Pyruvate enhances recovery of rat hearts after ischemia and reperfusion by preventing free radical generation.

Pyruvate protects myocardium from ischemic and anoxic injury, effects that have been attributed to beneficial metabolic alterations. Pyruvate also reacts with hydrogen peroxide in vitro, and pyruvate prevents free radical injury in other organs. Hearts supplied with 2 mM of pyruvate with glucose during reperfusion recovered significantly more mechanical function (81%) than those provided with 2 mM of acetate (which does not react with free radicals) and glucose (49%) or glucose alone (27%). Pyruvate significantly reduced free radical generation during reperfusion as measured with electron spin resonance using the spin-trap 5,5-dimethyl-1-pyrroline-1-oxide. In a model of direct oxidant stress, hearts were perfused with 0.28 mM of hydrogen peroxide. In this model, loss of function was almost entirely prevented by addition of 2 mM of pyruvate. From these results we conclude an important mechanism of protection when pyruvate is supplied during reperfusion is limitation of oxygen-derived free radical damage.

Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS).

OBJECTIVE: To assess the effects of lipid-lowering therapy with lovastatin on coronary angiographic findings in patients with coronary artery disease and to compare the findings with those of two lipid-lowering angiographic trials using similar end points. DESIGN: Randomized, double-blind, placebo-controlled, multicenter coronary angiographic trial. SETTING: Community- and university-based cardiac catheterization laboratories. PARTICIPANTS: A total of 270 patients, 37 to 67 years old, with total cholesterol ranging from 4.92 to 7.64 mmol/L (190 to 295 mg/dL) and angiographically defined coronary artery disease. INTERVENTION: A cholesterol-lowering diet and either lovastatin, 80 mg/day, or placebo. OUTCOME: Per-patient change in percent diameter stenosis as determined by quantitative coronary angiography (primary end point). Global change score, based on the consensus of blinded expert readers regarding angiographic change (secondary endpoint). RESULTS: Lovastatin lowered total cholesterol level by 32%, low-density lipoprotein cholesterol by 38%, and the apolipoprotein B by 26% and raised the high-density lipoprotein cholesterol by 8.5% (P < 0.001). Average percent diameter stenosis increased 2.2% in placebo recipients and 1.6% in lovastatin recipients (P > 0.20). For lesions 50% or greater, average percent diameter stenosis increased 0.9% in placebo recipients and decreased 4.1% in lovastatin recipients (P = 0.005). The mean global change score was +0.9 (indicating progression) in the placebo group and +0.4 in the lovastatin group (P = 0.002); 13 placebo recipients and 28 lovastatin recipients had global change scores indicating regression (P < 0.02). CONCLUSION: Treatment with lovastatin plus diet slows the rate of progression and increases the frequency of regression in coronary artery lesions (by global change score), especially in more severe lesions (by quantitative angiography). This is the third lipid-lowering trial to show a benefit using the global change score, an end point predictive of clinical coronary events. Differences between two of these trials, using quantitative coronary angiographic end points, may have theoretical bearing on the mechanisms by which lipid-lowering therapy operates at the level of the arterial wall.

The Monitored Atherosclerosis Regression Study (MARS). Design, methods and baseline results.

