Free radical scavenging properties of ?-adrenoceptor blockers are not relevant for cardioprotection in isolated rabbit hearts (original) (raw)
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Naunyn-Schmiedeberg's Archives of Pharmacology, 1994
Catecholamines have been demonstrated to be cardiotoxic. Besides hemodynamic alterations, oxygen free radicals generated by the auto-oxidation of catecholamines might contribute to their deleterious effects. We examined the influence of exogenous norepinephrine (NE), after inhibiting functional alterations by alpha and beta-adrenoceptor blockade, on acute regional ischemia (MI). Method: We used isolated electrically-driven rabbit hearts with depleted catecholamine stores (reserpine 7.0 mg/kg i.p. 16-24 h before preparation, Langendorff, constant pressure: 70cm H20, Tyrode solution, Ca 2+ 1.8 retool/l, 37°C, 185-200 beats/rain). Repetitive MI, separated by a reperfusion period of 50 min, was induced by coronary artery branch ligature and quantitated from epicardial NADH-fluorescence photography. Starting after a reperfusion period of 20 min, isolated hearts were treated with NE (10 -6 M), in the presence of propranolol (10-6M), phentolamine (10-6M) and vitamin C (3 × 10 -s M) in the perfusion buffer to prevent the functional effects of NE. The influence of the free radical scavenger superoxide dismutase (SOD) (30 U/ml) or captopril (10 .6 M) on MI was also examined. Results: Left ventricular pressure or coronary flow were not significantly affected by either treatment (p > 0.05). Epicardial NADH-fluorescence area and intensity were, however, significantly enhanced by NE (+22°7o) (P<0.05), although propranolol, phentolamine and vitamin C had no significant influence on MI (P>0.05). SOD had no significant effect on MI in control hearts (P> 0.05) but completely prevented MI enlargement by NE (P> 0.05). Captopril did not significantly affect MI in control hearts and did not inhibit MI enlargement by NE (P< 0.05). Conclusion: NE has deleterious effects ,on MI in isolated rabbit hearts that are independent of functional alterations. This MI enlargement by NE is mediated by superoxide anion radicals since it could be prevented by SOD. Free radical scavenging properties reported for vitamin C, propranolol or captopril in several in-vitro systems are unef-Correspondence to: A. E E. Rump at the above address fective in preventing NE cardiotoxicity mediated by oxygen free radicals in isolated rabbit hearts.
The Role of Antioxidant Drugs in Oxidative Injury of Cardiovascular Tissue
1999
For more than a decade, our laboratory has investigated the signi~cance of oxygen derived-free radicals during myocardial ischemia/reperfusion in several animal and clinical [7] models. We have also studied the antioxidant properties of cardiovascular drugs in vitro and in vivo and have assessed their ability to inhibit myocardial injury . Over the years, other laboratories have corroborated our~ndings. Animal studies and limited clinical observations have also lent support to the importance of antioxidant therapy for certain cardiovascular diseases including cardiomyopathy. By no means comprehensive, this communication serves as a brief review of these efforts for selected groups of pharmacological agents with antioxidant activities and their potential clinical relevance.
Free radicals in ischemic myocardial injury
Journal of Free Radicals in Biology & Medicine, 1985
Myocardial ischemia causes release of chemotactic factors, migration of neutrophils, peroxidation of lipids, and depletion of free radical scavengers. The invading neutrophils may injure the myocardial vasculature and sarcolemma by generating oxygen free radicals. Several agents that affect neutrophils or oxygen radicals were evaluated in a canine model of regional myocardial ischemia and reperfusion. Anesthetized dogs underwent occlusion and repeffusion of the left circumflex coronary artery. Infarct zone, area at risk of infarction, and total left ventricle were quantified by gravimetric and planimetric analysis. Limitation of infarct size by ibuprofen was associated with marked suppression of leukocyte accumulation within the ischemic myocardium. Neutrophil depletion by antiserum resulted in similar reductions of infarct size and was accompanied by a reduction in leukocyte infiltration. A combination of oxygen radical scavengers, superoxide dismutase plus catalase, decreased myocardial injury whether infusion began before occlusion or 75 rain after occlusion. None of the treatments significantly altered hemodynamic indices of myocardial oxygen demand. Reduction of infarct size by ibuprofen, neutrophil antiserum, and free radical scavengers indicates that neutrophils and oxygen radicals participate in producing the irreversible damage to the myocardium during ischemia and repeffusion.
