Effects of diuretics on sodium-dependent glucose... : Journal of Hypertension (original) (raw)

ORIGINAL PAPERS: Diabetes mellitus

Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor-induced changes in blood pressure in obese rats suffering from the metabolic syndrome

Rahman, Asadur; Kittikulsuth, Wararat; Fujisawa, Yoshihide; Sufiun, Abu; Rafiq, Kazi; Hitomi, Hirofumi; Nakano, Daisuke; Sohara, Eisei; Uchida, Shinichi; Nishiyama, Akira

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

Correspondence to Akira Nishiyama, MD, PhD, FAHA, Department of Pharmacology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. Tel: +81 87 891 2125; fax: +81 87 891 2126; e-mail: [email protected]

Abbreviations: AQP, aquaporin; BP, blood pressure; ENaC, epithelial sodium channel; GLUT, glucose transporter; HbA1c, hemoglobin A1C; HCTZ, hydrochlorothiazide; MAP, mean arterial pressure; NCC, sodium chloride cotransporter; NHE3, sodium–hydrogen exchanger 3; p-AQP, phosphorylated aquaporin; p-NCC, phosphorylated sodium chloride cotransporter; SGLT, sodium-dependent glucose cotransporter; SHR, spontaneously hypertensive rats; SHRcp, SHR/NDmcr-cp(+/+) rats; WKY, Wistar–Kyoto rats

Received 3 July, 2015

Revised 14 November, 2015

Accepted 23 December, 2015

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com).

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.

Conclusion:

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.