title: Troglitazone, a new antidiabetic agent possessing radical scavenging ability, improved decreased skin blood flow in diabetic rats.
abstract: Troglitazone is a new class of antidiabetic agent possessing radical scavenging ability similar to vitamin E. Because of this ability, it is expected to improve decreased nutritive capillary blood flow in diabetes. In the present study, we investigated the effects of troglitazone on skin blood flow(SBF) in normal and streptozotocin(STZ)-induced diabetic rats. Effects of troglitazone on vasodilation, PGI2 and PGE2 production were also assessed in perfused hindlimb, isolated rat aorta rings and 3T6 fibroblasts, respectively. SBF at the base of the tail was decreased in STZ diabetic rats (2.1+/-0.2 ml/min/100 g) compared with normal rats (3.8+/-0.2 ml/min/100 g). This decrease of SBF was significantly improved (2.9+/-0.2 ml/min/100 g) by troglitazone treatment (approximately 220 mg/kg/day) for 7 days in STZ diabetic rats without alleviating hyperglycemia. Similar troglitazone treatment (approximately 160 mg/kg/day for 7 days) tended to increase SBF (approximately 30%) even in normal rats. In normal rats, subcutaneous administration of troglitazone (60 mg/kg) acutely increased SBF and, this increase was suppressed by 70% with pretreatment (10 mg/kg s.c.) of indomethacin, cyclooxygenase inhibitor, suggesting that troglitazone increases skin blood flow predominantly by increasing PGI2 and PGE2 production. In hindlimb perfusion under fixed flow rate, troglitazone infusion (20 microM) significantly decreased perfusion pressure by 13%, which reflects vasodilation of blood vessels. This decrease of perfusion pressure was inhibited by concomitant infusion of indomethacin but not N-monomethyl-L-arginine, inhibitor of nitric oxide synthase. In vitro studies, using isolated rat aorta rings, revealed that troglitazone (4.5 to 45 microM) increases PGI2 production by 31 and 70%, respectively. In 3T6 fibroblast (a component of skin tissue), troglitazone at a low dose of 0.3 microM increased PGI2 and PGE2 by 200% and 25%, respectively. Overall all, these results suggest that troglitazone increases nutritive SBF probably by virtue of its radical scavenging thus the resulting in an increase in PGI2 and PGE2 production in blood vessels and fibroblast. Troglitazone may alleviate impaired microcirculation in diabetic patients through these effects.
authors.affiliation: Pharmacology & Molecular Biology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.forename: T
authors.initials: T
authors.lastname: Ohsawa
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: A
authors.initials: A
authors.lastname: Okuno
authors.forename: S
authors.initials: S
authors.lastname: Ushiyama
authors.forename: K
authors.initials: K
authors.lastname: Matsuda
authors.forename: H
authors.initials: H
authors.lastname: Horikoshi
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D011464:Epoprostenol / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006168:Guinea Pigs; D006614:Hindlimb / Q000098:blood supply; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014664:Vasodilation / Q000187:drug effects; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D002839:Chromans; D016166:Free Radical Scavengers; D007004:Hypoglycemic Agents; D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; D045162:Thiazolidinediones; D014810:Vitamin E; D011464:Epoprostenol; D000077288:Troglitazone; D015232:Dinoprostone