The Journal of Thoracic and Cardiovascular Surgery, 1988
The effect of oxygen free radical scavengers on the recovery of regional myocardial function after acute coronary occlusion and surgical reperfusion This study investigated the effects of the oxygen free radical scavengers superoxide dismutase and catalase, the peroxide ion inhibitor, in crystalloid potassium cardioplegic solution on infarct size and global and regional myocardial function after occlusion of the left anterior descending artery and surgical reperfusion in young sheep on cardiopulmonary bypass. After 1 hour of occlusion, the animals were randomized to receive either routine potassium cardioplegia or cardioplegia with superoxide dismutase and catalase. Global hemodynamics measured by maximum rate of pressure rise showed significant improvement after 5 hours of reperfusion in the group treated with superoxide dismutase and catalase (1843 ± 163 versus 979 ± 191, P < 0.001). Regional myocardial function was measured by ultrasonic crystals implanted in the ischemic area and in a nonischemic control segment. The percent systolic shortening or bulging was calculated. At end of reperfusion in the animals treated with superoxide dismutase and catalase, there was active shortening in the ischemic area after reperfusion of +9.2% ± 0.4% versus 2.1 % ± 0.8% in untreated animals (p < 0.001). Infarct size measured by triphenyltetrazolium chloride staining showed significant difference (p < 0.001) between animals treated with superoxide dismutase and catalase (0.9 % ± 0.1 %) and control animals (61 % ± 70 %). Superoxide dismutase and catalase given in the cardioplegic solution before reperfusion of an acutely ischemic area of myocardium enhances recovery of contractile function and results in a significant reduction in infarct size, which suggests improved salvage of the ischemic myocardium.
The Annals of Thoracic Surgery, 1992
We tested the hypothesis that 3,4,5,-trihydroxybenzamidoxime (VF 233), a demonstrated hydroxyl radical scavenger and an effective Fe3+ chelator, attenuates reperfusion injury and improves isovolumic left ventricular function. Eighteen isolated, perfused rabbit hearts with intracavitary balloons were subjected to normothermic, global ischemia until the initiation of ischemic contracture. Effects on the adenine nucleotide pool metabolites were determined by high-pressure liquid chromatography from right ventricular biopsy specimens before ischemia and at 15-minute intervals throughout reperfusion. In the experimental group (n = 9), a 5-mL bolus of 1 mol/L VF 233 was given immediately before reperfusion and followed by a continuous infusion (0.125 pmoll mid. The control group (n = 9) received the vehicle yocardial contractile dysfunction associated with M reperfusion has been attributed to many interrelated factors. Free radical species are thought to be a major cause of reperfusion injury. Reoxygenation initiates the formation of active oxygen species such as the superoxide radical (so-,), hydrogen peroxide (H202), and hydroxyl radicals (OH.). The hydroxyl radical is usually considered one of the most cytotoxic species of free radicals because of its strong oxidizing properties. Unlike the superoxide radical, no physiologic scavenging mechanism has been identified for the hydroxyl radical [l-61. The primary mechanism of clearance of *0-2 from biologic systems is superoxide dismutase, which catalyzes the dismutation of *O-, to H,O, and H,O [2]. Several studies have demonstrated that functional recovery of the ischemic myocardium is enhanced by agents that either scavenge oxygen free radicals, such as superoxide dismutase and catalase [3-51, or chelate iron, such as deferoxamine and dimethylthiourea . Prevention of hydroxyl radicalmediated injury may therefore be hypothesized to improve postischemic ventricular function. The optimum pharmacologic strategy to minimize oxygen-derived free radical-mediated reperfusion injury is not clear.
Canadian Journal of Physiology and Pharmacology, 2004
Previous studies have shown that reactive oxygen species mediated lipid peroxidation in patients undergoing cardiac surgery occurs primarily during cardiopulmonary bypass. We examined whether application of a high concentration of propofol during ischemia could effectively enhance postischemic myocardial functional recovery in the setting of global ischemia and reperfusion in an isolated heart preparation. Hearts were subjected to 40 min of global ischemia followed by 90 min of reperfusion. During ischemia, propofol (12 µg/mL in saline) was perfused through the aorta at 60 µL/min. We found that application of high-concentration propofol during ischemia combined with lowconcentration propofol (1.2 µg/mL) administered before ischemia and during reperfusion significantly improved postischemic myocardial functional recovery without depressing cardiac mechanics before ischemia, as is seen when high-concentration propofol was applied prior to ischemia and during reperfusion. The functional enhancement is associated with increased heart tissue antioxidant capacity and reduced lipid peroxidation. We conclude that highconcentration propofol application during ischemia could be a potential therapeutic and anesthetic strategy for patients with preexisting myocardial dysfunction.