title: Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor-induced changes in blood pressure in obese rats suffering from the metabolic syndrome.
abstract: OBJECTIVE
  Experiments were carried out to investigate whether diuretics (hydrochlorothiazide + furosemide) impact on the effects of a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor on glucose metabolism and blood pressure (BP) in metabolic syndrome SHR/NDmcr-cp(+/+) rats (SHRcp).
  
  
  METHODS
  Male 13-week-old SHRcp were treated with: vehicle; the SGLT2-inhibitor luseogliflozin (10 mg/kg per day); diuretics (hydrochlorothiazide; 10 mg/kg/day + furosemide; 5 mg/kg per day); or luseogliflozin + diuretics (n = 5-8 for each group) daily by oral gavage for 5 weeks. BP and glucose metabolism were evaluated by a telemetry system and oral glucose tolerance test, respectively.
  
  
  RESULTS
  Vehicle-treated SHRcp developed nondipper type hypertension (dark vs. light-period mean arterial pressure: 148.6 ± 0.7 and 148.0 ± 0.7 mmHg, respectively, P = 0.2) and insulin resistance. Compared with vehicle-treated animals, luseogliflozin-treated rats showed an approximately 4000-fold increase in urinary excretion of glucose and improved glucose metabolism. Luseogliflozin also significantly decreased BP and turned the circadian rhythm of BP from a nondipper to dipper pattern (dark vs. light-period mean arterial pressure: 138.0 ± 1.6 and 132.0 ± 1.3 mmHg, respectively, P < 0.01), which were associated with a significant increase in urinary excretion of sodium. Addition of diuretics did not influence luseogliflozin-induced improvement of glucose metabolism and circadian rhythm of BP in SHRcp.
  
  
  CONCLUSIONS
  These data suggest that a SGLT2 inhibitor elicits its beneficial effects on glucose metabolism and hypertension in study participants with metabolic syndrome undergoing treatment with diuretics.
authors.affiliation: aDepartment of Pharmacology bLife Science Research Center, Faculty of Medicine, Kagawa University, Kagawa cDepartment of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Asadur
authors.initials: A
authors.lastname: Rahman
authors.forename: Wararat
authors.initials: W
authors.lastname: Kittikulsuth
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujisawa
authors.forename: Abu
authors.initials: A
authors.lastname: Sufiun
authors.forename: Kazi
authors.initials: K
authors.lastname: Rafiq
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure; D004232:Diuretics / Q000008:administration & dosage / Q000627:therapeutic use*; D005665:Furosemide / Q000008:administration & dosage / Q000627:therapeutic use; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000627:therapeutic use; D006973:Hypertension / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications*; D009765:Obesity; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D004232:Diuretics; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D006852:Hydrochlorothiazide; D013012:Sorbitol; D005665:Furosemide; C549343:1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol