Lawrence D. Horwitz

Lidocaine reduces canine infarct size and decreases release of a lipid peroxidation product

Summary: Whether and how lidocaine reduced infarct size in a canine model of ischemia and reperfusion was investigated. Twenty dogs underwent a 90-min left anterior descending artery ligation and 300 min of reperfusion. Infarct size was measured by triphenyl tetrazolium chloride and the region at risk by 99Tc-labeled albumin microspheres injected during ischemia. In 10 dogs, lidocaine (70 μg/kg/min i.v.) was infused 90 min prior to and during ischemia and reperfusion, while 10 dogs were untreated. The ratio of infarct to risk area was 35.2 ± 3.4% (SEM) in lidocaine dogs vs. 48.5 ± 5.3% in untreated dogs (p < 0.05). Lidocaine did not reduce neutrophil accumulation in ischemic and reperfused myocardium at 5 h of reperfusion, inhibit stimulated neutrophil superoxide production, or scavenge superoxide in vitro. However, during early reperfusion, lidocaine reduced coronary sinus levels of a lipid peroxidation product (conjugated dienes). Thus, clinically relevant lidocaine infusion rates reduced myocardial infarct size when given prior to and during ischemia and reperfusion. This protective effect may be due to lidocaines membrane stabilizing effects, which could have protected the myocardial cell membrane from lipid peroxidation.

Acute Effects of Ethanol on Left Ventricular Performance

The cardiac effects of ethanol were studied in six conscious dogs chronically instrumented for measurement of left ventricular pressure, internal transverse diameter, and outflow. Successive intravenous infusions of ethanol produced blood levels of 120 ± 16 (SEM) mg% (infusion #1) and 311 ± 19 mg% (infusion #2). Stroke volume decreased from 20.1 ± 1.6 ml preinfusion to 17.2 ± 1.9 ml after infusion #1 (P < 0.01) and 13.6 ± 1.9 ml after infusion #2 (P < 0.01). Left ventricular end diastolic pressure increased 2.5 mm Hg with infusion #1 (P < 0.05) and 6.0 mm Hg with infusion #2 (P < 0.05). Left ventricular dp/dt max fell 17% with infusion #1 (P < 0.001) and 30% with infusion #2 (P < 0.01). Left ventricular diameter increased at end diastole and end systole with ethanol. Heart rate was unchanged with infusion #1 and increased with infusion #2; left ventricular systolic pressure was unaltered. Studies after pharmacological autonomic denervation with propranolol and atropine demonstrated changes in left ventricular dp/dt max, left ventricular end diastolic pressure, and stroke volume similar to unblocked results. Thus ethanol at blood levels commonly encountered in social usage is a potent myocardial depressant.

Influence of hypertonic mannitol on ventricular performance and coronary blood flow in patients.

The influence of a relatively small increase in serum osmolality produced by hypertonic mannitol on ventricular and systemic arterial hemodynamics and coronary blood flow was studied in 20 patients undergoing cardiac catheterization. Mannitol given to increase serum osmolality 10 mOsm resulted in a small but significant increase in mean systemic arterial pressure, maximum LV dp/dt, left ventricular end-diastolic pressure and cardiac output but no significant change in heart rate or hematocrit. The most prominent change in the patients studied, however, was in coronary blood flow which increased 39% after mannitol. Patients with severe two and three vessel coronary artery disease had increased in coronary blood flow similar to those in patients without coronary artery disease. The data suggest the need to further evaluate the physiological importance of the increase in coronary blood flow produced by mannitol in patients with coronary artery disease and indicate the possibility that mannitol might be of value in treating certain problems in patients with coronary artery disease,

Role of the Frank-Starling Mechanism In Exercise

The mechanisms which determine the response of stroke volume to mild, moderate, and severe exercise were compared in nine dogs running on a level treadmill. The dogs ran for 3-minute periods at 3–4 mph (mild exercise), 6–8 mph (moderate exercise), and 10–14 mph (severe exercise). Heart rate increased from a standing control value of 107 ± 6 beats/min to 191 ± 10 beats/min in mild, 221 ± 8 beats/min in moderate, and 263 ± 9 beats/min in severe exercise. Stroke volume increased 14%, 19%, and 15% for mild, moderate, and severe exercise, respectively. During mild exercise, left ventricular internal diameter decreased at end-systole but was unchanged at end-diastole. During moderate and severe exercise, end-diastolic diameter increased consistently as did left ventricular end-diastolic pressure. It was concluded that, despite extremely high heart rates, stroke volume increased during exercise. The augmentation in stroke volume was due to the combined effects of an increase in contractility, caused by increased sympathetic nervous system activity, and the operation of the Frank-Starling mechanism.

The lazaroid U74006F, a 21-aminosteroid inhibitor of lipid peroxidation, attenuates myocardial injury from ischemia and reperfusion.

Summary U74006F, a novel new 21-aminosteroid inhibitor of lipid peroxidation, has been effective in preventing free-radical-mediated injury in central nervous system models. To assess its ability to diminish myocardial injury due to ischemia and reperfusion, U74006F (n = 11) or its vehicle (n = 11) were administered intravenously to New Zealand white rabbits. After allowing for distribution, the hearts were excised and exposed to 30 min of stop-flow ischemia and 30 min of reperfusion on a nonrecirculating Langendorf apparatus. There was diminished creatine phosphokinase release; improved peak positive dP/dt, developed pressure, and peak negative dP/dt; and diminished diastolic pressure in the group treated with U74006F. Thus, pretreatment with U74006F diminished myocardial injury and enhanced systolic and diastolic functional recovery, probably by protecting the lipid component of cell membranes from peroxidation by reactive oxygen metabolites.

