Beneficial effects of the Ca 2+ sensitizer EMD 57033 in exercising pigs with infarction‐induced chronic left ventricular dysfunction

It is unknown how cardiac stimulation by Ca 2+ sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca 2+ ‐sensitizer/phosphodiesterase‐III inhibitor pimobendan. Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n =12). Studies in MI were performed in the awake state, 2 – 3 weeks after infarction. MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dt max (18%), and a doubling of LV end‐diastolic pressure, compared to normal pigs (N, n =13). In 11 resting MI, intravenous EMD 57033 (0.2 – 0.8 mg kg −1  min −1 ) increased LVdP/dt max (57±5%) and stroke volume (26±6%) with no effect on heart rate, LV filling pressure, and myocardial O 2 ‐consumption, similar to N. In MI, the effects of EMD 57033 (0.4 mg kg −1  min −1 , IV) on stroke volume and LVdP/dt max were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P <0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise. Compared to N, the cardiostimulatory effects of pimobendan (20 μg kg −1  min −1 , IV) were blunted in MI both at rest and during exercise compared to N. In conclusion, the positive inotropic actions of the Ca 2+ sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca 2+ ‐sensitizer/phosphodiesterase‐III inhibitor pimobendan are blunted.British Journal of Pharmacology (2001) 134 , 553–562; doi: 10.1038/sj.bjp.0704292