Vasorelaxant mechanisms of the antidiabetic anagliptin in rabbit aorta: roles of Kv channels and SERCA pump

• Published in: Acta diabetologica 2024-08
• Main Authors: Heo, Ryeon, Park, Minju, Mun, Seo-Yeong, Zhuang, Wenwen, Jeong, Junsu, Park, Hongzoo, Han, Eun-Taek, Han, Jin-Hee, Chun, Wanjoo, Jung, Won-Kyo, Choi, Il-Whan, Park, Won Sun
• Format: Article
• Language: English
• ISSN: 1432-5233; 1432-5233
• DOI: 10.1007/s00592-024-02351-9

The present study investigated the vasorelaxant mechanisms of an oral antidiabetic drug, anagliptin, using phenylephrine (Phe)-induced pre-contracted rabbit aortic rings. Arterial tone measurement was performed in rabbit thoracic aortic rings. Anagliptin induced vasorelaxation in a dose-dependent manner. Pre-treatment with the classical voltagedependent K (Kv) channel inhibitors 4-aminopyridine and tetraethylammonium significantly decreased the vasorelaxant effect of anagliptin, whereas pre-treatment with the inwardly rectifying K (Kir) channel inhibitor Ba , the ATP-sensitive K (K ) channel inhibitor glibenclamide, and the large-conductance Ca -activated K (BKCa) channel inhibitor paxilline did not attenuate the vasorelaxant effect. Furthermore, the vasorelaxant response of anagliptin was effectively inhibited by pre-treatment with the sarco/endoplasmic reticulum Ca -ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid. Neither cAMP/protein kinase A (PKA)-related signaling pathway inhibitors (adenylyl cyclase inhibitor SQ 22536 and PKA inhibitor KT 5720) nor cGMP/protein kinase G (PKG)-related signaling pathway inhibitors (guanylyl cyclase inhibitor ODQ and PKG inhibitor KT 5823) reduced the vasorelaxant effect of anagliptin. Similarly, the anagliptin-induced vasorelaxation was independent of the endothelium. Based on these results, we suggest that anagliptin-induced vasorelaxation in rabbit aortic smooth muscle occurs by activating Kv channels and the SERCA pump, independent of other vascular K channels, cAMP/PKA- or cGMP/PKG-related signaling pathways, and the endothelium.