Nitric oxide blockade enhances renal responses to superoxide dismutase inhibition in dogs

To examine the potential role of superoxide anion (O(2)(-)) and its interaction with NO in the regulation of renal hemodynamics and excretory function, we have evaluated the renal responses to enhancement in O(2)(-) activity before and during NO synthase inhibition in anesthetized dogs (n=6). Intraarterial infusion of a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DETC; 0.1 and 0.5 mg/kg per min) was made to enhance O(2)(-) activity in the kidney. Cortical (CBF), medullary (MBF), and total renal blood flow (RBF) responses were assessed using laser-Doppler needle flow probes and an electromagnetic flow probe. DETC caused dose-dependent changes in renal parameters, which were recovered within 30 minutes after the termination of DETC infusion. The high-dose infusion of DETC for 25 minutes resulted in an increase of 29 +/- 10% in renal vascular resistance (control, 35.4 +/- 4.4 mm Hg/mL per min per g) and decreases of 21 +/- 5% in RBF (control, 3.5 +/- 0.5 mL/min per g), 20 +/- 5% in CBF, 21 +/- 7% in MBF, 62 +/- 11% in urine flow (control, 10.5 +/- 2.2 microL/min per g), and 47 +/- 11% in sodium excretion (control, 2.1 +/- 0.2 micromol/min per g), without a significant change (-10 +/- 6%) in glomerular filtration rate (control, 0.74 +/- 0.09 mL/min per g). During NO synthase inhibition with intraarterial administration of nitro-L-arginine (50 microg/kg per min), the same dose of DETC showed a greater increase in renal vascular resistance (73 +/- 15%) and reductions in RBF (39 +/- 4%), CBF (32 +/- 5%), MBF (34 +/- 6%), urine flow (78 +/- 5%), and sodium excretion (67 +/- 0%), with a marked reduction in glomerular filtration rate (59 +/- 7%). These data indicate that O(2)(-) exerts renal vasoconstriction as well as antidiuretic and antinatriuretic effects. These responses are enhanced during NO synthase blockade, suggesting that NO serves a renoprotective effect against these action of O(2)(-).     

Comparison of isollurane with sodium nitroprusside for controlling hypertension during thoracic aortic cross-clamping

The aims of this randomized study were (1) to determine if isoflurane is effective in controlling blood pressure during thoracic aortic cross-clamping, and (2) to compare its effects on hemodynamics and oxygen transport to those of sodium nitroprusside. Sodium nitroprusside (SNP group, n = 10) or isoflurane (ISO group, n = 10) was started 2 minutes before cross-clamping and was adjusted to maintain systolic arterial pressure as near as possible to preinduction values. The duration of thoracic aortic cross-clamping was 26 ± 4 minutes in the SNP group and 30 ± 4 minutes in the ISO group. Administration of isoflurane and sodium nitroprusside was stopped 2 minutes before unclamping. The same anesthetic technique using fentanyl, 6 μg/kg, flunitrazepsm, 0.02 mg/kg, pancuronium, 0.1 mg/kg, and 50% N₂O was used for all patients. At the time of clamping, either isoflurane (maximal expired concentration, 2.6% ± 0.3%) or sodium nitroprusside (cumulative dose, 11.1 ± 1.0 mg) was effective in maintaining the systolic blood pressure below 160 mm Hg, whereas the pulmonary capillary wedge pressure did not change. However, only SNP was able to bring the arterial pressure above the cross-clamp back to postinduction levels. During clamping, stroke index values were similar in both groups, but cardiac index increased only in patients receiving SNP. In both groups, at clamping and unclamping, PvO₂ was higher than postinduction values, indicating that throughout the study the oxygen needs of the perfused area were adequately met. There was no evidence of acute left ventricular decompensation because pulmonary capillary wedge pressures did not abruptly increase, nor did pulmonary edema occur. It is concluded that isoflurane added to fentanyl anesthesia is acceptable for thoracic aortic aneurysm surgery because it allows safe and effective control of hypertension during clamping without compromising hemodynamics and oxygen transport.     

