UrotensinⅡ对大鼠心脏效应作用机制的研究
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摘要
目的应用Langendorff离体心脏灌注的方法,观察不同浓度尾加压素II (Urotensin II,UII)对正常与心衰大鼠心功能的影响,及特异性的PKA抑制剂(KT5720)对UII作用于大鼠心脏效应的影响,探讨UII作用于心脏的可能机制。
方法应用腹主动脉缩窄法建立大鼠心衰模型。在langendorff离体心脏灌注的模型上,观察:⑴UII处理组:给予不同浓度的U II后,正常及心衰大鼠心功能的变化;⑵KT5720+UII处理组:在灌流KT5720基础上给予UII( >IC50 ),正常与心衰大鼠心功能指标的变化;⑶KT5720对照组:给予KT5720后正常与心衰大鼠心功能的变化。
结果⑴UII处理组:给予不同浓度的U II (10~(-10)、10~(-9)、10~(-8)和10~(-7) mol﹒L~(-1)) ,①灌注正常大鼠心脏后,左心室压最大上升速率(+dp/dt_(max))分别降低16.48%、25.53%、31.53%、34.47% ,左心室压最大下降速率(-dp/dt_(max))分别降低22.78%、33.63%、46.09%、51.73%;②灌注心衰大鼠心脏后, +dp/dt_(max)分别降低19.01%、26.05%、34.36%、37.27%,-dp/dt_(max)分别降低27.71%、38.72%、53.41%、60.12%。心衰大鼠的抑制率大于正常大鼠。⑵KT5720+UII处理组:灌流KT5720基础上,①正常大鼠:给予UII(10-7 mol﹒L -1, >IC50)+dp/dt_(max)降低5.37%,-dp/dt_(max)降低7.59%;②心衰大鼠:给予UII(10~(-8) mol﹒L~(-1), >IC50) +dp/dt_(max)降低3.27%,-dp/dt_(max)降低3.15%。+dp/dt_(max)、-dp/dt_(max)抑制率与UII组(>IC50)比较,均有统计学差异(正常大鼠P<0.01;心衰大鼠P<0.01)。⑶KT5720对照组:给予KT5720后,①正常大鼠+dp/dt_(max)降低5.99%,-dp/dt_(max)降低7.63%;②心衰大鼠+dp/dt_(max)降低2.84%,-dp/dt_(max)降低2.96%;与KT5720对照组的±dp/dt_(max)抑制率比较无统计学差异(正常及心衰大鼠P值均>0.05)
结论UII对正常大鼠及心衰大鼠心脏功能均呈剂量依赖性抑制,KT5720可以阻断UII对大鼠心脏的抑制作用,UII对心功能的抑制作用可能是通过PKA途径起作用。
AIM To investigate the effect and signaling mechanism of urotensin II on cardiac function in normal and heart failure rats.
Methods Hearts were perfused in the Langendorff mode,⑴UII group: Urotensin II (10-10、10-9、10-8 and 10-7 mol﹒L-1) was given respectively perfusion , then investigated the normal and heart failure rat’s cardiac function;⑵KT5720+UII group : perfused UII( IC50 ) on the basis of KT5720 , observed normal and heart failure rat’s cardiac function ;⑶KT5720 group : recorded normal and heart failure rat’s hemodynamic index after perfused KT5720.
Results⑴UII group: After given UII (10~(-10)、10~(-9)、10~(-8) and 10~(-7) mol﹒L~(-1)) in the fluid ,①normal rats : +dp/dt_(max) decreased 16.48%、25.53%、31.53% and 34.47%, -dp/dt_(max) reduced 22.78%、33.63%、46.09% and 51.73%;②heart failure rats : +dp/dt_(max) decreased 19.01%、26.05%、34.36%、37.27%, -dp/dt_(max) reduced 27.71%、38.72%、53.41%、60.12%, respectively. The heart failure rats’ratio was higher than normal rats’.⑵KT5720+UII group : urotensin II( IC_(50) ) was given on the basis of KT5720 ,①normal rats : +dp/dt_(max) reduced 5.37%, -dp/dt_(max) decreased 7.59%;②heart failure rats : +dp/dt_(max) reduced 3.27%, -dp/dt_(max) decreased 3.15%. There were significantly differences between KT5700+UII and UII group in±dp/dt_(max)(normal rat and heart failure rat: P<0.01)⑶KT5720 group : after perfused KT5720 ,①normal rats: +dp/dt_(max) decreased 5.99%, -dp/dt_(max) decreased 7.63%;②heart failure rats : +dp/dt_(max) decreased 2.84%, -dp/dt_(max) decreased 2.96%. In normal and heart failure rats , there were no significantly differences between KT5720+UII group and KT5720 group in±dp/dt_(max), (P>0.05) .
Conclusions The inhibitory effect of UII on normal and heart failure rat’s cardiac function was dose dependent , KT5720 could inhibit this effect, so the mechanism of UII on normal and heart failure rat’s cardiac function was probably mediated by PKA.
