The vasorelaxant effect of antidiabetic drug nateglinide via activation of voltage‐dependent K⁺ channels in aortic smooth muscle

Summary Aims We investigated the vasorelaxant effect of nateglinide and its related mechanisms using phenylephrine (Phe)‐induced precontracted aortic rings. Methods Arterial tone measurement was performed in aortic smooth muscle. Results The application of nateglinide induced vasorelaxation in a concentration‐dependent manner. Pretreatment with the large‐conductance Ca 2+ ‐activated K + (BK Ca ) channel inhibitor paxilline, the inwardly rectifying K + (Kir) channel inhibitor Ba 2+ , and ATP ‐sensitive K + ( K ATP ) channel inhibitor glibenclamide did not affect the vasorelaxant effect of nateglinide. However, pretreatment with the voltage‐dependent K + (Kv) channel inhibitor 4‐aminopyridine (4‐ AP ) effectively reduced the vasorelaxant effect of nateglinide. Pretreatment with the Ca 2+ inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca 2+ ‐ ATP ase inhibitor thapsigargin did not change the vasorelaxant effect of nateglinide. Additionally, the vasorelaxant effect of nateglinide was not altered in the presence of an adenylyl cyclase, a protein kinase A, a guanylyl cyclase, or a protein kinase G inhibitor. The vasorelaxant effect of nateglinide was not affected by the elimination of the endothelium. In addition, pretreatment with a nitric oxide synthase inhibitor, L‐ NAME , and a small‐conductance Ca 2+ ‐activated K + ( SK C a ) channel inhibitor, apamin, did not change the vasorelaxant effect of nateglinide. Conclusion Nateglinide induced vasorelaxation via the activation of the Kv channel independent of other K + channels, Ca 2+ channels, intracellular Ca 2+ ([Ca 2+ ] i ), and the endothelium.