A raised plasma level of homocysteine or hyperhomocysteinaemia (HHcy) is a strong independent risk factor for atherosclerotic and/or thrombotic disease (1,2). It is not currently known whether HHcy is a cause or a symptom of these conditions; nonetheless it has been reported that homocysteine may be pro-inflammatory, or a stimulator of either oxidative or endoplasmic reticulum stress (1,2). To date the majority of studies have concentrated upon vascular endothelial cells, smooth muscle cells or monocytes (1,2) with relatively little known about the whole heart under normal and pathological conditions. Therefore the aim of this study was to investigate the effects of homocysteine upon the function of the isolated and perfused heart before, during and after exposure to global ischaemia. Hearts from male adult Wistar rats were perfused with oxygenated Krebs at 37°C in the Langendorff constant pressure mode as previously described (3). After an initial equilibration period (at least 20 min), hearts (n = 12-13 per group) were exposed to 45 min global normothermic ischaemia followed by 30 min reperfusion. Throughout the experiment cardiac function was monitored via a thin-walled fluid filled balloon inserted into the left ventricle (3). Where used, 0.5mM homocysteine was constantly present from 30 min before ischaemia until 10 min into reperfusion when it was washed out. Results are presented as means ± s.e.m. Under normal conditions pre-ischaemia, perfusion with 0.5mM homocysteine caused a significant increase in coronary flow compared to control without homocysteine (16.6 ± 0.5 vs. 13.9 ± 0.9ml/min; p < 0.02, t test). Thereafter, the homocysteine perfused hearts showed a poorer functional recovery. At 30 min reperfusion the rate pressure product (RPP, heart rate in beats per minute (bpm) x left ventricular developed pressure in mmHg x 10³) of control hearts was 9.3 ± 0.8 compared to 6.9 ± 0.8 in the with homocysteine group (p<0.05, t test). There were no significant differences in the RPP prior to ischaemia (control, 22.0 ± 1.3 vs. with homocysteine, 21.2 ± 1.0 bpm x mmHg x 10³) or in the time to ischaemic contracture between the two groups (control, 16.8 ± 1.2 vs. with homocysteine, 19.2 ± 1.1 min). These results suggest that homocysteine cause changes to the coronary blood flow and vessels, which increase susceptibility to a subsequent ischaemic insult.