Differentiation of Physiologically Significant Coronary Artery Lesions by Coronary Blood Flow Measurements During Isoproterenol Infusion

At cardiac catheterization, the effect of isoproterenol on coronary blood flow was compared in six patients with normal coronary arteries and normal left ventricular function, and eight patients with angiographically defined coronary lesions. Coronary blood flow was measured by selective coronary artery injection of xenon-133 and external monitoring of disappearance curves with a dual probe, digital scintillation counter. Resting values did not differ in the two groups. In the normal group isoproterenol increased mean coronary blood flow 93 ml/100 g/min (152%) and cardiac output 2.3 liters/min (42%); coronary resistance/100 g decreased 60 ± 4% (SEM), while total peripheral resistance decreased 29 ± 4%. In the coronary disease group coronary blood flow increased 20 ml/100 g/min (33%) and cardiac output increased 2.8 liters/min (62%); coronary resistance decreased 26 ± 9% and total peripheral resistance decreased 37 ± 4%. In all normal patients the percent increase in coronary blood flow markedly exceeded the percent increase in cardiac output and the percent fall in coronary resistance markedly exceeded the percent fall in total peripheral resistance. In six of the eight patients with coronary lesions the percent increase in coronary blood flow was less than the percent increase in cardiac output and the fall in coronary resistance was less than the fall in total peripheral resistance. Thus measurement of coronary blood flow, cardiac output, and aortic pressure before and during isoproterenol infusion may permit differentiation of those subjects with physiologically significant coronary obstructions.

Comparison of Isometric Exercise and Angiotensin Infusion as Stress Test for Evaluation of Left Ventricular Function

Abstract Isometric handgrip exercise and the angiotensin infusion test were compared to determine their relative usefulness in the assessment of ventricular reserve as adjuncts to cardiac catheterization. Both tests appeared to distinguish accurately normal from abnormal cardiac reserve. In all patients cardiac output, heart rate and minute work index were significantly higher with isometric exercise than with angiotensin infusion. Isometric exercise has a potential advantage over angiotensin infusion, since it evaluates function during a physiologic stress. Angiotensin infusion is more easily utilized in debilitated, sedated or uncooperative patients, but results may be more difficult to interpret because the drug may affect myocardial contractility and elicit reflex hemodynamic alterations. It is concluded that isometric stress testing is a useful and reliable method for the determination of cardiac reserve during cardiac catheterization.

Oxidation and release of glutathione from myocardium during early reperfusion

Glutathione (GSH) is an important intracellular defense against reactive oxygen metabolites. Reaction of GSH with peroxides generates oxidized glutathione (GSSG). We hypothesized that reperfusion would cause oxidation of GSH and release of GSSG as a potential marker of intracellular oxidative reactions. Ten dogs underwent 90 min left anterior descending (LAD) occlusion and 30 min reperfusion. Coronary sinus (CS) plasma was sampled from the great cardiac vein, which drains the LAD region, and from the aorta at pre-ischemia (I), 90 min ischemia, and during reperfusion (R). We found that both GSSG and GSH increased in coronary sinus plasma during early reperfusion. (Formula: see text) Measured GSSG did not arise from autoxidation of plasma GSH. GSH and GSSG release from myocardium not only may be evidence of intracellular oxidative injury, but loss of GSH also could impair metabolism of peroxides during early reperfusion and predispose to further injury.

Effect of acute volume loading on heart rate in the conscious dog.

The effect on heart rate of rapid elevation of ventricular filling pressure by intravenous infusion of isotonic solution was studied in 31 conscious dogs with autonomic innervation intact and during vagal, beta-receptor, or combined vagal and beta-receptor blockade. When parasympathetic innervation was intact, heart rate always rose during infusion and there was a consistent relationship between mean left atrial pressure and heart rate described by f = fm − (fm − fl) e−kp where f is the heart rate at any left atrial pressure, p, fm the maximum heart rate, fl the initial heart rate, and k a rate constant. Sympathetic blockade reduced the magnitude of the response and parasympathetic blockade prevented the response. It is concluded that a steady rise in filling pressure during intravenous infusion in a normally innervated, conscious dog invariably results in a tachycardia, which is due to either reflex inhibition of the parasympathetic nervous system or direct mechanical stimulation of the sinoatrial node.

Bucillamine prevents myocardial reperfusion injury

Injury during reperfusion can partially offset the benefit of relief of ischemia in myocardial infarctions rapidly treated with thrombolytic drugs or angioplasty. We assessed whether bucillamine (N-[2-mercapto-2-methylpropionyl]-L-cysteine) is potentially useful to treat myocardial reperfusion injury. Bucillamine is a potent sulfhydryl donor not previously tested as a treatment of reperfusion injury. Cardiac myocytes were exposed to hydrogen peroxide or a xanthine/xanthine oxidase system resulting in injury-induced release of lactate dehydrogenase. Bucillamine (125–500 &mgr;M) prevented lactate dehydrogenase release in a concentration-dependent manner. Bucillamine, which has two donatable thiol groups, was twice as protective as N-2-mercaptopropionyl glycine, which contains a single donatable thiol group. Dogs were then exposed to 90 min of coronary artery occlusion and 48 h of reperfusion before sacrifice. Beginning at the onset of reperfusion, bucillamine, 11 or 22 mg/kg per hour, or vehicle (saline) was administered intravenously for 3 h. There was a dose-related response to bucillamine for infarct size, normalized for size of the region at risk and adjusted for collateral blood flow to the ischemic region. Infarct size was reduced by 41% in the group treated with bucillamine 22 mg/kg per hour, compared with the vehicle group. Bucillamine, probably through an antioxidant mechanism, reduced infarct size when administered during reperfusion.