Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan.
Division of Nephrology and Hypertension, Departments of Medicine and Pharmacology, University of California-San Diego and Veterans Affairs San Diego Healthcare System, San Diego, California.
Am J Physiol Renal Physiol. 2022 Sep 1;323(3):F361-F369. doi: 10.1152/ajprenal.00070.2022. Epub 2022 Jul 28.
Loop diuretics are commonly used diuretics in the treatment of fluid retention but induce hypovolemia-related renal dysfunction. Na-glucose cotransporter 2 (SGLT2) inhibitors induce osmotic diuresis, but body fluid volume is maintained by stimulating vasopressin-induced fluid intake and collecting duct water reabsorption as previously reported in diabetic rats. We aimed to test the hypothesis that unlike SGLT2 inhibitors, loop diuretics lack activation of similar fluid homeostatic mechanisms. Nondiabetic male Sprague-Dawley rats were treated daily by oral gavage with vehicle, the SGLT2 inhibitor ipragliflozin (5 mg/kg), or the loop diuretic furosemide (50 mg/kg) and monitored in metabolic cages for 2 or 7 days. Ipragliflozin and furosemide similarly increased urine volume on . This was associated with increased serum Na concentration, urine vasopressin excretion, fluid intake, and solute-free water reabsorption in response to ipragliflozin but not to furosemide. Ipragliflozin maintained fluid balance (fluid intake - urine volume) on and total body water measured by bioimpedance spectroscopy and serum creatinine on . In comparison, furosemide decreased fluid balance on and decreased total body water and increased serum creatinine on . Furosemide, but not ipragliflozin, increased plasma renin activity, and systolic blood pressure was similar among the groups. In conclusion, the osmotic diuresis of the SGLT2 inhibitor increased serum Na concentration and the vasopressin-related stimulation of fluid intake and renal water retention maintained fluid balance, whereas the loop diuretic did not engage the compensatory vasopressin system. The data suggest differences in vasopressin and fluid homeostatic responses between SGLT2 inhibitors and loop diuretics. In nondiabetic rats, the Na-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin increased vasopressin-related stimulation of fluid intake and free water reabsorption and maintained fluid balance and serum creatinine, whereas the loop diuretic furosemide reduced vasopressin and induced a negative fluid balance followed by a subsequent increase in serum creatinine. This study suggests that differences in vasopressin secretion in response to a SGLT2 inhibitor or loop diuretic may contribute to differences in body fluid status and subsequent renal function.
袢利尿剂常用于治疗体液潴留，但会引起与血容量减少相关的肾功能障碍。钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂可诱导渗透性利尿，但如先前在糖尿病大鼠中所报道的，通过刺激血管加压素诱导的液体摄入和集合管水重吸收来维持体液量。我们旨在检验这样一个假设，即与 SGLT2 抑制剂不同，袢利尿剂缺乏对类似体液稳态机制的激活。非糖尿病雄性 Sprague-Dawley 大鼠每天通过口服灌胃接受 vehicle、SGLT2 抑制剂伊格列净（5mg/kg）或袢利尿剂呋塞米（50mg/kg）治疗，并在代谢笼中监测 2 或 7 天。伊格列净和呋塞米均同样增加了第 2 天的尿量。这与血清 Na 浓度、尿血管加压素排泄、液体摄入和溶质自由水重吸收的增加有关，而这些增加仅与伊格列净有关，与呋塞米无关。伊格列净在第 7 天维持了液体平衡（液体摄入-尿量），并通过生物阻抗谱和血清肌酐测量维持了第 7 天的总体水。相比之下，呋塞米在第 7 天降低了液体平衡，并降低了第 7 天的总体水和增加了血清肌酐。与呋塞米不同，伊格列净增加了血浆肾素活性，且各组的收缩压相似。总之，SGLT2 抑制剂的渗透性利尿增加了血清 Na 浓度和血管加压素相关的液体摄入刺激和肾水潴留，维持了液体平衡，而袢利尿剂则未激活代偿性血管加压素系统。这些数据表明 SGLT2 抑制剂和袢利尿剂之间在血管加压素和体液稳态反应方面存在差异。在非糖尿病大鼠中，SGLT2 抑制剂伊格列净增加了血管加压素相关的液体摄入刺激和自由水重吸收，维持了液体平衡和血清肌酐，而袢利尿剂呋塞米降低了血管加压素并引起随后的负液体平衡，随后血清肌酐增加。这项研究表明，对 SGLT2 抑制剂或袢利尿剂的血管加压素分泌反应的差异可能导致体液状态和随后的肾功能的差异。
