O. D. Mjös

Effect of free fatty acids on myocardial function and metabolism in the ischemic dog heart

Since elevation of plasma concentrations of free fatty acids (FFA) increases myocardial oxygen consumption without influencing mechanical performance in normal hearts, it was the purpose of this study to determine whether FFA would modify mechanical performance at limited oxygen supply. Left coronary blood flow was reduced by gradual clamping of a shunt from the left carotid artery until moderate ventricular dilatation supervened. Left ventricular systolic pressure (LVSP), its maximal rate of rise (dP/dt) and stroke volume (SV) were unchanged or slightly reduced. The ischemia resulted in a decrease in myocardial oxygen consumption (MVO(2)) from 9.7+/-1.1 ml/min to 7.9+/-0.8 ml/min, and myocardial lactate uptake was reduced or reversed to excretion. Increasing the plasma concentrations of FFA from 359+/-47 muEq/1 to 3688+/-520 muEq/1 by intravenous infusion of a triglyceride emulsion and heparin resulted in further ventricular dilatation, accompanied by increased excretion of lactate. The ventricular decompensation and enhancement of anaerobic myocardial metabolism associated with increased uptake of FFA was not related to changes in coronary flow, MVO(2), or LVSP. dP/dt and SV were virtually unchanged. Intravenous infusion of glucose/insulin, which lowered plasma concentrations of FFA, reversed ventricular dilatation and lactate excretion. The data support the hypothesis that high concentrations of FFA play a significant role in increasing myocardial oxygen requirement and thereby promote depression of contractility of the hypoxic heart in experimental animals.

Effect of Inhibition of Lipolysis on Infarct Size After Experimental Coronary Artery Occlusion

Recent studies have demonstrated a depressant effect of increased delivery of FFA to the hypoxic heart. Because catecholamines are released in acute myocardial infarction, it is likely that lipolytic activity is increased. The purpose of this study was to determine whether inhibition of hormone-sensitive lipases influence the extent and severity of myocardial ischemic injury produced by coronary occlusion. Myocardial infarction was produced by occlusion of the left anterior descending coronary artery in open-chest dogs. 15 min later a surface map of S-T segments was obtained with the use of 10-14 epicardial leads in the distribution area of the occluded artery. Average S-T segment elevation of all sites was used as an index of myocardial ischemic injury. Before coronary occlusion, the average S-T segment elevation was 0.3+/-0.2, which increased to 4.1+/-0.7 mV (SEM, 12 dogs) after occlusion. Inhibition of lipolytic activity by beta-pyridyl-carbinol before repeated coronary occlusion reduced the occlusion-induced S-T segment elevation to 2.1+/-0.6 mV (P < 0.001). When arterial concentrations of FFA were raised by i.v. infusion of a triglyceride emulsion and heparin, average S-T segment elevation after coronary occlusion increased from 1.2+/-0.7 to 2.2+/-0.8 mV (P < 0.05) in animals treated with beta-pyridyl-carbinol, which suggests an unfavorable effect of circulating FFA in this setting. Isoproterenol given before a repeated occlusion increased the severity and extent of the ischemic injury. The effect of isoproterenol on the occlusion-induced S-T segment elevation was reduced, however, when the lipolytic effect of the drug was inhibited by beta-pyridyl-carbinol. Our study suggests that beta-pyridyl-carbinol during acute coronary artery occlusion may be of importance in reducing the extent and severity of myocardial ischemic injury.

Importance of Free Fatty Acids as a Determinant of Myocardial Oxygen Consumption and Myocardial Ischemic Injury during Norepinephrine Infusion in Dogs

Increased delivery of free fatty acids raises myocardial oxygen consumption (MVO(2)) without influencing mechanical performance. The effects of norepinephrine on MVO(2) and on the size of ischemic injury after acute coronary occlusion were therefore studied before and during inhibition of lipolysis with beta-pyridylcarbinol. In spite of similar mechanical responses to norepinephrine, MVO(2) increased by 57+/-11% before and significantly less, 31+/-6%, (P < 0.01) during inhibition of lipolysis. After coronary occlusion the ischemic injury associated with norepinephrine infusion, as evidenced by epicardial mapping of S-T segment elevation, was larger before (7.9+/-1.1 mV) than during inhibited lipolysis (2.8+/-0.4 mV; P < 0.005). Average S-T segment elevation associated with norepinephrine infusion during inhibited lipolysis (2.8+/-0.4 mV) was even lower (P < 0.05) than during control occlusion alone, before drug administration (4.4+/-0.7 mV). In conjunction with an antilipolytic agent, norepinephrine was shown to reduce the extent and magnitude of the myocardial ischemic injury produced by acute coronary occlusion; this could be due to an improved balance between myocardial oxygen supply and requirement.

Compensatory mechanisms during graded myocardial ischemia

Abstract Hemodynamic and metabolic compensatory mechanisms in myocardial ischemia were studied in anesthetized dogs. Ischemia was produced by graded reduction in coronary blood flow in hearts in which the left coronary artery was perfused through a shunt from a carotid artery. Despite a reduction in myocardial oxygen supply of as much as 20 percent, cardiac output remained unchanged. At reductions in myocardial oxygen supply of 20 to 50 percent of control value, cardiac output was maintained, but at a lower level. Further reduction was not compatible with stable hemodynamic conditions. Reduction in coronary blood flow was closely associated with concomitant ventricular dilatation and reduced myocardial contractility, and this finding could explain the maintained cardiac output at a reduced level of myocardial oxygen supply. Decreased myocardial contractility reduced myocardial oxygen demand, whereas ventricular dilatation maintained stroke volume on a geometric basis. These alterations in myocardial mechanics were found to be the most important compensatory mechanism in reduced myocardial oxygen supply; the contributions of increased myocardial oxygen extraction and myocardial anaerobiosis were of minor significance.

