DIFFERENTIAL VASOACTIVE EFFECTS OF THE INSULIN SENSITIZERS ROSIGLITAZONE (BRL-49653) AND TROGLITAZONE ON HUMAN SMALL ARTERIES IN-VITRO

BRL 49653 (rosiglitazone) and troglitazone are thiazolidinedione insul in-sensitizing agents, which are undergoing clinical evaluation as tre atments for NIDDM. Potential side effects of thiazolidinediones includ e edema and hemodilution. Although the underlying mechanisms are prese ntly unclear, animal and human studies have demonstrated a vasodilator action of troglitazone, which could in theory cause fluid retention. This in vitro study compared the direct vasodilator effects of troglit azone and BRL 49653 in small arteries (n = 44) from human subcutaneous fat. In arterial rings with a functioning endothelium and preconstric ted with norepinephrine (NE; 6 mu mol/l), troglitazone (n = 22 vessels ), but not BRL 49653 (1-100 mu mol/l), caused a concentration-related relaxation (69.4 +/- 5.2% at 100 mu mol/l; P < 0.01). In the presence of indomethacin (IM; 10 mu mol/l; n = 12), this vasorelaxant effect of troglitazone was abolished (P < 0.01 vs. troglitazone alone) and repl aced by enhanced vasoconstriction (58.5 +/- 39.5% over the NE baseline ) similar in magnitude to that produced by troglitazone vehicle (ethan ol) alone (n = 16; NS vs. ethanol vehicle). By contrast, BRL 49653 (10 0 mu mol/l; n = 22) and an equivalent volume of ethanol alone (n = 12) caused similar degrees of vasoconstriction (18.7 +/- 14.6 and 22.5 +/ - 8.0%, respectively; NS). In the presence of IM (10 mu mol/l; n = 10) , the vasoconstrictor effect of BRL 49653 was enhanced (41.5 +/- 14.4% ), although not significantly (NS vs. BRL 49653 alone or ethanol alone ). Additional studies in Wistar rat arteries showed a similar vasodila tor effect of troglitazone that was not inhibited by L-NAME (100 pmol/ l), The alpha-tocopherol moiety alone had no vasorelaxant effect at co ncentrations up to 300 mu mol/l. Thus, in human arterial resistance ve ssels in vitro, BRL 49653 does not possess the direct, IM-sensitive va sorelaxant action of troglitazone. This vasodilation could, in theory, permit transmission of systemic pressure to the capillary bed.