Background: The ubiquitous nuclear receptor PPARβ/δ is increasingly being studied in
regards to numerous diseases including diabetes following on the finding that PPARβ/δ agonist GW0742
controls Type 1 Diabetes in rats. Studies have shown that GW0742 has off target, non- PPARβ/δ effects
in the cell although there are some key questions that remain to be addressed in respect to the significance
of this control on vascular tone.
Methods: Using isometric organ baths, rat aorta rings were exposed to ROCK inhibitors and the changes
in contraction and dilation measured.
Results: Our data shows that the PPARβ/δ agonist GW0742 (10-7M) inhibits contractile responses to
U46619 and phenylephrine, and that these responses are similar in normal and Streptozotocin (STZ)
diabetic rat aorta. ROCK inhibitors Fasudil and Y27632 significantly reduced GW0742 mediated dilation
of naïve rat aorta, but Fasudil had no effect on GW0742 dilation in STZ diabetic rat aorta. In contrast,
STZ diabetic rat aorta pre-contracted with high [K+] Krebs lacked a dilatory response to GW0742, which
taken together indicates that the mechanism of action of GW0742 mediated dilation changes in the
diabetic state compared to non-diabetic state.
Conclusion: This is the first direct evidence demonstrating the non- PPARβ/δ effect of GW0742 on contraction
is irrespective to the diabetic state, and that GW0742 has the potential to induce vasodilation via
multiple off-target mechanisms.