title: Troglitazone reduces contraction by inhibition of vascular smooth muscle cell Ca2+ currents and not endothelial nitric oxide production.
abstract: The insulin-sensitizing compound troglitazone has evolved into a promising therapeutic agent for type II diabetes. It improves insulin sensitivity and lipoprotein metabolic profiles and lowers blood pressure in humans and rodents. Because troglitazone has insulin-like effects on a number of tissues, we hypothesized that it may reduce vascular tone through stimulation of endothelial-derived nitric oxide (NO) production or by diminution of vascular smooth muscle cell (VSMC) intracellular calcium ([Ca2+]i). Our results show that troglitazone decreases norepinephrine-induced contractile responses in the rat tail artery, an effect not reversed by the NO inhibitor L-nitroarginine methyl ester (L-NAME). In contrast, troglitazone significantly inhibited L-type Ca2+ currents in freshly dissociated rat tail artery and aortic VSMCs and in cultured VSMCs. The data suggest that troglitazone attenuates vascular contractility via a mechanism involving VSMC [Ca2+]i but independent from endothelial generation of NO. Because insulin has been shown to affect vascular tone by both of these mechanisms, troglitazone only partially mimics insulin action in this tissue.
authors.affiliation: Department of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: J
authors.initials: J
authors.lastname: Song
authors.forename: M F
authors.initials: MF
authors.lastname: Walsh
authors.forename: R
authors.initials: R
authors.lastname: Igwe
authors.forename: J L
authors.initials: JL
authors.lastname: Ram
authors.forename: M
authors.initials: M
authors.lastname: Barazi
authors.forename: L J
authors.initials: LJ
authors.lastname: Dominguez
authors.forename: J R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
chemical_list: D015220:Calcium Channels; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone