Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variety of disease states. Recent interest has focused on the possibility that free radicals may be involved in ischemic myocardial damage. However, the exact types of damage that result from myocardial exposure to free radicals remains to be established. The purpose of this study was to evaluate the effects of superoxide and hydroxyl radicals on myocardial structure and function in an isolated perfused rabbit interventricular septal preparation. Superoxide was generated by adding purine (2.3 mM) and xanthine oxidase (0.01 U/ml) to the physiological solutions perfusing the septa. Hydroxyl radical generation was catalyzed by the addition of 2.4 microM Fe3+-loaded transferrin to the system. Exposure of normal septa to superoxide-generating solutions resulted in the development of structural alterations in the vascular endothelium including the development of vacuoles. Membranous cellular debris was evident in the extracellular space and within the vessels. Cardiac myocytes showed evidence of mild alterations. Exposure of septa to solutions capable of generating hydroxyl radicals resulted in more extensive and severe damage. Vascular endothelial cells showed evidence of vacuoles or blebs and edema. Severe swelling of mitochondria was evident in cardiac myocytes and vascular endothelial cells. In addition, myocytes often showed blebbing of the basement membrane. Normal septa exposed to superoxide showed no significant decrease in developed tension, whereas hydroxyl radical exposure resulted in a significant decrease in myocardial function.(ABSTRACT TRUNCATED AT 250 WORDS)

This study investigates the possible role of oscillatory release of calcium from sarcoplasmic reticulum in the genesis of ventricular arrhythmias during acute myocardial ischemia and reperfusion hi isolated rat hearts. We used ryanodine and caffeine, which are known to modulate the oscillatory release of calcium from sarcoplasmic reticulum.

Oxygen-derived free radicals, specifically superoxide (O-2) and the hydroxyl radical (OH.), have been implicated as possible mediators in the development of myocardial damage induced by ischemia and reflow. The purpose of this study was to examine the ability of superoxide dismutase (SOD), a O-2 scavenging enzyme, to protect the heart against functional and structural alterations due to ischemia and reflow. An isolated perfused rabbit interventricular septal preparation was used for these experiments. Septa were treated with SOD by adding either 10 or 20 micrograms/ml of the enzyme to the perfusion solution 15 min prior to ischemia and during reflow. Other septa were not treated. Septa were made ischemic for 1 h and reperfused for 1 h. The contractile performance of reperfused septa was found to be significantly improved in SOD-treated septa when compared with nontreated septa. After 60 min of reflow, values for nontreated, 10- and 20-micrograms/ml SOD-treated septa, respectively, were 48.5 +/- 5.2 (SE), 67.4 +/- 4.2, and 82.0 +/- 3.8% of control values for developed tension. The rise in resting tension observed with reflow was significantly decreased. SOD treatment also provided significant protection of myocardial ultrastructure. The percent of myocytes showing normal structure was increased approximately 40%, and the percentages of myocytes showing mild or severe damage were decreased approximately 30 and 15%, respectively, for SOD-treated septa. Vessel structure showed a similar trend. Thus SOD preserves myocardial function and structure in septa reperfused following ischemia. These results support the possibility that oxygen-derived free radicals may be involved in the damage resulting from ischemia and reflow.

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Myocardial ischemia and reperfusion have been shown to result in damage to the phospholipid components of cardiac myocyte cell membranes as indicated by the tissue accumulation of unesterified fatty acids (UFA). A portion of this damage and subsequent dysfunction may be a consequence of free radical-induced membrane lipid peroxidative events. alpha-Tocopherol, a lipophilic antioxidant, was used in this study as an agent by which the extent of ischemia and reperfusion injury might be decreased. Increasing rat myocardial tissue levels of alpha-tocopherol by 51% was found to attenuate lipid perturbations as determined by the accumulation of tissue UFA in an isolated heart model of global ischemia and reperfusion. Nontreated hearts made ischemic for 25 min with 30 min of reflow had a significantly increased total UFA level of 5,961 +/- 799 nmol/mg protein (P less than 0.05) compared with control perfused hearts containing 3,116 +/- 463 nmol UFA/mg protein and with alpha-tocopherol-treated ischemic and reperfused hearts containing 3,066 +/- 365 nmol UFA/mg protein. Contractile dysfunction, excessive accumulation of tissue calcium, and release of lactate dehydrogenase after ischemia and reperfusion were also reduced, demonstrating protective effects in alpha-tocopherol-treated hearts. Thus alpha-tocopherol proved effective in the attenuation of ischemia and reperfusion damage. These results suggest that reducing lipid alterations may prove beneficial in protecting against membrane damage subsequent to ischemia and reperfusion.