Role of the nitric oxide pathway in ischemia-reperfusion injury in isolated perfused guinea pig lungs.

We examined the role of the nitric oxide (NO) pathway on ischemia-reperfusion injury via the use of isolated perfused guinea pig lungs. We administered both L-Arginine and N-nitro-L-arginine methyl ester (L-NAME) to the lungs in or after 3 h of ischemia. We observed pulmonary artery pressures as well as tissue and perfusate malondialdehyde (MDA) and glutathione (GSH) levels. We observed that L-NAME significantly increased both tissue and perfusate GSH levels and pulmonary artery pressures, but it decreased both tissue and perfusate MDA levels. On the other hand, L-arginine significantly decreased pulmonary artery pressure and both tissue and perfusate glutathione levels, but it increased both tissue and perfusate MDA levels. Electron microscopic evaluation supported our findings by indicating the preservation of lamellar bodies of type II pneumocytes. We concluded that L-NAME administration during reperfusion improves lung recovery from ischemic injury.

Effects of melatonin in reducing the toxic effects of doxorubicin.

Anthracycline antibiotics, such as doxorubicin and daunorubicin, constitute a group of wide spectrum therapeutic agents. Application of these drugs in chemotherapy is limited because of their toxic effects. Melatonin, the main secretory product of pineal gland, was recently found as a free radical scavenger and antioxidant. We decided to evaluate the tissue protective effect of melatonin against toxic effects of doxorubicin in six groups of rats. Rats were given doxorubicin (Dx) (45 mg/kg dose), melatonin (MEL) (10 mg/kg), first doxorubicin and then melatonin (DM), first melatonin and then doxorubicin (MD). The degree of kidney, lung, liver and brain cells' alterations were examined biochemically. In doxorubicin-treated group, malondialdehyde (MDA) levels of kidney, lung, liver and brain tissues were significantly increased but glutathione (GSH) levels were decreased compared to control rats. In the group in which first doxorubicin and then melatonin were given, MDA levels were significantly decreased compared to the doxorubicin-treated group. In doxorubicin-treated group, serum levels of creatinine, uric acid, blood urea nitrogen (BUN), Gamma-glutamyl transpeptidase (GGT) and Lactic acid dehydrogenase (LDH) were significantly increased while serum albumin and total protein levels were significantly decreased compared to control rats. Melatonin decreased the intensity of the changes produced by the administration of doxorubicin alone. Melatonin was quite efficient in reducing the formation of lipid peroxidation, restoring the tissue GSH contents and alterations of serum levels.

Prevention of doxorubicin-induced cardiotoxicity by melatonin.

Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents. Cardiotoxicity made by these agents develops as a complication of the cancer chemotherapy. Melatonin, the chief secretory product of the pineal gland, was recently found to be a free radical scavenger and antioxidant. We decided to evaluate the tissue-protective effect of melatonin against myocardial toxic effects of doxorubicin in six groups of rats. Rats were given doxorubicin (Dx) (45 mg/kg dose) and melatonin (MEL) (10 mg/kg), first doxorubicin and then melatonin (DM), first melatonin and then doxorubicin (MD). The degree of cardiac muscle cell alterations were examined either histologically (mean total score technique) or biochemically. In doxorubicin-treated group, malondialdehyde (MDA) levels of the heart tissue were significantly increased, glutathione (GSH) levels were decreased compared to the control rats. In the group in which first doxorubicin and then melatonin was given, MDA levels were significantly decreased and glutathione (GSH) levels were increased compared to the doxorubicin-treated group. During ultrastructural analysis, in doxorubicin-treated group, cellular edema, mitochondrial deformation, decreased glycogen stores, and disordered myofibrillary structure were observed. In contrast, in first doxorubicin and then melatonin-treated group, normal cellular structure was observed. But, first melatonin and then doxorubicin-treated group was not significantly preserved from the doxorubicin-induced changes. By preventing lipid peroxidation and myocardial lesions, melatonin may be highly effective in protecting against doxorubicin-induced cardiotoxicity.

Effects of ischemic preconditioning in human heart.

BACKGROUND: The aim of this study is to investigate the effects of ischemic preconditioning (IP) on myocardium and the level of nitric oxide (NO) in patients undergoing aorta-coronary bypass surgery. METHODS: Twenty consecutive patients with coronary artery disease were subjected into two equal groups; the IP group and the control group. Following the onset of cardiopulmonary bypass in the study group, hearts were preconditioned with two 3-minute periods of cross-clamping separated by 2 minutes of reperfusion. In the control group, cardiopulmonary bypass was continued for 10 minutes without using cross-clamp. Arterial and coronary sinus blood samples were used to determine serum NO, malondialdehyde (MDA), creatine phosphokinase-MB (CKMB), and lactate dehydrogenase (LDH) levels. Need for defibrillation after cross-clamp removal, ECG changes, postoperative arrhythmias, ejection fraction, and fractional shortening rates were recorded as hemodynamic data. RESULTS: Serum NO level was higher in the study group 5 minutes after aortic clamp removal (199.3 +/- 92.7 vs. 112.2 +/- 35.8 micromol; p = 001). Serum MDA (2.55 +/- 0.4 vs. 4.06 +/- 0.5; etamol/ml; 5 minutes after the aortic clamp removal; p = 0.0002); CK-MB (22.8 +/- 2.5 vs. 37.4 +/- 4.1; U/L 12 hours after the operation, p < 0.0001), and LDH (501.8 +/- 46.7 vs. 611.4 +/- 128.3; IU/L 48 hours after the operation, p = 0.02) levels were significantly lower in the preconditioned group when compared with the control group. Also, need for electrical defibrillation was significantly lower in the study group; Ejection fraction (64.3 +/- 6.3 vs. 57.6 +/- 7.6; p = 0.04) and fractional shortening (31.7 +/- 3.9 vs. 26.2 +/- 4.0; p = 0.04) rates were better in the study group postoperatively. CONCLUSIONS: These data may suggest that cardioprotection by ischemic preconditioning offers higher NO production, a lower myocardial ischemia, and better functional recovery of the hearts in coronary artery surgery patients.

Effects of simvastatin treatment on oxidant/antioxidant state and ultrastructure of streptozotocin-diabetic rat lung.

In the present study, we investigated the effects of simvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, on lipid metabolism, lipid peroxidation, antioxidant enzyme activities and ultrastructure of diabetic rat lung. Diabetes was induced by a single injection of streptozotocin (45 mg kg(-1), i.p.). After 8 weeks induction of diabetes, some control and diabetic rats were treated with simvastatin (10 mg kg(-1) rat day(-1); orally) for 4 weeks. Diabetes resulted in significantly high levels of blood glucose and plasma lipids. Malondialdehyde levels were unchanged after 12-week-old diabetic rats, whereas catalase activity significantly decreased in the lung. Glutathione peroxidase activity and nitric oxide level were significantly elevated in the diabetic lung. Histological analysis of the diabetic lung revealed some deterioration in the structure. Simvastatin treatment reduced plasma lipid levels and partially decreased the severity of hyperglycaemia. Catalase, glutathione peroxidase activities and nitric oxide levels were partially restored and accompanied by improved structure in diabetic lung by the simvastatin treatment. These results suggest that structural disturbances and alteration of antioxidative enzyme activities occurred in diabetic lung. Simvastatin treatment may provide some benefits in the maintenance of antioxidant status and structural organization of diabetes-induced injury of lung.