Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects.
Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects.
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DOI：
10.1016/j.chembiol.2010.08.013
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发表时间：
2010-11-24
影响因子：
--
通讯作者：
Kunos G
中科院分区：
文献类型：
--
作者：
Godlewski G;Alapafuja SO;Bátkai S;Nikas SP;Cinar R;Offertáler L;Osei-Hyiaman D;Liu J;Mukhopadhyay B;Harvey-White J;Tam J;Pacak K;Blankman JL;Cravatt BF;Makriyannis A;Kunos G
脂肪酸酰胺水解酶（FAAH）催化内源性大麻素anandamide的体内降解，从而控制其对受体的作用。一种新的FAAH抑制剂，AM3506，正常化自发性高血压大鼠（SHR）的血压和心肌收缩力的升高，而不影响这些参数在正常血压大鼠。这些作用是由于FAAH的阻断和脑内大麻素水平的相应升高，导致CB 1受体介导的交感神经张力降低。SHR对CB 1受体介导的心血管抑制的超敏感性与CB 1受体的G蛋白偶联增加有关。重要的是，AM3506不会引起其他FAAH抑制剂或FAAH−/−小鼠中观察到的高血糖症和胰岛素抵抗，这与其无法抑制肝脏中的FAAH（由于肝脏快速摄取和代谢）有关。这种独特的活性特征为高血压提供了更好的治疗价值。
The enzyme fatty-acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB1 receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB1 receptor-mediated cardiovascular depression is related to increased G-protein coupling of CB1 receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH−/− mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.
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影响因子：
25
作者：
Marrs, William R.;Blankman, Jacqueline L.;Horne, Eric A.;Thomazeau, Aurore;Lin, Yi Hsing;Coy, Jonathan;Bodor, Agnes L.;Muccioli, Giulio G.;Hu, Sherry Shu-Jung;Woodruff, Grace;Fung, Susan;Lafourcade, Mathieu;Alexander, Jessica P.;Long, Jonathan Z.;Li, Weiwei;Xu, Cong;Moeller, Thomas;Mackie, Ken;Manzoni, Olivier J.;Cravatt, Benjamin F.;Stella, Nephi
通讯作者：
Stella, Nephi
影响因子：
10.6
作者：
Justinova, Zuzana;Mangieri, Regina A.;Bortolato, Marco;Chefer, Svetlana I.;Mukhin, Alexey G.;Clapper, Jason R.;King, Alvin R.;Redhi, Godfrey H.;Yasar, Sevil;Piomelli, Daniele;Goldberg, Steven R.
通讯作者：
Goldberg, Steven R.
DOI：
10.1073/pnas.0400997101
发表时间：
2004-06-08
影响因子：
11.1
作者：
Fegley, D;Kathuria, S;Piomelli, D
通讯作者：
Piomelli, D
影响因子：
10.8
作者：
Marcil, J;de Champlain, J;Anand-Srivastava, MB
通讯作者：
Anand-Srivastava, MB
影响因子：
7.3
作者：
Dziadulewicz, Edward K.;Bevan, Stuart J.;Zadrobilek, Jiri
通讯作者：
Zadrobilek, Jiri