Acetylcholine protects mesenteric arteries against hypoxia/reoxygenation injury via inhibiting calcium-sensing receptor.
The Ca(2+)-sensing receptor (CaSR) plays an important role in regulating vascular tone. In the present study, we investigated the positive effects of the vagal neurotransmitter acetylcholine by suppressing CaSR activation in mesenteric arteries exposed to hypoxia/reoxygenation (H/R). The artery rings were exposed to a modified 'ischemia mimetic' solution and an anaerobic environment to simulate an H/R model. Our results showed that acetylcholine (10(-6) mol/L) significantly reduced the contractions induced by KCl and phenylephrine and enhanced the endothelium-dependent relaxation induced by acetylcholine. Additionally, acetylcholine reduced CaSR mRNA expression and activity when the rings were subjected to 4 h of hypoxia and 12 h of reoxygenation. Notably, the CaSR antagonist NPS2143 significantly reduced the contractions but did not improve the endothelium-dependent relaxation. When a contractile response was achieved with extracellular Ca(2+), both acetylcholine and NPS2143 reversed the H/R-induced abnormal vascular vasoconstriction, and acetylcholine reversed the calcimimetic R568-induced abnormal vascular vasoconstriction in the artery rings. In conclusion, this study suggests that acetylcholine ameliorates the dysfunctional vasoconstriction of the arteries after H/R, most likely by decreasing CaSR expression and activity, thereby inhibiting the increase in intracellular calcium concentration. Our findings may be indicative of a novel mechanism underlying ACh-induced vascular protection.
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China.
Ming
M
Zhao
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China.
Xi
X
He
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China; Department of Pediatrics, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China.
Yong-Hua
YH
Yang
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China.
Xiao-Jiang
XJ
Yu
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China.
Xue-Yuan
XY
Bi
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China.
Yang
Y
Yang
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China.
Man
M
Xu
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China.
Xing-Zhu
XZ
Lu
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China. Electronic address: sunqiang@mail.xjtu.edu.cn.
Qiang
Q
Sun
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, PR China. Electronic address: zwj@mail.xjtu.edu.cn.
Wei-Jin
WJ
Zang
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries; D009281:Naphthalenes / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics* / Q000517:prevention & control*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D018377:Neurotransmitter Agents; D044169:Receptors, Calcium-Sensing; D010656:Phenylephrine; D011189:Potassium Chloride; D000109:Acetylcholine; D010100:Oxygen; D002118:Calcium
Acetylcholine; Calcium-sensing receptor; Hypoxia/reoxygenation; Mesenteric artery; Vascular function