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

Abstract

AimsWe investigated the vasorelaxant effect of nateglinide and its related mechanisms using phenylephrine (Phe)-induced precontracted aortic rings. MethodsArterial tone measurement was performed in aortic smooth muscle. ResultsThe application of nateglinide induced vasorelaxation in a concentration-dependent manner. Pretreatment with the large-conductance Ca2+-activated K+ (BKCa) channel inhibitor paxilline, the inwardly rectifying K+ (Kir) channel inhibitor Ba2+, 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 Ca2+ inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 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 Ca2+-activated K+ (SKCa) channel inhibitor, apamin, did not change the vasorelaxant effect of nateglinide. ConclusionNateglinide induced vasorelaxation via the activation of the Kv channel independent of other K+ channels, Ca2+ channels, intracellular Ca2+ ([Ca2+](i)), and the endothelium.