TROGLITAZONE REDUCES CONTRACTION BY INHIBITION OF VASCULAR SMOOTH-MUSCLE CELL CA2-OXIDE PRODUCTION( CURRENTS AND NOT ENDOTHELIAL NITRIC)

The insulin-sensitizing compound troglitazone has evolved into a promi sing therapeutic agent for type II diabetes. It improves insulin sensi tivity and lipoprotein metabolic profiles and lowers blood pressure in humans and rodents, Because troglitazone has insulinlike effects on a number of tissues, we hypothesized that it may reduce vascular tone t hrough 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 nore pinephrine-induced contractile responses in the rat tail artery, an ef fect not reversed by the NO inhibitor L-nitroarginine methyl ester (L- NAME), In contrast, troglitazone significantly inhibited L-type Ca2+ c urrents in freshly dissociated rat tail artery and aortic VSMCs and in cultured VSMCs. The data suggest that troglitazone attenuates vascula r contractility via a mechanism involving VSMC [Ca2+](i) but independe nt from endothelial generation of NO. Because insulin has been shown t o affect vascular tone by both of these mechanisms, troglitazone only partially mimics insulin action in this tissue.