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The effects of platelet-activating factor (PAF) on cardiac function and con tractility and its mechanism of action are not fully understood. The authors investigated the effects of PAF in the absence or presence of a potent PAF antag onist CV-6209 on the cardiac function and contractility; lipid peroxidation prod uct malondialdehyde (MDA), an indirect measure of oxygen free radicals; serum creatine kinase (CK); blood lactate; and pH in anesthetized dogs. CV- 6209 (1 mg/kg, IV) did not produce significant changes in the various parame ters studied. PAF (1 μg/kg, IV) produced decreases in the cardiac function (cardiac index, left ventricular work index) and indices of cardiac contractility [(+) and (-) dp/dt, dp/dt at CPIP, (dp/dt)/IP, dp/dt at CPIP/IP, Vmax] and in creases in the systemic and pulmonary vascular resistance. It also produced increases in cardiac MDA, serum CK, blood lactate, and H+ and decreases in blood pH and HCO3- . CV-6209 completely prevented the PAF-induced changes in the hemodynamic and biochemical parameters. These results suggest that PAF-induced cardiac depression may be due to PAF-induced release of oxyradicals from neutrophils and that PAF antagonist may be useful in counteracting the deleterious effects of PAF on the cardiovas cular system.

Hypochlorous acid (HOCI), produced by activated polymorphonuclear (PMN) leukocytes, has been reported to depress cardiac function and contractility. Var ious mechanisms exist for activation of PMN leukocytes during hemorrhagic shock and reperfusion. In order to determine the role of HOCI in hemorrhagic shock and reinfusion, the authors studied the effects of shock and reinfusion on the cardiac function, contractility, blood lactate, blood gases, and creatine kinase (CK) and MB fraction of CK (MBCK) with and without methionine (quencher of HOCI) in anesthetized dogs. Dogs were divided into two groups: Group I, hemorrhagic shock (two hours) and reinfusion (two hours): Group II, hemorrhagic shock and reinfusion with methionine treatment. Cardiac index, mean arterial pressure, and index of cardiac contractility were similar in the two groups during shock. Postinfusion recovery of cardiac function and con tractility was better in group II. Increases in blood lactate were similar in the two groups during shock. The rate of return of blood lactate to preshock values after reinfusion was greater in group II. The increases in serum CK and MBCK of the two groups during shock were similar but not significant. Following rein fusion the levels of these enzymes increased significantly, but the increases in group II were less.These results suggest that HOCI produced by activated PMN leukocytes may play a role in cardiac damage during hemorrhagic shock and reinfusion. Methio nine may have beneficial effects in the hemodynamic and metabolic recovery and may reduce cellular damage during hemorrhage shock and reinfusion.

In many clinical situations, including cardiac ischemia/reperfusion, elective cardiac arrest, and renal dialysis, the chances of increased production of oxygen free radicals (OFR) exist. OFR have been implicated as a causative factor of cell damage in several pathologic conditions. The effects of exogenous OFR, gener ated by xanthine plus xanthine oxidase, in the absence and in the presence of OFR scavenger (superoxide dismutase [SOD]) on the contractility of isolated perfused heart of rabbit were studied. OFR produced concentration-dependent decreases in the contractility of perfused heart. SOD prevented the OFR-in duced decreases in the left ventricular contractility. Xanthine produced an in crease in the contractility of isolated perfused rabbit's heart. Xanthine oxidase produced a marked decrease in the left ventricular contractility. Repeated ad ministration of xanthine oxidase produced accelerated and greater decreases in the contractility of perfused heart when compared with that of the initial admin istration of the drug. Effects of xanthine or xanthine oxidase on the cardiac function and contractility were also studied in anesthetized dogs. Xanthine alone had no significant effect on the cardiac function and indices of myocardial contractility. However, xanthine oxidase produced a marked decrease in the mean aortic pressure, left ventricular work index, heart rate, cardiac index, left ventricular systolic pressure, left ventricular end-diastolic pressure, (+) and ( — ) dp/dt of left ventricular pressure, and other indices of myocardial contrac tility [(dp/dt)/PAW (pulmonary arterial wedge pressure)]; and an increase in the total systemic and pulmonary vascular resistance. Repeated administration of xanthine oxidase in anesthetized dogs had lesser effects on the cardiovascular system when compared with those from the initial dose of the drug. These results suggest that OFR are cardiac depressant. Clinical situations wherein there is an increased production of OFR or increased formation of xanthine and xanthine oxidase may be associated with decreased cardiac func tion and contractility. Scavengers of OFR may protect the heart from the delete rious effects of OFR in such clinical conditions.

