Cardiac Peroxisome Proliferator-Activated Receptor δ (PPARδ) as a New Target for Increased Contractility without Altering Heart Rate

BACKGROUND AND AIMS: Agents having a positive inotropic effect on the heart are widely used for the treatment of heart failure. However, these agents have the side effect of altering heart rate. It has been established that peroxisome proliferator-activated receptor δ (PPARδ) is mediated in cardiac contraction, however the effect on heart rate is unknown. Thus, we used an agonist of PPARδ, GW0742, to investigate this issue in the present study. METHODS AND RESULTS: We used isolated hearts in Langendorff apparatus and hemodynamic analysis in catheterized rats to measure the actions of GW0742 extra-vivo and in vivo. In diabetic rats with heart failure, GW0742 at a dose sufficient to activate PPARδ reversed cardiac contraction without changes in heart rate. In normal rats, PPARδ enhanced cardiac contractility and hemodynamic dP/dtmax significantly more than dobutamine. Both actions were diminished by GSK0660 at a dose enough to block PPARδ. However, GW0742 at the same dose failed to modify heart rate, although it did produce a mild increase in blood pressure. Detection of intracellular calcium level and Western blotting analysis showed that the intracellular calcium concentration and troponin I phosphorylation were both enhanced by GW0742. CONCLUSION: Activation of PPARδ by GW0742 increases cardiac contractility but not heart rate. Thus, PPARδ may be a suitable target for the development of inotropic agents to treat heart failure without changing heart rate.