OBJECTIVE: The Monitored Atherosclerosis Regression Study (MARS) was designed to evaluate the effect of cholesterol lowering by monotherapy with an HMG-CoA reductase inhibitor on progression/regression of atherosclerosis in subjects with angiographically documented coronary artery disease. The purpose of this paper is to present the design, methods, and baseline results of MARS. DESIGN: MARS is a prospective, randomized, double-blind, placebo-controlled trial with baseline, 2-year, and 4-year coronary angiography as well as carotid, brachial, and popliteal ultrasonography. SETTING: Outpatient clinics at the University of Southern California School of Medicine and the University of Wisconsin School of Medicine. SUBJECTS: Two hundred seventy participants of both sexes were recruited directly from the cardiac catheterization laboratory or by chart review of patients having undergone cardiac catheterization in the past. Subjects were considered eligible if they had angiographically demonstrable atherosclerosis in 2 or more coronary artery segments, unaltered by angioplasty, with at least 1 lesion > or = 50% but < 100% diameter stenosis (%S). The inclusion range for total cholesterol (TC) was between 190 and 295 mg/dL. Exclusion factors were: triglycerides > or = 500 mg/dL; premenopausal females; uncontrolled hypertension; diabetes mellitus; untreated thyroid disease; liver dysfunction; renal insufficiency; congestive heart failure; major arrhythmia; left ventricular conduction defects; or any life-threatening disease. INTERVENTION: Subjects were placed on a low-fat, low-cholesterol diet and either 40 mg b.i.d. lovastatin (Mevacor) or placebo. Randomization was stratified by sex, smoking status, and TC. MAIN OUTCOME MEASURES: Per-subject average change in %S as determined by quantitative coronary angiography (QCA) is the primary angiographic endpoint. Secondary endpoints are: categorical analyses of the proportion of subjects with progression; human panel reading of coronary angiograms; and change in minimum lumen diameter (MLD) in mm by QCA. Carotid, brachial, and popliteal ultrasonography is also being performed. RESULTS: The subjects randomized into MARS are 91.5% male with an age range of 37 to 67 years (mean age 57.9 years). For the cohort, baseline lipids are (mean +/- SD): TC, 231 +/- 24 mg/dL; low-density lipoprotein cholesterol (LDL-C) by ultracentrifugation, 153 +/- 24 mg/dL; LDL-C, by calculation, 157 +/- 23 mg/dL; high-density lipoprotein cholesterol (HDL-C), 43 +/- 10 mg/dL; and triglycerides, 160 +/- 73 mg/dL. There were no significant differences between treatment groups in baseline lipid levels or baseline angiographic characteristics. CONCLUSIONS: MARS baseline data show adequacy of randomization with comparability of lovastatin and placebo groups in demographic, lipid, and angiographic characteristics.

Effects of oxygenated cardioplegic solutions on myocardial aerobic metabolism.

Oxygenated cardioplegic solutions can deliver sufficient oxygen to support aerobic metabolism of heart tissue during cardiac arrest, but little is known about oxygen use after cardioplegic solution infusion. Exhaustion of myocardial oxygen stores after infusion of oxygenated crystalloid cardioplegic solution or Krebs-Henseleit buffer was measured in rat hearts. Since nicotinamide adenine dinucleotide accumulates when mitochondria become anaerobic, the epicardium was monitored during perfusion and ischemia. As ischemia progressed, nicotinamide adenine dinucleotide fluorescence increased, indicating exhaustion of oxygen. After buffer perfusion, at 37 degrees C, 50% of peak fluorescence was seen at 13 +/- 1 seconds and 90% at 37 +/- 3 seconds. Oxygenated cardioplegic solution increased these intervals to 57 +/- 6 and 114 +/- 9 seconds, respectively. Oxygenated cardioplegic solution at 10 degrees C increased the time to 50% fluorescence to 238 +/- 12 seconds and to 90% to 320 +/- 14 seconds. Differences between buffer and cardioplegic solution were less at 10 degrees C. Aerobic metabolism was completely abolished 6 minutes after infusion of 10 degrees C oxygenated cardioplegic solution. Maintenance of continuous aerobic metabolism during surgical cardiac arrest would require frequent administration of oxygenated crystalloid cardioplegic solution.

Regression and stabilization of coronary artery lesions. Angiographic trials move beyond the NCEP treatment guidelines.

National Cholesterol Education Program Guidelines for the diagnosis and treatment of hypercholesterolemia have been formulated from population studies relating coronary events to blood lipids. Such population studies may not be relevant to patients with established coronary disease. Recent coronary angiographic studies allow meaningful comparisons of small groups of patients. These studies suggest that atherosclerotic lesions in coronary arteries can be stabilized, and further, that regression of coronary lesions can occur. The cholesterol and LDL levels achieved in angiographic studies are well below NCEP guidelines. Careful attention to correcting lipid abnormalities in patients with established coronary disease may alter the course of their illness.

Forearm vascular resistance increases during static exercise in heart transplant recipients.

