Hongliang Li1, Sung Eun Shin1, Mi Seon Seo1, Jin Ryeol An1, Il-Whan Choi2, Won-Kyo Jung3, Amy L Firth4, Dae-Sung Lee5, Mi-Jin Yim5, Grace Choi5, Jeong Min Lee5, Sung Hun Na6, Won Sun Park7. 1. Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea. 2. Department of Microbiology, Inje University College of Medicine, Busan 48516, South Korea. 3. Department of Biomedical Engineering, and Center for Marine-Integrated Biomedical Technology (BK21 Plus) Pukyong National University, Busan 608-737, South Korea. 4. Department of Pulmonary, Critical Care and Sleep Medicine, University of Southern California, Keck School of Medicine, Los Angeles CA90033, USA. 5. Department of Applied Research, National Marine Biodiversity Institute of Korea, Seocheon 33662, South Korea. 6. Institute of Medical Sciences, Department of Obstetrics and Gynecology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon 24341, South Korea. Electronic address: lahun@kangwon.ac.kr. 7. Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea. Electronic address: parkws@kangwon.ac.kr.
Abstract
AIM: Considering the clinical efficacy of dapagliflozin in patients with type 2 DM and the pathophysiological relevance of Kv channels for vascular reactivity. We investigate the vasodilatory effect of dapagliflozin and related mechanisms using phenylephrine (Phe)-induced contracted aortic rings. MATERIAL AND METHODS: Arterial tone measurement was performed in aortic smooth muscle. KEY FINDINGS: Application of dapagliflozin induced vasodilation in a concentration-dependent manner. Pre-treatment with the BKCa channel inhibitor paxilline, the KATP channel inhibitor glibenclamide, and the Kir channel inhibitor Ba2+ did not change dapagliflozin-induced vasodilation. However, application of the Kv channels inhibitor 4-AP effectively inhibited dapagliflozin-induced vasodilation. Application of the Ca2+ channel inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor thapsigargin did not alter the vasodilatory effect of dapagliflozin. Moreover, the adenylyl cyclase inhibitor SQ 22536 and the protein kinase A (PKA) inhibitor KT 5720 had no effect on dapagliflozin-induced vasodilation. Although guanylyl cyclase inhibitors, NS 2028 and ODQ, did not reduce the vasodilatory effect of dapagliflozin, the protein kinase G (PKG) inhibitor KT 5823 effectively inhibited dapagliflozin-induced vasodilation. The vasodilatory effect of dapagliflozin was not affected by elimination of the endothelium. Furthermore, pretreatment with the nitric oxide synthase inhibitor L-NAME or the small-conductance Ca2+-activated K (SKCa) channel inhibitor apamin did not change the vasodilatory effect of dapagliflozin. SIGNIFICANCE: We concluded that dapagliflozin induced vasodilation via the activation of Kv channels and PKG, and was independent of other K+ channels, Ca2+ channels, intracellular Ca2+, and the endothelium.
AIM: Considering the clinical efficacy of dapagliflozin in patients with type 2 DM and the pathophysiological relevance of Kv channels for vascular reactivity. We investigate the vasodilatory effect of dapagliflozin and related mechanisms using phenylephrine (Phe)-induced contracted aortic rings. MATERIAL AND METHODS: Arterial tone measurement was performed in aortic smooth muscle. KEY FINDINGS: Application of dapagliflozin induced vasodilation in a concentration-dependent manner. Pre-treatment with the BKCa channel inhibitor paxilline, the KATP channel inhibitor glibenclamide, and the Kir channel inhibitor Ba2+ did not change dapagliflozin-induced vasodilation. However, application of the Kv channels inhibitor 4-AP effectively inhibited dapagliflozin-induced vasodilation. Application of the Ca2+ channel inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor thapsigargin did not alter the vasodilatory effect of dapagliflozin. Moreover, the adenylyl cyclase inhibitor SQ 22536 and the protein kinase A (PKA) inhibitor KT 5720 had no effect on dapagliflozin-induced vasodilation. Although guanylyl cyclase inhibitors, NS 2028 and ODQ, did not reduce the vasodilatory effect of dapagliflozin, the protein kinase G (PKG) inhibitor KT 5823 effectively inhibited dapagliflozin-induced vasodilation. The vasodilatory effect of dapagliflozin was not affected by elimination of the endothelium. Furthermore, pretreatment with the nitric oxide synthase inhibitor L-NAME or the small-conductance Ca2+-activated K (SKCa) channel inhibitor apamin did not change the vasodilatory effect of dapagliflozin. SIGNIFICANCE: We concluded that dapagliflozin induced vasodilation via the activation of Kv channels and PKG, and was independent of other K+ channels, Ca2+ channels, intracellular Ca2+, and the endothelium.
Authors: David C Poole; Steven W Copp; Trenton D Colburn; Jesse C Craig; David L Allen; Michael Sturek; Donal S O'Leary; Irving H Zucker; Timothy I Musch Journal: Am J Physiol Heart Circ Physiol Date: 2020-03-20 Impact factor: 4.733