Pan-PPAR agonists directly target BK channels for the acute relaxation of pulmonary arteries.

<bold>Background:</bold> We showed that prostanoids utilize the PPAR pathway to achieve their vasodilative effects. Specifically, PPAR beta/delta serves as a key mediator, altering membrane potential via potassium channels from the extracellular side. PPAR agonists have recently recognition as promising novel drugs with anti-proliferative, anti-inflammatory with potential for treating pulmonary hypertension (PH). However, the molecular mechanisms through which PPAR agonists modulate pulmonary vascular tone remain largely unknown. The current study aims to evaluate the effect of lanifibranor (a pan-PPAR agonist) on the activation of large conductance calcium-activated potassium channels (BK) channels. <bold>Methods:</bold> Freshly isolated intrapulmonary arteries from mice were utilized in wire myography experiments to evaluate the acute effect of the pan-PPAR agonist on pulmonary vascular tone. Xenopus oocytes expressing BK channel were employed in the two-electrode voltage-clamp technique. BK currents in HEK cells were measured using the whole-cell patch-clamp technique. <bold>Results:</bold> The PAN-PPAR agonist Lanifibranor significantly activated potassium current in Xenopus oocytes injected with the BK channel. Notably, experiments conducted in the inside-out configuration Lanifibranor similarly activated BK channels in HEK cells. Furthermore, PAN-PPAR agonist’s stimulated vasodilation was markedly reduced by pharmacological inhibition of the BK channel or in BK knockout mice. <bold>Conclusion:</bold> The observed vasoactive effects of pan-PPAR are dependent of BK channel activation, delineating direct PPAR agonism on BK channels. Suggesting Pan-PPAR agonists could hold promise as a therapeutic option for patients with PH