Key result
PPARδ agonist GW0742 increases cardiac contractility ~80% without altering heart rate in rat models.
Why the study?
Agents with positive inotropic effects for heart failure alter heart rate, and the effect of PPARδ activation on heart rate is unknown.
Does GW0742 increase cardiac contractility without altering heart rate in rat models?
Does GW0742 increase cardiac contractility without altering heart rate in rat models?
Absolute Event Rate: 24.45% vs 13.6%
p-value: p=<0.01
Activation of PPARδ by GW0742 increases cardiac contractility without altering heart rate, suggesting a potential new target for inotropic agents in heart failure.
May offer inotropy without chronotropy in HF models; leaves open clinical translation in humans.
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.
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Chen et al. (2013) studied Heart failure and Type 1 diabetes. GW0742 vs. Vehicle control was evaluated on Developed Pressure (ΔmmHg) in isolated rat hearts (p=<0.01). Activation of PPARδ by GW0742 significantly increased cardiac contractility without altering heart rate in rat models, suggesting a potential target for inotropic agents.
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