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This study was undertaken to investigate whether the normal dog heart would switch to lactate as the preferred substrate when the arterial lactate level was raised. Sodium L-Lactate (pH adjusted to 7.0) was infused intravenously in sufficient quantity to raise the arterial lactate levels to those found in moderate to severe exercise (over 4.5 mmol . litre-1). The dogs were studied under chloralose anaesthesia breathing spontaneously. Blood samples were obtained from a branch of the femoral artery and the coronary sinus, and analysed for lactate, glucose, fatty free acids (FFA) and oxygen content. The ratio of lactate consumption to oxygen consumption was used to express the amount of lactate oxidised as a percentage of total substrate. This ratio was found to be a function of arterial lactate and reached a maximum at an arterial lactate concentration of 4.5 mmol . litre-1; this was uninfluenced by raised arterial glucose or FFA--the myocardium preferred lactate to glucose or FFA. A direct measurement of lactate oxidised as a percentage of total fuel was obtained in experiments with L-Lactate-[14C(U)], these showed that when the arterial lactate concentration was above 4.5 mmol . litre-1, even in the presence of high glucose or FFA, 87% of the total substrate oxidised was lactate. These results show that when the normal dog heart is presented with a choice of substrates, lactate is the preferred substrate for energy production.

We measured glucose metabolism in five dogs before and 3 weeks after cardiac denervation; after this time myocardial norepinephrine is depleted. The discharge by the myocardium, of 14CO2 from infused 14C-D-glucose (U), decreased following denervation (P = 0.05). The ratio of 14CO2 to total CO2 production, which measured the proportion of glucose to total substrate oxidized, also decreased following denervation (P = 0.05). The inhibition of glucose oxidation by denervation was not due to an increase in arterial lactate concentration. There was an associated increase in myocardial content of fructose-6-phosphate in an additional seven dogs (P < 0.01). We postulate that myocardial tissue norepinephrine is one of the controllers of the activity of phosphofructokinase.

The metabolic and haemodynamic effects of adrenaline were investigated in 6 intact anaesthetized dogs, which were subjected to an infusion of adrenaline. The dose given was similar to the endogenous production rate of adrenaline in experimental myocardial infarction. Adrenaline infusion (0.8, 1.17 ot 1.05 micrograms . kg-1 . min-1) over two hours led to a variable rise in blood level of this amine, regardless of the rate of infusion. Dogs with high blood adrenaline (over 3.5 ng . ml-1) exhibited haemodynamic deterioration, i.e. a rise in peripheral vascular resistance together with a fall in cardiac output and external cardiac work. Dogs with low blood adrenaline showed little change in peripheral vascular resistance, a rise in cardiac output and external cardiac work. The myocardial consumption of each of the substrates lactate, pyruvate, glucose and FFA was measured, and its equivalent oxygen consumption expressed as a percentage of the total myocardial oxygen consumption. No relationship was found between myocardial utilisation of individual substrates and the type of haemodynamic response. Thus in intact dogs exposed to adrenaline excess, similar to that found in acute myocardial infarction, the different types of haemodynamic response cannot be attributed to the type of substrate utilization by the myocardium, but to different rates of clearance of adrenaline. Low clearance rates lead to high blood adrenaline levels and an unfavourable response of the cardiovascular system.

Substrate extraction is the disappearance of a substance from arterial blood into the myocardium, substrate utilization being the combustion of that substrate. The terms used for extraction and utilization are defined. There are many problems of accurately measuring glucose and free fatty acid oxidation. Lactate is the preferred substrate of the normal, blood-perfused heart. If the substrate oxidized affects the myocardial oxygen consumption, this could be of considerable importance under conditions of limited oxygen supply. At present there is conflicting evidence. It may be beneficial to switch the heart from one substrate to another, e.g., from fat to carbohydrate fuels. The conditions of ischaemia and hypoxaemia are not the same, and future investigations should be made under carefully controlled conditions.

1. Mongrel dogs were anaesthetized with chloralose, paralysed, ventilated and vagotomized and given a beta-blocking drug, sotalol, in sufficient doses to block the effects of 5 microgram of adrenaline. 2. Changes in inspired CO2 concentration were produced, causing increases of arterial PCO2 up to 120 mmHg. The effects on myocardial blood flow were measured with radioactive microspheres. Coronary sinus and arterial blood was sampled. 3. In the absence of beta-blockade, an increase in arterial PCO2 produced variable effects. In some dogs coronary blood flow increased, while in others there was no change. There was a mean increase in coronary blood flow at arterial PCO2 values above 85 mmHg which was abolished by beta-blockade. 4. In the presence of beta-blockade, an increase of arterial PCO2 produced depression of left ventricular performance, i.e. a fall of maximum rate of rise of left ventricular pressure and a rise of left ventricular end-diastolic pressure. 5. In the presence of beta-blockade, there were no consistent changes in myocardial blood flow, left ventricular pressure or cardiac output. 6. In the absence of beta-blockade, coronary arterial minus venous ocygen content was reduced by hypercapnia. In the presence of beta-blockade, the changes were small and not statistically significant. The direct coronary vasodilator effect was therfore negligible. 7. It is concluded that the previously reported hypercapnic vasodilatation was mainly an effect of sympatho-adrenergic stimulation by hypercapnia. 8. In the presence of beta-blockade, coronary sinus PO2 increased markedly, with little change in coronary sinus oxygen content; this was consistent with a shift to the right of the oxy-haemoglobin dissociation curve. Under circumstances of hypercapnia, a rise in coronary sinus (and presumably tissue) PO2 failed to produce vasoconstriction. 9. It is argued that the vasodilator effect of hydrogen ions and the vasoconstrictor effect of oxygen probably cancel one another when the arterial PCO2 is raised.