In heart transplant recipients but not in normal humans, total peripheral vascular resistance increases during static exercise. To determine whether this augmented vasoconstriction limits the vasodilation normally seen in the nonexercising forearm, we measured arterial pressure, heart rate, and forearm blood flow during 30% maximal static handgrip in 9 heart transplant recipients and 10 control subjects. Handgrip evoked comparable increases in mean arterial pressure in the transplant recipients and control subjects (+19 +/- 2 vs. +20 +/- 2 mmHg). Heart rates increased by 14 +/- 3 beats/min in the control subjects but did not change in the transplant recipients. Directionally opposite patterns of forearm vascular resistance were observed in the two groups. In the control subjects, forearm resistance fell during handgrip (-8.8 +/- 1.9 units, P less than 0.05). In contrast, in the transplant recipients, forearm resistance rose during this intervention (+9.0 +/- 2.9 units, P less than 0.05). Thus the vasodilation that normally occurs in the nonexercising forearm during static handgrip is reversed in heart transplant recipients. Vasoconstriction in the forearm contributes to the increase in total peripheral resistance that occurs during static exercise in these individuals.

Thoracic epidural anesthesia reduces myocardial infarct size after coronary artery occlusion in dogs.

The effect of thoracic epidural anesthesia (TEA) with lidocaine on regional myocardial blood flow (RMBF), hemodynamic performance, and myocardial infarct size after coronary artery occlusion was assessed in 21 dogs. In seven dogs, the left anterior descending coronary artery (LAD) was temporarily occluded twice: once before TEA (control) and once during TEA. Systemic hemodynamic parameters, RMBF (using radionuclide-labeled microspheres), and epicardial electrocardiographic maps (15 sites) were obtained before and 15 min after each temporary LAD occlusion. Compared with the ischemic period before TEA, the following were decreased during ischemia with TEA: heart rate, ST segment elevation, cardiac index, the peak first time derivative of left ventricular (LV) pressure, LV tension-time index, the rate-pressure product, and LV stroke-work index. Ischemic zone endocardial RMBF was increased from a control value of 26 +/- 6% to 36 +/- 6% of normal during TEA (P less than 0.05). An additional 14 dogs randomly received either TEA (1% lidocaine, 10 ml/hr) or epidural saline plus 1% lidocaine (10 ml/hr, intramuscularly), beginning 1 hr after LAD occlusion. After 6 hr, the heart was removed and the left ventricle was sectioned parallel to the atrioventricular groove. The infarcts (tetrazolium-stained) were 46% smaller with TEA than with saline, 15.4 +/- 1.8% vs 28.7 +/- 2.3% of the left ventricle (P less than 0.05). Thus TEA reduced hemodynamic correlates of myocardial O2 consumption, improved regional (ischemic zone) endocardial perfusion, and reduced the extent of myocardial infarction.

Improved myocardial preservation with oxygenated cardioplegic solutions as reflected by on-line monitoring of intramyocardial pH during arrest.

To examine the relationship between intramyocardial pH during global ischemic arrest and subsequent functional and biochemical recovery, 40 canine hearts were subjected to 4 hours of arrest at 10 degrees C. Four groups, each containing 10 hearts, were differentiated by the oxygen concentration of a hyperkalemic crystalloid cardioplegic solution (CCS), which was infused every 20 minutes. In group 1 the CCS was equilibrated at 4 degrees C with nitrogen to remove oxygen. In group 2 the CCS was aerated at 4 degrees C. In group 3 the CCS was treated to achieve an oxygen tension (PO2) similar to group 2 but with a reduced nitrogen content to prevent bubble formation, which is theoretically possible during reperfusion ("myocardial bends"). In group 4 the CCS was fully oxygenated at 4 degrees C. The resulting PO2 of CCS measured at 10 degrees C was less than 20, 170, 170, and 750 mm Hg in groups 1, 2, 3, and 4, respectively. Left ventricular function (LVF) was assessed from function curves at constant mean aortic pressure and heart rate. Functional recovery, expressed as a percentage of prearrest LVF, was 38.1% +/- 10.7% in group 1 and 84.0% +/- 8.1% in group 4 (p less than 0.008). Functional recovery was 64.9% +/- 5.5% and 69.1% +/- 7.0% in groups 2 and 3, which had similar PO2. Differences in recovery between groups 2 and 3 and group 1 approached statistical significance (p less than 0.05, NS). The mean-integrated intramyocardial pH during arrest was higher (p less than 0.003) in group 4 (7.14 +/- 0.05) than in group 1 (6.84 +/- 0.06) or group 2 (6.86 +/- 0.07). The minimum intramyocardial pH during arrest was higher in group 4 than in any other group (p less than 0.002). Myocardial adenosine triphosphate concentration at the end of arrest, expressed as a percentage of its prearrest value, was highest in group 4 (75.9% +/- 8.1%) and lowest in group 1 (54.3% +/- 5.7%), a difference approaching statistical significance (p less than 0.05, NS). These data suggest that the measurement of intramyocardial pH is a useful on-line indicator of the adequacy of preservation during hypothermic arrest and that excess nitrogen in aerated CCS had little or no effect on recovery. The data confirm the hypothesis that oxygenation of CCS is associated with good myocardial preservation, which may be attributed to the provision of oxygen for the support of aerobic metabolism during arrest.

