Continuing metabolism is crucial for the function and cellular integrity of the ischaemic myocardium, and may be critically dependent on the substrate used. It can be manipulated by changing arterial substrate concentrations and/or by altering the metabolic regulation of the ischaemic myocardium directly, leading to a reduction in the severity of the ischaemic injury. One approach to alter metabolism is the use of anti-lipolytic drugs, which reduced in a series of independent studies ischaemia induced ST-segment elevation. On the other hand glucose utilisation may be enhanced, by a drug, dichloroacetate, shown to be effective in the normal myocardium. Enhanced glucose utilisation by the ischaemic zone after administration of dichloroacetate was associated with reduced ST-segment elevation, and a reduction in lactate release. Intralipid/heparin as a model to raise plasma free fatty acids was re-examined with improved methodology avoiding in vitro lipolysis. Arterial plasma free fatty acid concentrations were in the physiological range and related to fatty acid turnover. Plasma free fatty acid concentrations were raised without severe haemodynamic and arrhythmic side-effects by direct infusion of sodium oleate in normal dogs using a continuous blood cell separator. Sodium oleate was also infused during acute myocardial ischaemia, and did not precipitate serious ventricular arrhythmias. Xschaemic myocardial extraction of free fatty acids was raised, and did not influence that of glucose. The reduction in ST-segment elevation and free fatty acid extraction by the ischaemic myocardium after the administration of anti-lipolytic drugs support and extend other evidence that they reduce the severity of myocardial ischaemic injury. The most likely mechanism is inhibition of ischaemia-induced myocardial lipolysis, in view of the lack of a detrimental effect of sodium oleate infusion. However, a synergistic effect of reduced plasma free fatty acids can not be excluded.