Mechanisms Underlying Pioglitazone-Mediated Relaxation in Isolated Blood Vessel

作者：Nomura Hidemi; Yamawaki Hideyuki^*; Mukohda Masashi; Okada Muneyoshi; Hara Yukio

来源：Journal of Pharmacological Sciences, 2008, 108(3): 258-265.

DOI：10.1254/jphs.08117FP

• diabetes
• endothelium
• smooth muscle
• nitric oxide
• potassium channel

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 mu M, 30 min) inhibited noradrenaline (NA) (1 nM-1 mu M)-induced contraction. In NA (100 nM)-pre-contracted aorta, pioglitazone (1-10 mu M) 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 mu M) significantly inhibited the relaxation. In End (-) aorta, neither indomethacin nor cimetidine affected the relaxation, but tetraethyl ammonium (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 mu M), 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

• 出版日期2008-11