--- - |2 Abstract 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 cross‐over design at successive one‐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. This article is protected by copyright. All rights reserved. - 'Clinical and Experimental Pharmacology and Physiology, Volume 0, Issue ja, -Not available-. '