TRPV4 channel activation leads to endothelium-dependent relaxation mediated by nitric oxide and endothelium-derived hyperpolarizing factor in rat pulmonary artery

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• 作者：Susanth V. Sukumaran ; Thakur Uttam Singh ; Subhashree Parida ; Ch.E. Narasimha Reddy ; Ramasamy Thangamalai ; Kannan K ; asamy ; Vishakha Singh ; Santosh Kumar Mishra
• 关键词：TRPV4 ; transient receptor potential vanilloid 4 ; L-NAME ; NG-nitro-l-arginine methyl ester ; PE ; phenylephrine ; TRAM 34 ; 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole ; GSK ; GSK1016790A ; ODQ ; 1H-[1 ; 2 ; 4]oxadiazolo[4 ; 3-a]quinoxalin-1-one ; DMSO ; dimethyl sulphoxide ; SNP ; sodium nitroprusside ; EDHF ; endothelium-derived hyperpolarizing factor ; ACh ; acetylcholine ; ATP ; adenosine triphosphate ; 4伪-PDD ; 4伪-phorbol-12 ; 13-didecanoate ; EET ; epoxyeicosatrienoic acids ; SKCa ; small conductance potassium channe
• 刊名：Pharmacological Research
• 出版年：December, 2013
• 年：2013
• 卷：78
• 期：Complete
• 页码：18-27
• 全文大小：1635 K

文摘

The purpose of the present study was to characterize TRPV4 channels in the rat pulmonary artery and examine their role in endothelium-dependent relaxation. Tension, Real-Time polymerase chain reaction (Real-Time PCR) and Western blot experiments were conducted on left and right branches of the main pulmonary artery from male Wistar rats. TRPV4 channel agonist GSK1016790A (GSK) caused concentration-related robust relaxation (E_max 88.6 卤 5.5%; pD₂ 8.7 卤 0.2) of the endothelium-intact pulmonary artery. Endothelium-denudation nearly abolished the relaxation (E_max 5.6 卤 1.3%) to GSK. TRPV4 channel selective antagonist HC067047 significantly attenuated GSK-induced relaxation (E_max 56.2 卤 6.6% vs. control E_max 87.9 卤 3.3%) in endothelium-intact vessels, but had no effect on either ACh-induced endothelium-dependent or SNP-induced endothelium-independent relaxations. GSK-induced relaxations were markedly inhibited either in the presence of NO synthase inhibitor L-NAME (E_max 8.5 卤 2.7%) or sGC inhibitor ODQ (E_max 28.1 卤 5.9%). A significant portion (E_max 30.2 卤 4.4%) of endothelium-dependent relaxation still persisted in the combined presence of L-NAME and cyclooxygenase inhibitor indomethacin. This EDHF-mediated relaxation was sensitive to inhibition by 60 mM K⁺ depolarizing solution or K⁺ channel blockers apamin (SK_Ca; K_Ca2.3) and TRAM-34 (IK_Ca; K_Ca3.1). GSK (10^鈭?0 鈭?#xA0;10^鈭? M) caused either modest decrease or increase in the basal tone of endothelium-intact or denuded rings, respectively. We found a greater abundance (>1.5 fold) of TRPV4 mRNA and protein expressions in endothelium-intact vs. denuded vessels, suggesting the presence of this channel in pulmonary endothelial and smooth muscle cells as well. The present study demonstrated that NO and EDHF significantly contributed to TRPV4 channel-mediated endothelium-dependent relaxation of the rat pulmonary artery.