尼莫地平、环磷酰胺、SOD联合治疗大鼠脑缺血再灌注损伤疗效分析

目的研究尼莫地平、环磷酰胺和超氧化物歧化酶（SOD）联合治疗对大鼠脑缺血再灌注损伤的保护作用。方法93只成年雄性Wistar大鼠随机分成：单药治疗组（A、B、组）、二联药物治疗组（D、E、F组）、三联药物治疗组（G组）及对照组（H组）。线栓法制作大鼠MCAO模型,再灌注前20 min、再灌注后12 h和36 h尾静脉给药。缺血4 h再灌注48 h后计算大鼠存活率、神经功能评分和脑梗死体积。结果与对照组相比,联合药物治疗组的大鼠存活率显著增加,神经功能缺损明显减少,脑梗死体积明显减少（P〈0.05或P〈0.01）。结论SOD、尼莫地平、环磷酰胺联合治疗抗脑缺血再灌注损伤效果显著,疗效优于两种药物联合治疗与单药治疗。     

CuZn superoxide dismutase, Mn superoxide dismutase, catalase and glutathione peroxidase in lymphocytes and erythrocytes in insulin-dependent diabetic children

CuZn superoxide dismutase, Mn superoxide dismutase, catalase and glutathione peroxidase activities in lymphocytes and erythrocytes were studied in 9 children with insulin-dependent diabetes mellitus (IDDM) as well as in 21 healthy children. The mean erythrocyte CuZn superoxide dismutase and glutathione peroxidase were statistically significantly lower in the IDDM group compared with the controls although almost all IDDM results fell within the mean +/- 2 SD limits of the controls. The small differences found can hardly be assigned biological significance. Erythrocyte catalase as well as lymphocyte CuZn superoxide dismutase and Mn superoxide dismutase did not differ from the controls.     

Manganese-containing superoxide dismutase in blood and urine during open-heart surgery.

Concentrations of Manganese-containing superoxide dismutase (Mn-SOD) were measured perioperatively by enzyme immunoassay in serial samples of arterial and coronary sinus blood and urine taken from 18 patients undergoing mitral valve surgery. The mean Mn-SOD concentration in the arterial blood samples was 66.2 (SD 16.1 ng/ml) at induction of anesthesia, increased gradually after reperfusion and peaked on the 2nd post-operative day [150 (SD 58.3) ng/ml]. The mean concentration of Mn-SOD in the coronary sinus blood samples was significantly higher than in the arterial samples only at the 6th hour after reperfusion [97 (SD 21.8) ng/ml vs 90.3 (SD 20.9) ng/ml, p < 0.05]. Although concentrations of Mn-SOD in blood did not increase in 8 patients who underwent midline sternotomy for a mediastinal tumor, they increased dramatically in 3 patients who sustained a perioperative myocardial infarction. During open heart surgery the peak values of plasma Mn-SOD concentrations were correlated to that of plasma creatine kinase-MB concentrations (r = 0.5532, n = 18, p < 05) and cardiac ischemic period (r = 0.5186, n = 18, p < 05). Although the meaning of an increase in plasma Mn-SOD concentrations during open heart surgery is not clarified, it may be released from the heart and anywhere also in the body damaged during cardiopulmonary bypass.     

Effect of superoxide dismutase on infarct size and postischemic recovery of myocardial contractility and metabolism in dogs

The effects of superoxide dismutase treatment on infarct size, postischemic recovery of contractile function and tissue content of high energy phosphates were examined in a canine model of myocardial ischemia and reperfusion. Ischemia was induced by thrombotic occlusion of a coronary artery and reperfusion was achieved by intravenous thrombolysis. Average duration of ischemia was 90 min. Fifty closed chest anesthetized dogs were randomized to receive either superoxide dismutase (34,000 IU/min intravenously) or placebo, starting approximately 30 min before and continuing for 30 min into the reperfusion phase. Left ventricular ejection fraction and regional segmental shortening of the postischemic area were calculated from contrast angiograms after 4 h, 48 h and 1 week of reperfusion. Tissue content of high energy phosphates was determined from transmural biopsy after 4 h and 1 week. Infarct size was measured by planimetry of dye-stained heart slices. In the superoxide dismutase and placebo-treated groups, respectively, the mortality rate was 25% and 16%, collateral flow 20 +/- 10 and 23 +/- 18 ml/min per 100 g, area at risk 25 +/- 6% and 26 +/- 7% of the left ventricle and infarct size 28 +/- 19% and 36 +/- 27% of the area at risk. Multiple regression analysis failed to show any beneficial effect of superoxide dismutase treatment on infarct size. Left ventricular ejection fraction, regional segmental shortening of the postischemic area and tissue content of high energy phosphates recovered to a similar extent and at a similar rate in both treated and placebo groups up to 1 week after reperfusion. Thus, in this model of coronary occlusion and reperfusion superoxide dismutase treatment is of no benefit.     

Comparison of unipolar and bipolar ventricular paced evoked responses

Objectives—To study the differences between endocardial bipolar and unipolar ventricular paced evoked responses and surface electrocardiograms.

