SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery
SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery
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DOI：
10.1152/ajplung.00167.2015
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发表时间：
2015-11-01
影响因子：
4.9
通讯作者：
Makino, Ayako
中科院分区：
文献类型：
--
作者：
Han, Ying;Cho, Young-Eun;Makino, Ayako
钠-葡萄糖协同转运蛋白（SGLT）2抑制剂是一类新型口服药物，用于2型糖尿病患者，通过抑制肾脏葡萄糖重吸收降低血糖水平。越来越多的证据表明SGLT 2抑制剂对血糖控制具有有益作用;然而，关于SGLT 2抑制剂对心血管结局影响的信息较少。本研究旨在确定SGLT抑制剂是否调节小鼠肺动脉和冠状动脉的血管舒张。根皮苷（一种非特异性SGLT抑制剂）和卡格列净（一种SGLT 2特异性抑制剂）以剂量依赖性方式舒张肺动脉，但对冠状动脉几乎没有影响。根皮苷或卡格列净预处理显著抑制硝普钠（SNP;一氧化氮供体）诱导的肺动脉血管舒张，但不抑制冠状动脉血管舒张。根皮苷对cGMP依赖性肺动脉舒张无影响。SNP诱导人肺动脉平滑肌细胞膜超极化，根皮苷和卡格列净预处理细胞通过降低SNP诱导的K+活性来减弱SNP诱导的膜超极化。与SGLT抑制剂离体实验中观察到的结果相反，长期给予卡格列净未改变肺动脉中的SNP依赖性舒张。另一方面，卡格列净给药显著增强了糖尿病小鼠冠状动脉的SNP依赖性舒张。这些数据表明，SGLT抑制剂根据动脉类型、治疗持续时间和健康状况（如糖尿病）差异调节血管舒张。
Inhibitors of sodium-glucose cotransporter (SGLT) 2 are a new class of oral drugs for type 2 diabetic patients that reduce plasma glucose levels by inhibiting renal glucose reabsorption. There is increasing evidence showing the beneficial effect of SGLT2 inhibitors on glucose control; however, less information is available regarding the impact of SGLT2 inhibitors on cardiovascular outcomes. The present study was designed to determine whether SGLT inhibitors regulate vascular relaxation in mouse pulmonary and coronary arteries. Phlorizin (a nonspecific SGLT inhibitor) and canagliflozin (a SGLT2-specific inhibitor) relaxed pulmonary arteries in a dose-dependent manner, but they had little or no effect on coronary arteries. Pretreatment with phlorizin or canagliflozin significantly inhibited sodium nitroprusside (SNP; a nitric oxide donor)-induced vascular relaxation in pulmonary arteries but not in coronary arteries. Phlorizin had no effect on cGMP-dependent relaxation in pulmonary arteries. SNP induced membrane hyperpolarization in human pulmonary artery smooth muscle cells, and pretreatment of cells with phlorizin and canagliflozin attenuated SNP-induced membrane hyperpolarization by decreasing K+ activities induced by SNP. Contrary to the result observed in ex vivo experiments with SGLT inhibitors, SNP-dependent relaxation in pulmonary arteries was not altered by chronic administration of canagliflozin. On the other hand, canagliflozin administration significantly enhanced SNP-dependent relaxation in coronary arteries in diabetic mice. These data suggest that SGLT inhibitors differentially regulate vascular relaxation depending on the type of arteries, duration of the treatment, and health condition, such as diabetes.