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.
Nomura
Hidemi
H
Department of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Aomori, Japan.
Yamawaki
Hideyuki
H
Mukohda
Masashi
M
Okada
Muneyoshi
M
Hara
Yukio
Y
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D000077205:Pioglitazone; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D045162:Thiazolidinediones; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D011188:Potassium; D000077205:Pioglitazone; D009638:Norepinephrine