Patients—10 patients with conduction system disease awaiting insertion of a permanent pacemaker were studied with temporary ventricular pacing from the right ventricular apex.

Main outcome measure—Comparison of the durations of the QRS complexes and QTa and QTe intervals of the endocardial bipolar paced evoked response and the surface electrocardiogram with those of the reference unipolar paced evoked response.

Results—By comparison with the unipolar reference, the mean durations of the QRS complexes of the bipolar signal and the surface electrocardiogram were 41·8% and 132·1% respectively. The mean QTa interval was 85·9% and 112·2% respectively and the mean QTe interval was 86·9% and 109·5% respectively. All these differences were significant. The amplitudes of the unipolar QRS complexes and T waves were significantly larger than those recorded in the bipolar configuration.

Conclusions—Differences between the unipolar and bipolar ventricular paced evoked responses are significant. The time course of the unipolar signal is closer to that of the surface electrocardiogram. This indicates that the unipolar paced evoked response does not reflect local electrophysiological events, as has been suggested previously.

     

Comparison of unipolar and bipolar ventricular paced evoked responses

Objectives—To study the differences between endocardial bipolar and unipolar ventricular paced evoked responses and surface electrocardiograms.Patients—10 patients with conduction system disease awaiting insertion of a permanent pacemaker were studied with temporary ventricular pacing from the right ventricular apex.Main outcome measure—Comparison of the durations of the QRS complexes and QTa and QTe intervals of the endocardial bipolar paced evoked response and the surface electrocardiogram with those of the reference unipolar paced evoked response.Results—By comparison with the unipolar reference, the mean durations of the QRS complexes of the bipolar signal and the surface electrocardiogram were 41·8% and 132·1% respectively. The mean QTa interval was 85·9% and 112·2% respectively and the mean QTe interval was 86·9% and 109·5% respectively. All these differences were significant. The amplitudes of the unipolar QRS complexes and T waves were significantly larger than those recorded in the bipolar configuration.Conclusions—Differences between the unipolar and bipolar ventricular paced evoked responses are significant. The time course of the unipolar signal is closer to that of the surface electrocardiogram. This indicates that the unipolar paced evoked response does not reflect local electrophysiological events, as has been suggested previously.     

Oxidative stress and superoxide dismutase in development, aging and gene regulation

Free radicals and other reactive oxygen species are produced in the metabolic pathways of aerobic cells and affect a number of biological processes. Oxidation reactions have been postulated to play a role in aging, a number of degenerative diseases, differentiation and development as well as serving as subcellular messengers in gene regulatory and signal transduction pathways. The discovery of the activity of superoxide dismutase is a seminal work in free radical biology, because it established that free radicals were generated by cells and because it made removal of a specific free radical substance possible for the first time, which greatly accelerated research in this area. In this review, the role of reactive oxygen in aging, amyotrophic lateral sclerosis (a neurodegenerative disease), development, differentiation, and signal transduction are discussed. Emphasis is also given to the role of superoxide dismutases in these phenomena.     

Comparison of unipolar and bipolar ventricular paced evoked responses.

OBJECTIVES--To study the differences between endocardial bipolar and unipolar ventricular paced evoked responses and surface electrocardiograms. PATIENTS--10 patients with conduction system disease awaiting insertion of a permanent pacemaker were studied with temporary ventricular pacing from the right ventricular apex. MAIN OUTCOME MEASURE--Comparison of the durations of the QRS complexes and QTa and QTe intervals of the endocardial bipolar paced evoked response and the surface electrocardiogram with those of the reference unipolar paced evoked response. RESULTS--By comparison with the unipolar reference, the mean durations of the QRS complexes of the bipolar signal and the surface electrocardiogram were 41.8% and 132.1% respectively. The mean QTa interval was 85.9% and 112.2% respectively and the mean QTe interval was 86.9% and 109.5% respectively. All these differences were significant. The amplitudes of the unipolar QRS complexes and T waves were significantly larger than those recorded in the bipolar configuration. CONCLUSIONS--Differences between the unipolar and bipolar ventricular paced evoked responses are significant. The time course of the unipolar signal is closer to that of the surface electrocardiogram. This indicates that the unipolar paced evoked response does not reflect local electrophysiological events, as has been suggested previously.     