Clinical Physiology: Effects of Nicotine and Inhalation of Cigarette Smoke on Total Body Oxygen Consumption in Dogs

The effects on total body oxygen consumption of nicotine infused intravenously and of simulated cigarette smoking were studied in intact anesthetized dogs. Nicotine infusion and simulated cigarette smoking raised total body oxygen consumption by 9 plus or minus 2% (mean plus or minus S.E.M.; P smaller than 0.02) and 6 plus or minus 2% (P smaller than 0.05), respectively, and arterial concentration of free fatty acids (FFA) by 29 plus or minus 9% (P smaller than 0.05) and 12 plus or minus 3% (P smaller than 0.01). When nicotine infusion and simulated cigarette smoking were repeated during inhibition of lipolysis with beta-pyridylcarbinol, no rise in total body oxygen consumption occurred, although the mean aortic blood pressure and heart rate remained elevated to levels similar to those during intact lipolysis. It is concluded that the rise in total body oxygen consumption induced by intravenously infused nicotine or simulated cigarette smoking was probably mediated through increased mobilization and consumption of FFA.

Cardiac effects of isoproterenol during graded myocardial ischemia.

Conflicting results of isoproterenol administration to patients with ischemic heart disease suggest that the effect of isoproterenol on cardiac function is related to the severity of myocardial ischemia. Myocardial oxygen consumption (MVO2) was therefore reduced by graded reductions in coronary blood flow before and after coronary administration of isoproterenol in 9 anesthetized dogs. When coronary blood flow was reduced by less than 50 per cent of control value, cardiac output and maximal value of left ventricular pressure rise (dP/dt) were higher with isoproterenol than without at similar values of MVO2. When coronary blood flow was further reduced, however, cardiac output and dP/dt were depressed by isoproterenol. Myocardial lactate production was at any MVO2 value higher during isoproterenol administration than during control periods, and stimulation of myocardial glycolysis by isoproterenol might –- at least in part –- explain an improved cardiac function during moderate ischemia. From these experim...

Effects of nicotine on myocardial metabolism and performance in dogs.

Nicotine infused i.v. is known to increase plasma free fatty acids (FFA). As increased delivery of FFA raises myocardial oxygen consumption (MVO2) without influencing mechanical performance, the effect of nicotine i.v. on MVO2 was studied before and during inhibition of lipolysis with β-pyridyl-carbinol. Although mechanical responses to nicotine –- evidenced by left ventricular pressure, maximal rate of rise of left ventricular pressure (dP/dt), cardiac output, and mean aortic blood pressure - rose similarly in both settings, MVO2 increased by 4.1 ± 0.9 ml · min−1 · 100 g−1 (mean ± S.E.M.) before and 2.1 ± 0.6 ml · min−1 · 100 g−1 (P < 0.005) during inhibition of lipolysis. In conclusion about 50 per cent of the nicotine-induced rise in MVO2 was related to enhanced mechanical activity of the heart, the remainder being attributable to a metabolic stimulation of high concentrations of FFA.

Effects of Glucagon and Isoproterenol on Severity of Acute Myocardial Ischemic Injury

Comparison was made between the effects of isoproterenol and glucagon on myocardial ischemic injury following acute coronary artery occlusion in 8 dogs. Maximal rate of left ventricular pressure rise (dP/dt) was similarly increased by isoproterenol (63 ± 6 %) (mean ± S.E.M.) and glucagon (65 ± 5 %) infusions. Ischemic injury was measured as the sum of S-T segment elevations in epicardial ECG recordings from 8–10 sites (σST). σST during coronary artery occlusion alone averaged 22 ± 1 mV. Reocclusion of the artery performed during isoproterenol infusion increased σST to 70 ± 7 mV, while during glucagon σST rose to only 51 ± 7 mV. The difference in σST obtained with isoproterenol and glucagon was statistically significant (P < 0.001). Arterial concentrations of free fatty acids (FFAa) were raised from 225 ± 26 to 1213 ± 166 μEq/l by isoproterenol (P < 0.001), whereas glucagon had no significant effect upon FFAa. The experiments were repeated after inhibition of catecholamine-induced lipolysis with β-pyridyl ...

Effect of nicotine on severity of acute myocardial ischemic injury in dogs.

This study was undertaken to examine the effect of nicotine intravenously (i.v.) on the severity of myocardial ischemic injury following acute coronary artery occlusion in dogs. The myocardial ischemic area was measured by the sum of ST-segment elevations (ST) in epicardial ECG-registrations from 5–12 sites in nine anesthetized open-chest dogs. During coronary artery occlusion alone, ST averaged 22.7 ± 4.6 mV (mean ± S.E.M.). At reocclusion of the coronary artery during a continuous i.v. infusion of nicotine, ∑ ST rose by 6.4 ± 1.8 mV (P < 0.01). Arterial concentration of free fatty acids (FFA) rose from 251 ± 31 μEq/l to 323 ± 50 μEq/l (P < 0.05). When lipolysis was inhibited with β-pyridyl carbinol, as examined in six dogs, nicotine i.v. failed to raise ∑ ST at coronary occlusion, nor did arterial concentration of FFA rise. In conclusion the increased severity of acute myocardial ischemic injury induced by nicotine is probably related in increased myocardial oxygen requirements caused by excess myocardi...