Oxygen free radicals are known to produce cellular injury. There are various mechanisms during hemorrhagic shock that can lead to an increase in the oxy gen free radicals, which would produce a loss of membrane integrity and a decrease in cardiac function and cardiac contractility. The authors studied the effect of acute hemorrhage and reperfusion on the hemodynamics, blood lac tate, and oxygen free radicals. Dogs were divided into two groups, group I, hemorrhagic shock and reinfu sion; group II, hemorrhagic shock and reinfusion with superoxide dismutase (SOD) and catalase treatment. The dogs were bled (50% of the estimated blood volume) over a period of five to twelve minutes. After an hour of bleeding, the shed blood was transfused over twenty to twenty-five minutes. Group II re ceived SOD (0.7 mg/kg, IV) and catalase (0.7 mg/kg, IV) within ten minues of bleeding. The hemodynamic measurements and collection of blood samples for measurement of oxygen free radicals and lactate were made before hemorrhage and at fifteen, thirty, and sixty minutes of hemorrhage and at fifteen, thirty, and sixty minutes after reperfusion of shed blood. There was a decrease in the cardiac function and index of myocardial con tractility associated with an increase in the blood lactate after hemorrhage in group I. Similar but less marked changes in these parameters were observed in group II. Recovery of hemodynamic parameters with reinfusion was better in group II as compared with that in group I. There was an increase in blood oxygen free radicals (superoxide anions) in group I, especially after reinfusion. No such changes were observed in group II. These results suggest that oxygen free radicals might be involved in acute hemorrhagic shock. Use of scavengers of oxygen free radicals might, therefore, be helpful in hemorrhagic shock.

We hypothesize that oxygen free radicals are involved in the genesis and maintenance of volume and pressure overload heart failure. Pressure and vol ume overload would produce myocardial ischemia. During ischemia there will be an increase in xanthine and xanthine oxidase; and a decrease in the superox ide dismutase and glutathione peroxidase activity leading to an increase in the oxygen free radicals. A decrease in the cellular pH during ischemia would re lease phospholipase which would, in turn, release arachidonic acid from phos pholipids. Leukotrienes and prostaglandins will be synthesized through arachidonic acid metabolism. During this synthesis not only oxygen free radi cals will be produced but also there will be formation of leukotriene, LTB4, which is known to activate neutrophil and hence increased secretion of oxygen free radicals. Increased circulatory catecholamines due to compensatory mech anism would also lead to an increase in the oxygen free radicals. Oxygen free radicals are known to depress Ca++ binding and uptake of sarcoplasmic retic ulum which would lead to a decrease in the myocardial contractility. We have shown that oxygen free radicals depress cardiac function and cardiac contractil ity. It is, therefore, suggested that oxygen free radicals might be involved in the development of heart failure. The use of agents that reduce the amount of oxy gen free radicals would be of value in the prevention and treatment of heart failure.

Oxygen free radicals are known to produce cellular injury by peroxidation of phospholipids in the cell membrane. These free radicals might damage the endothelial cell and thus set the stage for atherosclerosis. The authors studied the effect of high-cholesterol diets on the genesis of atherosclerosis and lipid peroxidation products, malondialdehyde (MDA) in rabbits. The animals were divided into four groups each comprising 5 rabbits, on the basis of their diets. Group I, control diet; group II, cholesterol; group III, coconut oil; group IV, a mixture of cholesterol, coconut oil, and cholic acid. Rabbits were sacrificed five months after being on the respective diets. Blood samples were obtained for the measurements of total cholesterol, high density lipoprotein cholesterol (HDL- C), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), triglycerides, and MDA at the end of the protocol. The aortas were removed from different animals for the identification of athero sclerotic plaques. Plaques were detected in all the animals in group II and group IV. The serum total cholesterol, LDL-C, and VLDL-C were significantly higher in animals of group II and IV than in those of group I. The values for serum total cholesterol, HDL-C, LDL-C, and VLDL-C in group III were not signifi cantly different from those in group I. The blood MDA and serum triglycerides were also higher in animals of group II and IV than in those of group I. There were, however, no significant differences in these parameters in group III as compared with those in group I. This study showed that there was an increase in the lipid peroxidation product (MDA) in all those rabbits that had atheroscler otic changes in the aorta. This increase might be due to an increase in oxygen free radicals, which may be involved in the genesis and maintenance of choles terol-induced atherosclerosis.

Oxygen free radicals have been linked to a wide variety of cellular damage in biological systems. Poly morphonuclear (PMN) leukocytes stimulation is one of the known sources for oxygen free radicals. It has been suggested that oxygen free radicals depress the excitation-con traction coupling in cardiac muscle. It is possible that a decrease in the myocardial contractility in heart fail ure might be due to an increased oxy gen-free-radical-producing activity of PMN leukocytes. The authors studied, therefore, the release of oxy gen free radicals, as measured by luminol-dependent chemilumines cence activity, from the PMN leuko cytes in dogs with heart failure due to aortic stenosis. Hemodynamics and phagocytic activity of PMN leuko cytes were studied in 6 control dogs and 6 dogs with aortic stenosis of six to nine months' duration. There was a significant decrease in the index of myocardial contractility and an in crease in the left ventricular end- diastolic pressure in dogs with aortic stenosis, suggesting left ventricular failure in these dogs. Although there was a tendency for a decrease in the cardiac index in dogs with aortic stenosis, the decrease was not signifi cant. Phagocytic activity of PMN leu kocytes in blood was studied in con trol dogs and dogs with aortic steno sis. Phagocytosis was initiated by ad dition of opsonized zymosan and chemiluminescence was monitored by use of a luminometer. The peak chemiluminescence activity of the PMN leukocytes in blood of dogs with heart failure was about threefold greater than that in the blood from control dogs. The presence of super oxide dismutase, a scavenger of oxy gen free radicals, reduced the chemi luminescence from PMN leukocytes in both the control dogs and dogs with aortic stenosis. These results suggest that the increased production of oxygen free radicals by PMN leu kocytes might contribute to a de crease in the myocardial contractility and, hence, to heart failure in dogs with aortic stenosis.