Opposing actions of TRPV4 channel activation in the lung vasculature.
OBJECTIVE
Transient receptor potential vanilloid 4 (TRPV4) calcium channels are known to promote endothelium-dependent relaxation of mouse mesenteric arteries but TRPV4's role in the pulmonary vasculature is uncertain. Thus, we characterized TRPV4 channel vascular tone regulation in mouse main pulmonary artery rings and in the isolated perfused pulmonary circulation and studied possible mechanisms behind these characterizations.


RESULTS
Using myography and a TRPV4 specific agonist GSK1016790A in a C57BL/6 WT mouse model of isolated constant-flow lung perfusion, we studied vascular tone regulation in arterial rings from the main left and right pulmonary arteries and vascular resistance of the intra-pulmonary circulation beyond the second branches of the pulmonary arteries. Removal of the endothelium confirmed endothelial dependence. GSK1016790A relaxed the main pulmonary artery (EC50 4 × 10(-8)mol/L), which was inhibited by removal of the endothelium from main pulmonary artery rings. GSK1016790A significantly increased vascular resistance of the pulmonary circulation in isolated perfused lungs, but these effects were inhibited by a TRPV4 antagonist AB159908. A nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and K(+) channel blockers apamin plus charybdotoxin (ChTx) significantly inhibited GSK1016790A in the main pulmonary artery and in an isolated perfused lung in vitro.


CONCLUSIONS
Activated TRPV4 channels increase pulmonary vascular resistance and vasodilate the main pulmonary artery.
Department of the First Clinical Medical College of Fujian Medical University, 350005 Fuzhou, Fujian, China.
Sun-Kui
SK
Ke
Zhongshan Hospital, Xiamen University, 361004 Xiamen, Fujian, China.
Lan
L
Chen
Zhongshan Hospital, Xiamen University, 361004 Xiamen, Fujian, China.
Hong-Bing
HB
Duan
The First Affiliated Hospital of Fujian Medical University, 350005 Fuzhou, Fujian, China. Electronic address: 18959229186@163.com.
Yuan-Rong
YR
Tu
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008955:Models, Cardiovascular; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013449:Sulfonamides; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D018999:Charybdotoxin; D001030:Apamin; D009569:Nitric Oxide; D007930:Leucine; D019331:NG-Nitroarginine Methyl Ester
Intermediate conductance potassium channel (IK(Ca)); Lung perfusion; Pulmonary artery; Small conductance potassium channel (SK(Ca)); TRPV4