Endocannabinoids And The Control Of Cardiovascular Function

抑制脂肪酸酰胺水解酶（FAAH）（负责内源性大麻素anandamide的选择性体内降解的酶）、electin CB 1受体介导的抗焦虑、镇痛和心血管降压作用，而不诱导预测成瘾潜力的行为效应。我们最近已经证明，一种新的，高效的，在体内有效的FAAH抑制剂，AM3506，正常化的血压升高和不适当增加的心脏收缩性麻醉和清醒的自发性高血压大鼠（SHR），而不影响这些参数在血压正常的动物。SHR的心血管降压作用在神经节阻滞和加压素输注恢复血压后得以维持，因此可以归因于内源性大麻素通过激活中枢神经系统中的CB 1受体引起的交感神经紧张度降低。我们进一步表明，高血压动物相对于血压正常的动物对CB 1 R介导的心血管降压作用的更大的敏感性与CB 1 R与G蛋白偶联的效率增加有关。这些发现表明，靶向内源性大麻素系统可能对高血压有治疗价值。此外，我们发现AM3506不会引起代谢副作用，包括高血糖症/葡萄糖耐受不良。这种作用在其他FAAH抑制剂如URB 597或FAAH-/-小鼠中常见，是由于肝脏中FAH的抑制以及随后导致肝脏CB 1受体激活的肝脏腺苷酸酰胺水平的增加。我们已经证明，AM3506独特的缺乏这种副作用是由于其非常快速的肝脏代谢，导致其无法阻断肝脏中的FAAH。这些结果在化学与生物学出版社出版。

Inhibition of fatty acid amidohydrolase (FAAH), the enzyme responsible for the selective in vivo degradation of the endocannabinoid anandamide, elicits CB1 receptor-mediated anxiolytic, analgesic and cardiovascular depressor effects, without inducing behavioral effects predictive of addictive potential. We have recently demonstrated that a novel, highly potent, in vivo effective FAAH inhibitor, AM3506, normalizes the elevated blood pressure and inappropriately increased cardiac contractility of both anesthetized and conscious spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive animals. The cardiovascular depressor effects in SHR were maintained following ganglionic blockade and restoration of blood pressure by vasopressin infusion, and thus could be attributed to a reduction in sympathetic tone elicited via activation of CB1 receptors in the central nervous system by endogenous anandamide. We further showed that the greater sensitivity of hypertensive relative to normotensive animals to CB1R-mediated cardiovascular depressor effects is related to increased efficiency of coupling of CB1R to G proteins. These findings suggest that targeting the endocannabinoid system may have therapeutic value in hypertension. Additionally, we have found that AM3506 does not induce metabolic side effects including hyperglycemia/glucose intolerance. Such effects are commonly seen with other FAAH inhibitors, such as URB597, or in FAAH-/- mice, and are due to inhibition of FAH in the liver and the consequent increase in hepatic anndamide levels that result in activation of hepatic CB1 receptors. We have demonstrated that the the unique lack of such side effects with AM3506 is due to its very rapid metablism by the liver, resulting in ts inabiliity to block FAAH in the liver. These results are in press at Chemistry & Biology.