Abstract
The isolated rabbit heart (IRH) model has been used to investigate the proarrhythmic potential of marketed drugs or drugs intended for market. In addition, hemodynamic effects of a compound on left ventricular contractility can be measured in this model. We have validated negative and positive inotropic agents, including milrinone and diltiazem.Oligomycin is a natural antibiotic which inhibits mitochondrial complex V (ATP synthase). It inhibited both solution based Complex V activity with an IC50 of 0.34 μM and inhibited immuno‐Captured Complex V activity with an IC50 of 0.053 μM. Cardiac contraction requires high‐energy utilization and therefore is exquisitely sensitive to energy depletion. To test the effect of oligomycin on left ventricular contractility, IRH was perfused with increasing concentrations (0.1, 0.3, 1, and 3 μM) for 20 min at each concentration or with a single concentration of 0.3μM for 60 min. Oligomycin was found to decrease LV contractility in a dose‐ and time‐dependent manner. The time‐dependent effects of oligomycin as well as the prominent prolongation of PR intervals distinguished it from the standard Ca channel inhibitor, diltiazem. Our data suggests that oligomycin decreases LV contractility of IRH by primarily inhibiting mitochondrial Complex V.
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