方法应用腹主动脉缩窄法建立大鼠心衰模型。在langendorff离体心脏灌注的模型上,观察:⑴UII处理组:给予不同浓度的U II后,正常及心衰大鼠心功能的变化;⑵KT5720+UII处理组:在灌流KT5720基础上给予UII( >IC50 ),正常与心衰大鼠心功能指标的变化;⑶KT5720对照组:给予KT5720后正常与心衰大鼠心功能的变化。
结果⑴UII处理组:给予不同浓度的U II (10~(-10)、10~(-9)、10~(-8)和10~(-7) mol﹒L~(-1)) ,①灌注正常大鼠心脏后,左心室压最大上升速率(+dp/dt_(max))分别降低16.48%、25.53%、31.53%、34.47% ,左心室压最大下降速率(-dp/dt_(max))分别降低22.78%、33.63%、46.09%、51.73%;②灌注心衰大鼠心脏后, +dp/dt_(max)分别降低19.01%、26.05%、34.36%、37.27%,-dp/dt_(max)分别降低27.71%、38.72%、53.41%、60.12%。心衰大鼠的抑制率大于正常大鼠。⑵KT5720+UII处理组:灌流KT5720基础上,①正常大鼠:给予UII(10-7 mol﹒L -1, >IC50)+dp/dt_(max)降低5.37%,-dp/dt_(max)降低7.59%;②心衰大鼠:给予UII(10~(-8) mol﹒L~(-1), >IC50) +dp/dt_(max)降低3.27%,-dp/dt_(max)降低3.15%。+dp/dt_(max)、-dp/dt_(max)抑制率与UII组(>IC50)比较,均有统计学差异(正常大鼠P<0.01;心衰大鼠P<0.01)。⑶KT5720对照组:给予KT5720后,①正常大鼠+dp/dt_(max)降低5.99%,-dp/dt_(max)降低7.63%;②心衰大鼠+dp/dt_(max)降低2.84%,-dp/dt_(max)降低2.96%;与KT5720对照组的±dp/dt_(max)抑制率比较无统计学差异(正常及心衰大鼠P值均>0.05)
结论UII对正常大鼠及心衰大鼠心脏功能均呈剂量依赖性抑制,KT5720可以阻断UII对大鼠心脏的抑制作用,UII对心功能的抑制作用可能是通过PKA途径起作用。
AIM To investigate the effect and signaling mechanism of urotensin II on cardiac function in normal and heart failure rats.
Methods Hearts were perfused in the Langendorff mode,⑴UII group: Urotensin II (10-10、10-9、10-8 and 10-7 mol﹒L-1) was given respectively perfusion , then investigated the normal and heart failure rat’s cardiac function;⑵KT5720+UII group : perfused UII( IC50 ) on the basis of KT5720 , observed normal and heart failure rat’s cardiac function ;⑶KT5720 group : recorded normal and heart failure rat’s hemodynamic index after perfused KT5720.
Results⑴UII group: After given UII (10~(-10)、10~(-9)、10~(-8) and 10~(-7) mol﹒L~(-1)) in the fluid ,①normal rats : +dp/dt_(max) decreased 16.48%、25.53%、31.53% and 34.47%, -dp/dt_(max) reduced 22.78%、33.63%、46.09% and 51.73%;②heart failure rats : +dp/dt_(max) decreased 19.01%、26.05%、34.36%、37.27%, -dp/dt_(max) reduced 27.71%、38.72%、53.41%、60.12%, respectively. The heart failure rats’ratio was higher than normal rats’.⑵KT5720+UII group : urotensin II( IC_(50) ) was given on the basis of KT5720 ,①normal rats : +dp/dt_(max) reduced 5.37%, -dp/dt_(max) decreased 7.59%;②heart failure rats : +dp/dt_(max) reduced 3.27%, -dp/dt_(max) decreased 3.15%. There were significantly differences between KT5700+UII and UII group in±dp/dt_(max)(normal rat and heart failure rat: P<0.01)⑶KT5720 group : after perfused KT5720 ,①normal rats: +dp/dt_(max) decreased 5.99%, -dp/dt_(max) decreased 7.63%;②heart failure rats : +dp/dt_(max) decreased 2.84%, -dp/dt_(max) decreased 2.96%. In normal and heart failure rats , there were no significantly differences between KT5720+UII group and KT5720 group in±dp/dt_(max), (P>0.05) .
Conclusions The inhibitory effect of UII on normal and heart failure rat’s cardiac function was dose dependent , KT5720 could inhibit this effect, so the mechanism of UII on normal and heart failure rat’s cardiac function was probably mediated by PKA.
引文
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[2] Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, Ao Z, Disa J, Holmes SD, Stadel JM, Martin JD, Liu WS, Glover GI, Wilson S, McNulty DE, Ellis CE, Elshourbagy NA, Shabon U, Trill JJ, Hay DW, Ohlstein EH, Bergsma DJ, Douglas SA.. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 [J]. Nature ,1999,401(6750): 282?6.
[3] Tal M, Ammar DA, Karpuj M, Krizhanovsky V, Naim M, Thompson DA. A novel putative neuropeptide receptor expressed in neural tissue, including sensory epithelia [J]. Biochem. Biophys. Res. Commun. 1995,209(2): 752?9.
[4] Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams DL Jr, Davidoff M, Wang R, Austin CP, McDonald TP, Bai C, George SR, Evans JF, Caskey CT. Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14 [J]. Biochem. Biophys. Res. Commun. 1999,266(1): 174?8.
[5] Mori M, Sugo T, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y, Kurokawa T, Onda H, Nishimura O, Fujino M.. Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14) [J]. Biochem. Biophys. Res. Commun. 265(1): 123-9.
[6] Katano Y, Ishihata A, Aita T, Ogaki T, Horie T..Vasdilator effect of urotensin II,one of the most potent vasoconstritlng factors, on rat coronary arteries [J].Eur J Pharmacology,2000,402(1-2):R5-7
[7]张勇刚,杨军,夏春芳,等.尾加压素II在心血管系统中的作用[J].北京医科大学学报,2000, 32: 133
[8] Douglas SA, Tayara L, Ohlstein EH et al. Congestive heart failure and expression of myocardial urotensin II.[J]. Lancet , 2002,359(9322): 1990-7.
[9] Lapp H, Boerrigter G, Costello-Boerrigter LC et al . Elevated plasma human urotensin-II-like immunoreactivity in ischemic cardiomyopathy. [J].Int J cardiol, 2004; 94(1):93-7.
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