Definition of the safe lower limits of aortic resection during surgical procedures on the thoracoabdominal aorta: use of somatosensory evoked potentials

The technique of intraoperative monitoring of somatosensory evoked potentials was applied to a canine model of spinal cord ischemia in an attempt to determine the safe lower limits of aortic resection during thoracic aortic surgery. Fifteen animals underwent left thoracotomy with institution of partial left atrial/femoral artery bypass for maintenance of distal aortic perfusion after proximal descending thoracic aortic exclusion. In Group I animals (n = 6, control), no further interventions were performed so that the effect of exclusion of vessels noncritical to spinal cord blood supply could be assessed by measurements of spinal cord blood flow and somatosensory evoked potentials. In Group II animals (n = 8), the level of distal aortic exclusion was progressively lowered until loss of somatosensory evoked potential (critical vessel exclusion) occurred. The effect of critical vessel exclusion on spinal cord blood flow was then assessed. Exclusion of multiple vessels noncritical to spinal cord blood supply (Group I) had no effect on spinal cord blood flow or function (somatosensory evoked potentials). Exclusion of vessels critical to spinal cord blood supply resulted in significant spinal cord ischemia (83.4% flow reduction, probability [p] less than 0.05 versus baseline) and ischemic spinal cord dysfunction (loss of somatosensory evoked potential).(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of human immune responses to the cytosolic superoxide dismutase and glutathione S-transferase from Onchocerca volvulus

In onchocerciasis patients and in O. volvulus -exposed individuals without signs of onchocerciasis, T- and B-cell responses to two recombinantly expressed O. volvulus enzymes were analysed and compared to responses to total protein extract of adult parasites. The cytosolic enzymes Cu/Zn superoxide dismutase 1 (OvSOD1) and glutathione S-transferase 2 (OvGST2) represent 2 detoxifying molecules which may play an important role in parasite defense against host-induced oxidative stress. The T-cell response to the two recombinant proteins was analysed by investigating the cytokine responses of peripheral blood mononuclear cells. Induction of IL-5 at the mRNA level and IL-5 and IL-10 at the protein level was demonstrated in patients with the generalized form of onchocerciasis and endemic normals without clinical manifestations. IFN-γ was not found to be induced by either antigen. This pattern of lymphokine expression is indicative of a Th2-type response. Compared to patients with the generalized form, a higher level of cytokine induction was observed in the group of endemic normals. Low but significant IgG levels were observed against OvSOD1 in patients with onchocerciasis; higher antibody levels were found against OvGST2 in patients and endemic normals. The highest IgG levels were detected against the crude O. volvulus extract. These results indicate that the two recombinant O. volvulus proteins induce moderate T and B cell responses.     

Expression of manganese superoxide dismutase in esophageal and gastric cancers

The tumor-killing activity of radiotherapy and chemotherapy for cancer is closely associated with the production of active oxygen, and the relation between therapeutic resistance and active oxygen scavengers produced by the tumor itself is gaining more attention. It is considered that manganese superoxide dismutase (MnSOD) protects host cells from oxidative stress, in synergy with other antioxidant enzymes. In this study, we used a quantitative polymerase chain reaction assay to measure MnSOD mRNA in resected specimens from patients with esophageal and gastric cancers. In both esophageal and gastric cancers, the level of MnSOD mRNA was significantly elevated in cancer tissue compared to non-cancer tissue (P < 0.01). In gastric cancer tissue, the MnSOD mRNA level was significantly higher than in esophageal cancer tissue (P < 0.01). The significance of MnSOD in cancer tissue was investigated further by measuring MnSOD content in resected specimens using an enzyme-linked immunosorbent assay, and by examining its location by an immunohistochemical method. Upregulation of MnSOD in cancer tissue most likely serves as a protective mechanism against anti-cancer therapies known to produce superoxide radicals as a key component of their tumor-killing activity. (Received June 30, 1997; accepted June 26, 1998)     

The role of manganese superoxide dismutase in health and disease

Manganese superoxide dismutase (MnSOD) is the mitochondrial enzyme that disposes of superoxide generated by respiratory chain activity. Of all electrons passing down the mitochondrial respiratory chain, 1–2% are diverted to form superoxide; thus production of hydrogen peroxide occurs at a constant rate due to MnSOD activity. Mice lacking MnSOD develop cardiomyopathy and basal ganglia lesions, have no lipid peroxidation products, but show destruction of enzymes with 4Fe–4S centres. Patients with complex I (NADH-CoQ oxidoreductase) deficiency show variable hyperinduction of MnSOD that is at least partially dependent on the extent of disturbance of redox state. This in turn appears to result in production of excess hydroxyl radicals, which are damaging to proteins, lipids and DNA. An alternative method of protection from oxygen radicals is employed by complex I-deficient cell types that do not induce MnSOD in that they show induction of the bcl-2 protein.