Godlewski Grzegorz, Alapafuja Shakiru O, Bátkai Sándor, Nikas Spyros P, Cinar Resat, Offertáler László, Osei-Hyiaman Douglas, Liu Jie, Mukhopadhyay Bani, Harvey-White Judith, Tam Joseph, Pacak Karel, Blankman Jacqueline L, Cravatt Benjamin F, Makriyannis Alexandros, Kunos George
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, MD 20852, USA.
Chem Biol. 2010 Nov 24;17(11):1256-66. doi: 10.1016/j.chembiol.2010.08.013.
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.
脂肪酸酰胺水解酶（FAAH）可催化内源性大麻素花生四烯乙醇胺在体内的降解，从而控制其在受体上的作用。一种新型FAAH抑制剂AM3506可使自发性高血压大鼠（SHR）升高的血压和心脏收缩力恢复正常，而对正常血压大鼠的这些参数无影响。这些作用归因于FAAH的阻断以及脑内花生四烯乙醇胺水平相应升高，导致CB₁受体介导的交感神经张力降低。SHR对CB₁受体介导的心血管抑制的超敏反应与CB₁受体的G蛋白偶联增加有关。重要的是，AM3506不会引发其他FAAH抑制剂或FAAH⁻/⁻小鼠中出现的高血糖和胰岛素抵抗，这与其因肝脏快速摄取和代谢而无法抑制肝脏中的FAAH有关。这种独特的活性谱为高血压治疗提供了更高的治疗价值。