Myocardial recovery after hypothermic arrest: a comparison of oxygenated crystalloid to blood cardioplegia. The role of calcium.

We compared multidose crystalloid hyperkalemic cardioplegic solutions with and without added red cells in 24 canine hearts subjected to 5 hr of arrest at 10 degrees C. All cardioplegic solutions were fully oxygenated at 4 degrees C before delivery. Since blood cardioplegia contained Ca++ carried over with the red cells, Ca++ was added to the crystalloid solution in one group. The table below shows the hematocrit (HCT) and ionized Ca++ concentrations of the cardioplegic solutions, and coronary arteriovenous oxygen difference during infusion of cardioplegic solution (AVO2) (ml O2/100 ml). Recovery during reperfusion is shown as percent of prearrest left ventricular function (LVF) and prearrest myocardial ATP concentration.

Regional myocardial lidocaine concentration determines the antidysrhythmic effect in dogs after coronary artery occlusion.

Ischemic ventricular dysrhythmias were produced in 40 of 47 anesthetized mongrel dogs by high ligation of the left anterior descending coronary artery. Dysrhythmias were treated with a single iv bolus of 20, 40, 80, or 120 mg of lidocaine (L) in order to determine the dose at which approximately 50% of animals had an antidysrhythmic response. Cardiac output and regional myocardial blood flow (RMBF) were measured by using radionuclide labeled microspheres. Lidocaine concentration [( L]) was measured from samples of arterial and venous blood and normal and ischemic myocardium. All dogs treated with 40, 80, or 120 mg of L had an antidysrhythmic effect. However, with 20 mg of L the dysrhythmia persisted in 12 and resolved in 14. With 20 mg of L, ischemic myocardial [L] was greater in dogs with an antidysrhythmic effect than in those with persistent dysrhythmias (1.14 +/- 0.12 vs. 0.76 +/- 0.04 micrograms X g-1), but no difference was seen for arterial, venous, and normal myocardial [L]. Ischemic RMBF was higher in the dogs that had an antidysrhythmic effect than in those that did not, 9.8 +/- 1.5 versus 6.9 +/- 1.3% of normal. With 20 mg of L, [L] in ischemic myocardium correlated well with ischemic RMBF. The antidysrhythmic response to L had a threshold at a tissue concentration of greater than or equal to 1.0 microgram X g-1 (chi-square = 8.55, P less than 0.005). For this model, the [L] in ischemic myocardium during acute ischemia correlates with the antidysrhythmic response to L, while the concentration in normal myocardium or blood does not.

Reduction of postischemic myocardial dysfunction by substrate repletion during reperfusion.

We studied the effect of selected metabolic substrates on recovery of myocardial function and ATP concentration when added to the reperfusate after normothermic ischemia. The hearts of 30 anesthetized, open-chest mongrel dogs were subjected to 45 min of global ischemia at 37 degrees C followed by 90 min of reperfusion. Left ventricular function curves were generated on right heart bypass before and at 30 min intervals after the ischemic period. ATP concentration was measured before, at the end of, and 90 min after the ischemic period. Experiments were randomized into five groups distinguished by the content of the myocardial reperfusate during the first 10 min of the reperfusion period. Hearts received either unmodified oxygenated pump blood (control; group I), normothermic oxygenated 28 mmol/liter potassium-blood cardioplegic solution (KBC; group II), 25 mmol/liter glutamate in KBC (group III), 250 mumol/liter adenosine with 1 mg erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA) and glutamate in KBC (group IV), or 2 mmol/liter ribose and glutamate (group V) in KBC. Hearts reperfused with KBC showed improvement early (group II vs group I; p less than .02) but not late recovery of left ventricular function over control. Glutamate, which replenishes Krebs cycle intermediates lost during ischemia, increased functional recovery (group III vs group II; p less than .002). Ribose, which is important in purine salvage and resynthesis, added to glutamate-KBC further improved functional recovery (group V vs group III; p less than .01). Adenosine, a precursor of ATP, with EHNA, an inhibitor of rapid adenosine catabolism, added to glutamate-KBC depressed early recovery (group IV vs group III; p less than .01); however, recovery improved with time. Both glutamate and ribose with glutamate in KBC improved ATP recovery (groups III and V vs group II; p less than .002). Thus selective substrate repletion during initial reperfusion after severe normothermic ischemia can improve recovery of myocardial function and ATP concentration.

