2 assay). In a second set of experiments, the arterial rings were preincubated with 8,000 units/ml CuZn SOD (50 micrograms/ml) or EC-SOD C (69 micrograms/ml) during 30 minutes, followed by washing, before the effect of pyrogallol on EDRF-mediated relaxation was studied in SOD-free buffer.(ABSTRACT TRUNCATED AT 250 WORDS)