TRPM4 inhibitor 9‐phenanthrol activates endothelial cell intermediate conductance calcium‐activated potassium channels in rat isolated mesenteric artery

Background and Purpose Smooth muscle transient receptor potential melastatin 4 ( TRPM 4) channels play a fundamental role in the development of the myogenic arterial constriction that is necessary for blood flow autoregulation. As TRPM 4 channels are present throughout the vasculature, we investigated their potential role in non‐myogenic resistance arteries using the TRPM 4 inhibitor 9‐phenanthrol. Experimental Approach Pressure and wire myography were used to assess the reactivity of rat arteries, the latter in combination with measurements of smooth muscle membrane potential. Immunohistochemistry (IHC) and endothelial cell ( EC ) calcium changes were assessed in pressurized vessels and patch clamp measurements made in isolated EC s. Key Results The TRPM 4 inhibitor 9‐phenanthrol reversibly hyperpolarized mesenteric arteries to circa E K and blocked α 1 ‐adrenoceptor‐mediated vasoconstriction. Hyperpolarization was abolished and vasoconstriction re‐established by damaging the endothelium. In mesenteric and cerebral artery smooth muscle, 9‐phenanthrol hyperpolarization was effectively blocked by the K Ca 3.1 inhibitor TRAM‐34. 9‐Phenanthrol did not increase mesenteric EC [ Ca 2+ ] i , and Na + substitution with N ‐methyl‐ D ‐glucamine only increased the muscle resting potential by 10 m V . Immunolabelling for TRPM 4 was restricted to the endothelium and perivascular tissue. Conclusions and Implications These data reveal a previously unrecognized action of the TRPM 4 inhibitor 9‐phenanthrol – the ability to act as an activator of EC K Ca 3.1 channels. They do not indicate a functionally important role for TRPM 4 channels in the reactivity of non‐myogenic mesenteric arteries.