Cardiac dysfunction resulting from a myocardial infarction (MI) is a leading cause of death in Western society. Chronic application of K201 (a 1,4-benzothiazepine derivative1) to animal models of cardiac dysfunction has been shown to attenuate a decline in cardiac performance in vivo 2;3. This effect has been attributed to improved calcium handling in ventricular cardiomyocytes. However, the effects of K201 are not limited to cardiac tissue since K201 improves skeletal muscle fatigue3 and enhances glomerular filtration rate4. The acute effects of K201 on hearts with MI independent of systemic involvement is unknown. In order to investigate this question, adult New Zealand White rabbits (2.5-3.5 kg) were premedicated with intramuscular fentanyl/fluanizone (0.3ml.kg-1) and induced with intravenous midazolam (1-2mg.kg-1). Under maintained anaesthesia (1:1 mixture of nitrous oxide and oxygen containing 2% halothane) the circumflex branch of the left coronary artery was ligated to induce MI (n=4). Sham control animals (n=4) underwent identical surgery without coronary artery ligation. 8 weeks after surgery, echocardiographic assessment of left ventricular (LV) size and function was performed under anaesthesia (fentanyl/fluanizone 0.3ml.kg-1). Hearts were then removed under terminal anaesthesia (pentobarbitone, i.v.) and cannulated onto an isolated working heart system. Preload (7 mmHg) and afterload (60 mmHg) were kept constant. Mechanical function was assessed by insertion of a 3F multi-segmental pressure volume catheter. Hearts were paced at 200 beats.min-1. Values are mean ± S.E.M., compared by 2-sample Student’s t-test. Comparison of ligation (MI) and sham animals via echocardiographic assessment revealed significantly increased LV end diastolic dimension (20.4±0.5 mm vs. 17.3±0.5 mm, p<0.05) and reduced ejection fraction (EF) (42.5±2.2% vs. 69.5±1.6%, p<0.05; MI vs. sham) indicating left ventricular dysfunction. Pressure-volume catheterisation of the same 4 isolated working hearts revealed significantly reduced dP/dtmin (-1661.9±60.0 mmHg.s-1 vs. -2112.0±131.9 mmHg.s-1, p<0.05; MI vs. sham) and EF (51.8±4.1% vs. 68.7±1.4%, p<0.05; MI vs. sham) and elevated end systolic volumes (1081.1±41.9 µL vs. 647.9±58.3 µL, p<0.05; MI vs. sham). After 9 min perfusion with 1.0µM K201 the % change from pre-K201 values in developed pressure (93.7±1.5% vs. 98.6±0.9%, p<0.05), dP/dtmax (84.1±2.1% vs. 92.5±0.7%, p<0.05) and dP/dtmin (86.6±3.9 vs. 98.4±2.3%, p<0.05; sham vs. MI) was significantly greater in sham vs. MI. Coronary flow was unaltered by 1.0µM K201. The reasons for the lack of effect observed with acute application of K201 in hearts with MI is unknown, however the data demonstrate distinct effects of K201 on cardiac inotropy in normal compared to failing hearts.