Superoxide dismutase: pharmacological developments and applications.
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Down Syndrome↗
Biomedical subjects
B A Omar
Publications and source records attributed to B A Omar.
Interstitial equilibration of superoxide dismutase correlates with its protective effect in the isolated rabbit heart.
We examined the effect of preischemic equilibration of the rabbit heart with superoxide dismutase (SOD) on the extent of recovery of contractile function following an episode of ischemia. First, hearts were perfused with Krebs-Henseleit buffer. The pulmonary artery was cannulated and its flow diverted as the vascular effluent, and all other orifices were tied off. The fluid seeping from the epicardial surface represented the interstitial outflow. SOD was added to the perfusate and the interstitial and vascular effluents were assayed for SOD at regular intervals. Second, hearts were perfused in the Langendorff mode. SOD was included in the perfusate at all times at 20,000 U/l. After either 15 or 50 min of equilibration the hearts were subjected to 1 h of ischemia followed by 1 h of reperfusion. The developed tension was measured via a balloon in the left ventricle. Control hearts showed a recovery of developed tension of 63 +/- 12%. Human recombinant (h) Cu,Zn-SOD, which equilibrated with the interstitial fluid by 20 +/- 10% and 92 +/- 7% after 15 and 60 min of perfusion respectively, caused a recovery of 68 +/- 29% (non-significant) and 92 +/- 18% (P less than 0.01) with 15 and 50 min of equilibration respectively. The positively charged hrMn-SOD and sheep Cu,Zn-SOD, however, equilibrated much faster reaching 84 +/- 13% and 95 +/- 11% at 15 min respectively, which correlated with a recovery of 99 +/- 11% and 96 +/- 10% (P less than 0.01) respectively. HrCu,Zn-SOD conjugated to polyethylene glycol equilibrated much slower reaching 38 +/- 10% after 1 h, which correlated with lack of protection even after 50 min of equilibration. Therefore, the protection afforded by SOD to the isolated rabbit heart correlates with the concentration of SOD in the interstitial fluid. The rate of equilibration depends on the charge as well as the size of the enzyme.
Analysis of Variance↗
Ischemic preconditioning is not mediated by free radicals in the isolated rabbit heart.
Preconditioning has been implicated to involve a free radical mechanism in the in vivo infarct size model. We have demonstrated preconditioning in the isolated rabbit heart and studied the effect of Mn-superoxide dismutase (SOD) on preconditioning. Buffer perfused control hearts (C) were subjected to 1-h global ischemia followed by 1-h reperfusion, and the percent recovery of developed tension (%DT; relative to preischemic) was measured via a left ventricular balloon connected to a polygraph recorder. The coronary effluent was assayed for lactate dehydrogenase release (LDH; IU/kg BW). Preconditioned hearts (P) received a single episode of 5-min ischemia and 5-min reperfusion before 1 h of ischemia and reperfusion. SOD treated hearts received SOD at 5 mg/L in the buffers at all times. The results show that while SOD attenuated enzyme release and functional loss in control hearts, it had no effect on preconditioned hearts. Therefore, preconditioning is unlikely to be mediated by superoxide anion in the isolated rabbit heart.
Animals↗
Cardioprotection by Cu,Zn-superoxide dismutase is lost at high doses in the reoxygenated heart.
Limited dose-response curves for superoxide dismutase (SOD) were assessed in isolated and in vivo hearts. SOD at 2.3, 7, 20, or 50 mg/L suppressed CK release in Langendorff rat hearts by 61%, 63%, 72%, and 30%, respectively. SOD at 0.5, 1, 5, and 50 mg/L suppressed LDH release in Langendorff rabbit hearts by 32%, 48%, 54%, and -12%, respectively. In rabbit hearts subjected to coronary artery ligation and reperfusion in vivo, SOD at 2, 5, or 15 mg/kg reduced infarct size by 10%, 30% or 19%, respectively, while 50 mg/kg increased infarct size by 28%. In conclusion, while SOD was protective at low doses in all models, protection was lost at higher doses in the isolated rat and rabbit hearts, and exacerbation of damage was seen in the in vivo rabbit hearts.
Animals↗
The cardioprotective effect of Mn-superoxide dismutase is lost at high doses in the postischemic isolated rabbit heart.
The loss of protection by human recombinant (hr) Cu.Zn-superoxide dismutase (SOD) at higher doses reported previously may have been due to the weak peroxidase activity of this enzyme. To test this possibility we studied the dose-response relationship of hrMn-SOD, which lacks peroxidase activity. Isolated, buffer perfused rabbit hearts were subjected to 1 h of global ischemia followed by 1 h of reperfusion, and the percent recovery of developed tension (relative to preischemic) was measured via a left ventricular balloon connected through a pressure transducer to a polygraph recorder. The coronary effluent was assayed for lactate dehydrogenase (LDH) release. While hrMn-SOD almost completely protected against loss of function and LDH release at 2 and 5 mg/L (p less than 0.01), it exacerbated the damage at 50 mg/L concentration (p less than 0.05 against controls), thus giving an even sharper bell-shaped curve than seen with the hrCu,Zn-SOD. Therefore we conclude that, first, while the hrMn-SOD protects the reperfused heart at lower doses, it may exacerbate the damage at higher doses. Second, that the lack of protection seen at higher doses of hr-Cu,Zn-SOD is unlikely to be due only to its peroxidase activity.
Animals↗