The effect of halothane anesthesia on myocardial necrosis, hemodynamic performance, and regional myocardial blood flow in dogs following coronary artery occlusion.

The effect of halothane anesthesia on myocardial necrosis resulting from coronary artery ligation was examined in 28 anesthetized mongrel dogs. In 18 dogs, the left anterior descending coronary artery (LAD) was ligated immediately proximal to the first apical diagonal branch, and 1 h later the dogs were assigned randomly either to receive halothane, 0.5-1.0% inspired in room air for 12 h (n = 10) or to awaken without further intervention (control, n = 8). Infarct size was measured by staining the myocardium with triphenyl tetrazolium chloride 24 h after LAD ligation. Infarct size in halothane-treated dogs was 17.8 +/- 2.0% of the left ventricle, compared with 27.3 +/- 3.3% in control dogs (P less than 0.05). Myocardial salvage was present transmurally but was greatest in epicardial regions. In 10 additional dogs, hemodynamic variables (heart rate, arterial pressure, left ventricular end-diastolic pressure, peak left ventricular dP/dt, tension-time index, and rate-pressure product) were measured or calculated, and radionuclide-labeled microspheres were injected for measurement of cardiac output and regional myocardial blood flow (RMBF). Thirty minutes after LAD ligation and after initial hemodynamic measurements and microsphere injection, these dogs were assigned randomly to receive either halothane, 1.0%, inspired in room air (n = 5) or no intervention (control, n = 5). After 15 min of halothane inhalation (45 min after LAD ligation in control dogs), measurements were repeated. Halothane inhalation reduced heart rate, arterial pressure, and indexes of left ventricular contractile and pump performance. During halothane treatment, RMBF declined in normal myocardium but not in ischemic regions, while neither normal nor ischemic zone RMBF changed in control dogs. Systemic vascular resistance was unchanged in either group. Thus, halothane was associated with a 35% smaller myocardial infarct, transmural myocardial salvage, reduced heart rate, reduced left ventricular contractile and pump performance, reduced RMBF to nonischemic regions, and unchanged RMBF in the ischemic myocardium.

A flow- and time-dependent index of ischemic injury after experimental coronary occlusion and reperfusion.

The purpose of the present study was to determine whether an ischemic index--expressed as the product of flow deprivation (FD) and the duration of occlusion (T), FD X T--correlated with biochemical and early morphologic alterations of the subendocardial myocardium and could predict ultimate development of irreversible injury after coronary reperfusion. Myocardial biopsy specimens for measurement of ATP and other purines and for ultrastructure studies were obtained in vivo during coronary occlusion in a canine model and were considered relative to development of necrosis after coronary reperfusion. FD X T correlated negatively with ATP content [ATP, nmol/mg of cardiac protein = 23.6 - 0.24(FD X T) + 0.0007(FD X T)2; r = -0.81] and with a semiquantitative early histologic index of damage (r = 0.70). Values of (FD X T) less than 18 were associated with reversible injury--i.e., complete salvage after coronary reperfusion. (FD X T) greater than 18 was associated with varying degrees of necrosis; necrosis was severe (78 +/- 12% of subendocardial biopsy specimens) when ATP less than 10 nmol/mg of protein and total purine pool was decreased by 50%. FD X T correlated with the eventual percentage of subendocardial necrosis (r = 0.85). Accordingly, as an index of ischemic injury, FD X T may be useful in assessing whether ischemic myocardial tissue will benefit from early restoration of blood flow to the ischemic area.

Enhanced myocardial protection during ischemic arrest. Oxygenation of a crystalloid cardioplegic solution.

