Mechanisms underlying pioglitazone-mediated relaxation in isolated blood vessel

Pioglitazone is a widely used anti-type 2 diabetic drug. Beside its insulin-sensitizing effects, pioglitazone exerts preventive roles against ischemic heart disease. Since one possible explanation is anti-hypertensive action, we examined effects of pioglitazone on contractility of isolated blood vessel. Endothelium-intact [End (+)] or -removed [End (-)] rat aorta is isolated and isometric tension is recorded. In both End (+) and End (-) aorta, pretreatment with pioglitazone (3 - 10 microM, 30 min) inhibited noradrenaline (NA) (1 nM - 1 microM)-induced contraction. In NA (100 nM)-pre-contracted aorta, pioglitazone (1 - 10 microM) directly induced a relaxation. The relaxant effect is higher in End (-) aorta than in End (+) aorta. In End (+) aorta, N(G)-nitro-L-arginine methyl ester (100 microM) significantly inhibited the relaxation. In End (-) aorta, neither indomethacin nor cimetidine affected the relaxation, but tetraethylammonium (10 mM) inhibited it. Furthermore, the relaxation was significantly inhibited by a voltage-dependent K+ (K(V))-channel blocker, 4-aminopyridine (1 mM), or an inward rectifying K+ (K(IR))-channel blocker, BaCl2 (1 mM). GW9662 (2 microM), a blocker of peroxisome proliferator-activated receptor (PPAR)-gamma was ineffective against the relaxation. The present study demonstrated that pioglitazone causes PPAR-gamma-independent relaxation. While endothelium-dependent relaxation is mediated via nitric oxide, the endothelium-independent one is responsible for smooth muscle K+ (K(V), K(IR))-channel opening.