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Dipeptidyl peptidase-4 inhibitor sitagliptin induces vasorelaxation via the activation of Kv channels and PKA.
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.taap.2019.114799 Hongliang Li 1 , Mi Seon Seo 2 , Jin Ryeol An 2 , Hee Seok Jung 2 , Kwon-Soo Ha 3 , Eun-Taek Han 4 , Seok-Ho Hong 5 , Young Min Bae 6 , Sung Hun Na 7 , Won Sun Park 2
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.taap.2019.114799 Hongliang Li 1 , Mi Seon Seo 2 , Jin Ryeol An 2 , Hee Seok Jung 2 , Kwon-Soo Ha 3 , Eun-Taek Han 4 , Seok-Ho Hong 5 , Young Min Bae 6 , Sung Hun Na 7 , Won Sun Park 2
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The present study investigated the vasorelaxant effects of sitagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor in aortic rings pre-contracted with phenylephrine (Phe). Sitagliptin induced vasorelaxation in a concentration-dependent manner but the inhibition of voltage-dependent K+ (Kv) channels by pretreatment with 4-aminopyridine (4-AP) effectively reduced this effect. By contrast, the inhibition of inward rectifier K+ (Kir) channels by pretreatment with barium (Ba2+), large-conductance calcium (Ca2+)-activated K+ (BKCa) channels with paxilline, and adenosine triphosphate (ATP)-sensitive K+ (KATP) channels with glibenclamide did not change this effect. Although the application of SQ 22536, which is an adenylyl cyclase inhibitor, also did not change this effect, treatment with KT 5720, a protein kinase A (PKA) inhibitor, effectively reduced the vasorelaxant effects of sitagliptin. ODQ, which is a guanylyl cyclase inhibitor, and KT 5823, a protein kinase G (PKG) inhibitor, did not impact the effect. Furthermore, neither the inhibition of Ca2+ channels by pretreatment with nifedipine nor the inhibition of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps by pretreatment with thapsigargin changed the effect. Similarly, the effects of sitagliptin were not altered by eliminating the endothelium, by pretreatment with a nitric oxide (NO) synthase inhibitor (L-NAME), or by inhibition of small- and intermediate-conductance Ca2+-activated K+ channels (SKCa and IKCa) using apamin and TRAM-34. Taken together, these results suggest that sitagliptin induces vasorelaxation by inhibiting both membrane potential (Em)-dependent and -independent vasoconstriction and activating PKA and Kv channels independently of PKG signaling pathways, other K+ channels, SERCA pumps, and the endothelium.
中文翻译：
二肽基肽酶-4抑制剂西他列汀通过激活Kv通道和PKA诱导血管舒张。
本研究调查了西他列汀的血管舒张作用，西他列汀是一种二苯肽基肽酶4（DPP-4）抑制剂，在与苯肾上腺素（Phe）预收缩的主动脉环中。西他列汀以浓度依赖性方式诱导血管舒张，但是通过用4-氨基吡啶（4-AP）预处理抑制电压依赖性K +（Kv）通道可有效降低该作用。相比之下，用钡（Ba2 +）预处理，大电导钙（Ca2 +）活化的K +（BKCa）通道用paxilline预处理以及对三磷酸腺苷（ATP）敏感的K +（KATP）抑制内向整流器K +（Kir）通道含格列本脲的通道并没有改变这种作用。尽管作为腺苷酸环化酶抑制剂的SQ 22536的应用也没有改变这种效果，但使用蛋白激酶A（PKA）抑制剂KT 5720进行治疗，有效降低西格列汀的血管舒张作用。ODQ是一种鸟苷酸环化酶抑制剂，而KT 5823是一种蛋白激酶G（PKG）抑制剂，对效果没有影响。此外，用硝苯地平预处理对Ca2 +通道的抑制作用或用毒胡萝卜素预处理对肌浆/内质网Ca2 + -ATPase（SERCA）泵的抑制作用都没有改变。类似地，西他列汀的作用不会因消除内皮，通过一氧化氮（NO）合酶抑制剂（L-NAME）预处理或通过抑制小和中电Ca2 +激活的K +通道（SKCa和IKCa）而改变），使用阿帕明和TRAM-34。在一起
更新日期：2019-11-01
中文翻译：
二肽基肽酶-4抑制剂西他列汀通过激活Kv通道和PKA诱导血管舒张。
本研究调查了西他列汀的血管舒张作用，西他列汀是一种二苯肽基肽酶4（DPP-4）抑制剂，在与苯肾上腺素（Phe）预收缩的主动脉环中。西他列汀以浓度依赖性方式诱导血管舒张，但是通过用4-氨基吡啶（4-AP）预处理抑制电压依赖性K +（Kv）通道可有效降低该作用。相比之下，用钡（Ba2 +）预处理，大电导钙（Ca2 +）活化的K +（BKCa）通道用paxilline预处理以及对三磷酸腺苷（ATP）敏感的K +（KATP）抑制内向整流器K +（Kir）通道含格列本脲的通道并没有改变这种作用。尽管作为腺苷酸环化酶抑制剂的SQ 22536的应用也没有改变这种效果，但使用蛋白激酶A（PKA）抑制剂KT 5720进行治疗，有效降低西格列汀的血管舒张作用。ODQ是一种鸟苷酸环化酶抑制剂，而KT 5823是一种蛋白激酶G（PKG）抑制剂，对效果没有影响。此外，用硝苯地平预处理对Ca2 +通道的抑制作用或用毒胡萝卜素预处理对肌浆/内质网Ca2 + -ATPase（SERCA）泵的抑制作用都没有改变。类似地，西他列汀的作用不会因消除内皮，通过一氧化氮（NO）合酶抑制剂（L-NAME）预处理或通过抑制小和中电Ca2 +激活的K +通道（SKCa和IKCa）而改变），使用阿帕明和TRAM-34。在一起
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