To determine if, during elective cardiac arrest, the myocardial protection afforded by a cold (4 degrees C) crystalloid potassium cardioplegic solution could be improved by oxygenation of the solution, we placed 16 dogs on cardiopulmonary bypass and subjected their hearts to 4 hours of cold cardioplegic arrest. Group 1 hearts (n = 8) received aerated crystalloid solution perfused through the aortic root every 20 minutes. Group 2 hearts (n = 8) were treated identically except that the crystalloid cardioplegic solution was fully oxygenated. Left ventricular function curves (ejecting heart) were generated before arrest (control) and after 45 minutes of reperfusion. A cardiac output of 1,000 ml/min could be attained in only two hearts of Group 1 after reperfusion, whereas all but one heart of Group 2 had excellent functional preservation. Mean postreperfusion adenosine triphosphate (ATP) levels in Group 1 and Group 2 hearts were 62% and 89% of control, respectively (p less than 0.01). Myocardial water content had increased significantly (p less than 0.002) after reperfusion in Group 1, but not in Group 2. During cardioplegic solution infusion, myocardial oxygen consumption (MVO2) was 1.42 +/- 0.15 ml O2/min/100 gm LV for Group 1 and 6.91 +/- 1.27 ml O2/min/100 gm LV for Group 2 (p less than 0.001). Oxygen consumed per minute of arrest was 0.027 +/- 0.003 ml O2/min/100 gm LV for Group 1 and 0.128 +/- 0.015 ml O2/min/100 gm LV for Group 2 (p less than 0.001). Postreperfusion ultrastructural evaluation of two of the Group 1 hearts revealed severe ischemic damage in contrast to the normal ultrastructural appearance of two of the Group 2 hearts. With careful attention given to maintenance of myocardial hypothermia and cardioplegic delivery methods, the myocardial protection afforded by an oxygenated crystalloid cardioplegic solution exceeds that provided by the aerated control and compares favorably with other methods of myocardial protection during ischemic arrest.

Effects of ortho-iodo sodium benzoate on acute myocardial ischemia, hemodynamic function, and infarct size after coronary artery occlusion in dogs.

Ortho-iodo sodium benzoate (OISB) decreases the affinity of blood for oxygen, thus enhancing potential tissue oxygen delivery. To test the hypothesis that a change in oxygen affinity would ameliorate regional myocardial ischemic injury resulting from occlusion of the left anterior descending (LAD) coronary artery, experiments were carried out in 55 anesthetized dogs which received an intravenous infusion of OISB. In Protocol I studies (n = 9), preocclusion intravenous infusion of OISB (500 mg/kg) reduced epicardial S-T segment elevation 15 minutes after coronary occlusion, while a similar volume of normal saline solution did not affect this index of ischemic damage. In Protocol II experiments, 34 dogs were randomized to either an OISB or saline group, after which the LAD was ligated, the chest closed, and the animal allowed to recover from anesthesia. Myocardial infarction (MI) size was assessed after the animal died or was killed 8 to 24 hours later, and was found to be 29% smaller in dogs receiving OISB. In 6 dogs, blood P50 (the partial oxygen pressure at which hemoglobin is 50% saturated with oxygen) was increased by OISB infusion, confirming that its administration effected a rightward shift in the oxyhemoglobin dissociation curve. Protocol III studies assessed the effects of OISB on cardiac hemodynamic function and acute myocardial ischemic damage when infusion was begun 15 minutes after LAD occlusion: average epicardial S-T segment elevation was not altered by saline solution, but decreased when OISB was infused during the last 15 minutes of myocardial ischemia. Reductions in heart rate, left ventricular dP/dt, and cardiac output were observed in 7 dogs during OISB infusion, but there were no changes in these measurements during coronary occlusion in 5 dogs receiving a constant infusion of saline solution. There were no changes in regional myocardial blood flow (microsphere technique) to either ischemic or nonischemic zones in either the saline control or OISB treatment groups. Thus, both acute myocardial ischemic injury (assessed by epicardial electrocardiographic mapping) and ultimate MI size are reduced when OISB is infused before experimental coronary artery occlusion. OISB also reduces myocardial ischemic injury when its administration is begun 15 minutes after coronary occlusion, while effecting decreases in heart rate, left ventricular contractility, and cardiac output.