The vasorelaxant effect of mitiglinide via activation of voltage-dependent K⁺ channels and SERCA pump in aortic smooth muscle

초록

Aims: The vasorelaxant effects of the anti-diabetic drug, mitiglinide in phenylephrine (Phe)-pre-contracted aortic rings were examined. Materials and methods: Arterial tone measurement was performed in aortic smooth muscle cells. Key findings: Mitiglinide dose-dependently induced vasorelaxation. Application of the large-conductance Ca2+-activated K+ (BKCa) channel blocker paxilline, inwardly rectifying K+ (Kir) channel blocker Ba2+, and ATP sensitive K+ (K-ATP) channel blocker glibenclamide did not affect the vasorelaxant effect of mitiglinide. However, application of the voltage-dependent K+ (Kv) channel blocker 4-AP, effectively inhibited mitiglinide-induced vasorelaxation. Although pretreatment with the Ca2+ channel blocker nifedipine did not alter the mitiglinide-induced vasorelaxation, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor thapsigargin and cyclopiazonic add reduced the vasorelaxant effect of mitiglinide. In addition, the vasorelaxant effect of mitiglinide was not affected by the inhibitors of adenylyl cyclase, protein kinase A, guanylyl cyclase, or protein kinase G. Elimination of the endothelium and inhibition of endothelium-dependent vasorelaxant mechanisms also did not change the vasorelaxant effect of mitiglinide. Significance: We proposed that mitiglinide induces vasorelaxation via activation of Kv channels and SERCA pump. However, the vasorelaxant effects of mitiglinide did not involve other K+ channels, Ca2+ channels, PKA/PKG signaling pathways, or the endothelium.

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