title: SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery.
abstract: Inhibitors of sodium-glucose cotransporter (SGLT)2 are a new class of oral drugs for type 2 diabetic patients that reduce plasma glucose levels by inhibiting renal glucose reabsorption. There is increasing evidence showing the beneficial effect of SGLT2 inhibitors on glucose control; however, less information is available regarding the impact of SGLT2 inhibitors on cardiovascular outcomes. The present study was designed to determine whether SGLT inhibitors regulate vascular relaxation in mouse pulmonary and coronary arteries. Phlorizin (a nonspecific SGLT inhibitor) and canagliflozin (a SGLT2-specific inhibitor) relaxed pulmonary arteries in a dose-dependent manner, but they had little or no effect on coronary arteries. Pretreatment with phlorizin or canagliflozin significantly inhibited sodium nitroprusside (SNP; a nitric oxide donor)-induced vascular relaxation in pulmonary arteries but not in coronary arteries. Phlorizin had no effect on cGMP-dependent relaxation in pulmonary arteries. SNP induced membrane hyperpolarization in human pulmonary artery smooth muscle cells, and pretreatment of cells with phlorizin and canagliflozin attenuated SNP-induced membrane hyperpolarization by decreasing K(+) activities induced by SNP. Contrary to the result observed in ex vivo experiments with SGLT inhibitors, SNP-dependent relaxation in pulmonary arteries was not altered by chronic administration of canagliflozin. On the other hand, canagliflozin administration significantly enhanced SNP-dependent relaxation in coronary arteries in diabetic mice. These data suggest that SGLT inhibitors differentially regulate vascular relaxation depending on the type of arteries, duration of the treatment, and health condition, such as diabetes.
authors.affiliation: Department of Physiology, The University of Arizona, Tucson, Arizona; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois, Chicago, Illinois; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois, Chicago, Illinois; and.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Cho
authors.affiliation: Department of Medicine, The University of Arizona, Tucson, Arizona.
authors.forename: Ramon
authors.initials: R
authors.lastname: Ayon
authors.affiliation: Department of Physiology, The University of Arizona, Tucson, Arizona;
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Physiology, The University of Arizona, Tucson, Arizona;
authors.forename: Katia D
authors.initials: KD
authors.lastname: Youssef
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois, Chicago, Illinois; and.
authors.forename: Minglin
authors.initials: M
authors.lastname: Pan
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois, Chicago, Illinois; and.
authors.forename: Anzhi
authors.initials: A
authors.lastname: Dai
authors.affiliation: Department of Medicine, The University of Arizona, Tucson, Arizona.
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.affiliation: Department of Physiology, The University of Arizona, Tucson, Arizona; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois, Chicago, Illinois; and aymakino@email.arizona.edu.
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology*; D009928:Organ Specificity; D010695:Phlorhizin / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000378:metabolism*; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D009599:Nitroprusside; D009569:Nitric Oxide; D010695:Phlorhizin
keywords: diabetic vascular complications; membrane potential; nitric oxide; sodium-glucose cotransporters; vasodilatation