Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
Clin Exp Pharmacol Physiol. 2019 Mar;46(3):266-273. doi: 10.1111/1440-1681.13053. Epub 2018 Dec 27.
The first dose of a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor induces osmotic diuresis and can thereby affect cardiovascular activity in hyperglycemic patients. We aimed to determine whether the first dose of the selective SGLT2 inhibitor ipragliflozin affects cardiovascular activity in non-diabetic Sprague-Dawley (SD) rats and Spontaneously Diabetic Torii (SDT) fatty rats in two studies, a urine collection study and a telemetry study. In the former study, urine was collected for 24 hours after a single oral dose of ipragliflozin. In the latter study, systolic blood pressure (SBP) and heart rate (HR) were continuously monitored for 24 hours under conscious and unrestrained conditions from immediately before the administration of ipragliflozin. The telemetry study was conducted in a crossover design at successive 1 week intervals. Cardiovascular autonomic nerve activity was calculated from the SBP and HR. SDT fatty rats exhibited polyuria, glucosuria and hyperglycemia. In addition, the mean and standard deviation of SBP were higher, while the coefficient of variance of HR was lower than the respective parameters in SD rats. Ipragliflozin increased both urine output and urinary glucose excretion, and the increases were more pronounced in SDT fatty rats than in SD rats. In contrast, ipragliflozin had no effect on SBP, the standard deviation of SBP, HR, and the coefficient of variance of HR, or on autonomic nerve activity in either rat strain. These results suggest that the first dose of the SGLT2 inhibitor ipragliflozin has little impact on cardiovascular activity despite causing glucosuria with osmotic diuresis.
钠依赖性葡萄糖共转运蛋白 2（SGLT2）抑制剂的首剂可引起渗透性利尿，从而影响高血糖患者的心血管活性。我们旨在确定选择性 SGLT2 抑制剂伊格列净的首剂是否会影响非糖尿病 Sprague-Dawley（SD）大鼠和自发性糖尿病 Torii（SDT）肥胖大鼠的心血管活性，为此进行了两项研究，即尿收集研究和遥测研究。在前一项研究中，SDT 肥胖大鼠和 SD 大鼠在单次口服伊格列净后 24 小时内收集尿液。在后一项研究中，在口服伊格列净前立即进行 24 小时的清醒和不受约束的条件下连续监测收缩压（SBP）和心率（HR）。该遥测研究采用交叉设计，在连续的 1 周间隔内进行。从 SBP 和 HR 计算心血管自主神经活动。SDT 肥胖大鼠表现出多尿、糖尿和高血糖。此外，SDT 肥胖大鼠的 SBP 平均值和标准差较高，而 HR 的变异系数则低于 SD 大鼠的相应参数。伊格列净增加了尿量和尿糖排泄，在 SDT 肥胖大鼠中比在 SD 大鼠中更为明显。相反，伊格列净对 SBP、SBP 的标准差、HR 和 HR 的变异系数或对两种大鼠的自主神经活动均无影响。这些结果表明，尽管 SGLT2 抑制剂伊格列净的首剂可引起渗透性利尿导致糖尿，但对心血管活性的影响很小。
