Wy14643 improves vascular function in the aorta of the spontaneously hypertensive rat mainly by activating peroxisome proliferator-activated receptors alpha

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• 作者：Chen Qu¹ ; ^a ; ^{venaqu@gmail.com} ; Susan W.S. Leung^a ; ^{swsleung@hku.hk} ; Paul M. Vanhoutte^a ; ^b ; ^{vanhoutt@hku.hk} ; Ricky Y.K. Man^a ; ^{rykman@hku.hk}
• 关键词：Endothelial dysfunction ; Endothelium-derived contracting factor ; Nitric oxide ; Peroxisome proliferator-activated receptor agonist ; Prostaglandin
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 出版时间：5 December, 2012
• 年：2012
• 卷：696
• 期：1-3
• 页码：101-110
• 全文大小：1151 K

文摘

Experiments were designed to determine if Wy14643 ([[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]-acetic acid), a preferential agonist at peroxisome proliferator-activated receptors (PPAR) ¦Á, improves vascular function in hypertension, and if so, the mechanism(s) involved. Isometric tension was measured in isolated thoracic aorta of spontaneously hypertensive rats (SHR). Wy14643-induced relaxations in SHR aortic rings were greater than those induced by fenofibrate or rosiglitazone (PPAR¦Á or PPAR¦Ã agonists, respectively) and were larger in rings with endothelium than those without. Both MK886 [(1-[(4-chlorophenyl)methyl]-3-1,1-dimethylethyl)thio]-(¦Á,¦Á-dimethyl-5-1-methylethyl)-1H-indole-2-propanoic acid (PPAR¦Á antagonist) and GW9662 (2-chloro-5-nitrobenzanilide) (PPAR¦Ã antagonists) inhibited Wy14643-induced relaxations. The inhibitory effect of MK886 was more pronounced in rings with endothelium than those without. In SHR aortic rings with endothelium, L-NAME (N^¦Ø-nitro-L-arginine methyl ester, nitric oxide synthase inhibitor), ODQ (1H-1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one, soluble guanylyl cyclase inhibitor) and compound C [adenosine monophosphate-activated protein kinase (AMPK) inhibitor] reduced Wy14643-induced relaxations. Western blotting studies indicated that Wy14643 and fenofibrate, but not rosiglitazone, increased the phosphorylation of endothelial nitric oxide synthase and AMPK; these effects were abolished by compound C but not L-NAME. Endothelium-dependent contractions evoked by acetylcholine in quiescent SHR aorta in the presence of L-NAME were reduced by Wy14643 and fenofibrate but not by rosiglitazone. MK886, but not GW9662, prevented this effect. Wy14643 and fenofibrate inhibited acetylcholine-induced prostanoid release to the same extent. These findings suggest that PPAR¦Á agonists induce nitric oxide-mediated relaxation through activation of AMPK and reduce the release of endothelium-dependent contracting factors. Because also of the ability to activate smooth muscle PPAR¦Ã to induce relaxation, Wy14643 offers additional protection against vascular dysfunction of spontaneous hypertension.