The anti-diabetic drug repaglinide induces vasorelaxation via activation of PKA and PKG in aortic smooth muscle

Abstract

We investigated the vasorelaxant effect of repaglinide and its related signaling pathways using phenylephrine (Phe)-induced pre-contracted aortic rings. Repaglinide induced vasorelaxation in a concentration-dependent manner. The repaglinide-induced vasorelaxation was not affected by removal of the endothelium. In addition, application of a nitric oxide synthase inhibitor (L-NAME) and a small-conductance Ca2+-activated K+ (SKca) channel inhibitor (apamin) did not alter the vasorelaxant effect of repaglinide on endothelium-intact arteries. Pretreatment with an adenylyl cyclase inhibitor (SQ 22536) or a PKA inhibitor (KT 5720) effectively reduced repaglinide-induced vasorelaxation. Also, pretreatment with a guanylyl cyclase inhibitor (ODQ) or a PKG inhibitor (Kt 5823) inhibited repaglinide-induced vasorelaxation. However, pretreatment with a voltage-dependent K+ (Kv) channel inhibitor (4-AP), ATP-sensitive K+ (K-ATP) channel inhibitor (glibenclamide), large-conductance Ca2+-activated K+ (BKCa) channel inhibitor (paxilline), or the inwardly rectifying K+ (Kir) channel inhibitor (Ba2+) did not affect the vasorelaxant effect of repaglinide. Furthermore, pretreatment with a Ca2+ inhibitor (nifedipine) and a sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor (thapsigargin) did not affect the vasorelaxant effect of repaglinide. The vasorelaxant effect of repaglinide was not affected by elevated glucose (50 mM). Based on these results, we conclude that repaglinide induces vasorelaxation via activation of adenylyl cyclase/PKA and guanylyl cyclase/PKG signaling pathways independently of the endothelium, K+ channels, Ca2+ channels, and intracellular Ca2+ ([Ca2+](i)). (C) 2016 Elsevier Inc. All rights reserved.