Endocannabinoids And Control Of Cardiovascular Function

内源性大麻素anandamide通过大麻素受体（CB）发挥神经行为，心血管和免疫调节作用。脂肪酸酰胺水解酶（FAAH）是一种负责花生四烯酸在体内降解的酶。最近的实验研究表明，通过FAAH抑制剂靶向内源性大麻能系统是治疗焦虑、炎症和高血压的一种有前途的新方法。在这项研究中，我们比较了FAAH基因敲除（FAAH-/-）小鼠和野生型（FAAH+/+）同窝小鼠的心脏性能，并使用Millar压力-体积电导导管系统分析了花生四烯酸对血流动力学的影响。FAAH-/-和FAAH+/+小鼠的基线心血管参数、不同前负荷下的收缩和舒张功能以及压力反射敏感性相似。与FAAH+/+同窝小鼠相比，FAAH-/-小鼠对大麻素诱导的CB 1介导的低血压的敏感性增加，心肌收缩力降低。相反，合成的CB 1激动剂HU 210的抑制效力和心肌CB 1的表达水平在两种菌株中相似。与FAAH+/+小鼠相比，FAAH-/-小鼠的花生四烯酸乙醇胺和油酰乙醇胺的心肌水平增加，但2-花生四烯酸甘油没有增加。这些结果表明，缺乏FAAH的小鼠具有正常的血流动力学特征，其对花生四烯酸诱导的低血压和心脏抑制的反应性增加是由于花生四烯酸降解减少，而不是靶器官对CB 1受体激动剂的敏感性增加。 大麻素改变冠状动脉血管张力和心脏功能的机制是有争议的。我们研究了各种大麻素在自发跳动的Langendorff灌注大鼠心脏中的作用。大剂量注射花生四烯酸（0.1-1？Ymol）对冠脉流量（CF）和左室收缩压（LVSP）无明显影响。在用加压素预灌注以诱导血管收缩张力的心脏中，花生四烯酸或选择性CB 1受体激动剂ACEA（1-100 nmol）剂量依赖性地增加CF高达267%和LVSP 20 mmHg。代谢稳定的内源性大麻素衍生物，R-methanandamide（0.1-1？Ymol）和noladin-ether（10-100 nmol）的作用相似。异常大麻二酚（abn-cbd，10-100 nmol），在假定的内皮大麻素受体的选择性激动剂也增加CF。相比之下，？你好吗？9-THC（10-100 nmol），大麻的主要精神活性成分，强烈降低CF和LVSP。CB 2受体激动剂JW-133（10-100 nmol）仅在较高剂量下引起血管扩张和正性肌力作用。CB 1拮抗剂SR 141716 A和AM-251以及钾通道抑制剂四乙铵和伊比利亚毒素阻断了大麻素诱导的CF和LVSP增加，而CB 2拮抗剂SR 144528和推定的内皮大麻素受体拮抗剂O-1918没有抑制作用。免疫组化显示存在心脏CB 1，但没有CB 2受体。SR 141716可减弱abn-cbd引起的CF增加，但AM-251或O-1918不能。在心脏组织中检测到花生四烯酸和2-花生四烯酸甘油。然而，联合应用脂肪酸酰胺水解酶抑制剂和转运抑制剂AM-404以增加内源性大麻素的组织水平对CF或LVSP没有影响。 我们的结论是，在大鼠离体心脏与重建血管收缩张力，大麻素，包括大麻素引起冠状动脉血管舒张和二次增加收缩通过CB 1受体和钾通道。

The endocannabinoid anandamide exerts neurobehavioral, cardiovascular and immune-regulatory effects through cannabinoid receptors (CB). Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the in vivo degradation of anandamide. Recent experimental studies have suggested that targeting the endocannabinergic system by FAAH inhibitors is a promising novel approach for the treatment of anxiety, inflammation and hypertension. In this study we compared the cardiac performance of FAAH knockout (FAAH-/-) mice and their wild-type (FAAH+/+) littermates, and analyzed the hemodynamic effects of anandamide using the Millar pressure-volume conductance catheter system. Baseline cardiovascular parameters, systolic and diastolic function at different preloads and baroreflex sensitivity were similar in FAAH-/- and FAAH+/+ mice. FAAH-/- mice displayed increased sensitivity to anandamide-induced, CB1-mediated, hypotension and decreased cardiac contractility compared to FAAH+/+ littermates. In contrast, the hypotensive potency of synthetic CB1 agonist HU210, and the level of expression of myocardial CB1 were similar in the two strains. The myocardial levels of anandamide and oleoylethanolamide, but not 2-arachidonylglycerol, were increased in FAAH-/- compared to FAAH+/+ mice. These results indicate that mice lacking FAAH have a normal hemodynamic profile, and their increased responsiveness to anandamide-induced hypotension and cardiodepression is due to the decreased degradation of anandamide rather than an increase in target organ sensitivity to CB1 receptor agonists. The mechanisms by which cannabinoids alter coronary vascular tone and cardiac performance are controversial. We investigated the effects of various cannabinoids in spontaneously beating Langendorff-perfused rat hearts. Bolus injections of anandamide (0.1-1 ?Ymol) caused no change in coronary flow (CF) and left ventricular systolic pressure (LVSP). In hearts preperfused with vasopressin to induce vasoconstrictor tone, anandamide or the selective CB1 receptor agonist ACEA (1-100 nmol) dose-dependently increased CF by up to 267 % and LVSP by 20 mmHg. The metabolically stable endocannabinoid derivatives, R-methanandamide (0.1-1 ?Ymol) and noladin-ether (10-100 nmol), displayed similar effects. Abnormal cannabidiol (abn-cbd, 10-100 nmol), a selective agonist at putative endothelial cannabinoid receptors also increased CF. In contrast,?n?'9-THC (10-100 nmol), the major psychoactive ingredient of cannabis, strongly decreased CF and LVSP. The CB2 receptor agonist JW-133 (10-100 nmol) elicited vasodilator and positive inotropic effects only at higher doses. The CB1 antagonists SR141716A and AM-251 as well as the potassium channel inhibitors tetraethylammonium and iberiotoxin blocked the anandamide- induced increases in CF and LVSP, whereas the CB2 antagonist SR144528 and the putative endothelial cannabinoid receptor antagonist O-1918 did not have an inhibitory effect. Immunohistochemistry revealed the presence of cardiac CB1 but no CB2 receptors. The increases in CF caused by abn-cbd were attenuated by SR141716, but not by AM-251 or O-1918. Anandamide and 2-arachidonoyl-glycerol were detected in heart tissue. However, combined application of fatty acid amidohydrolase inhibitors and the transport inhibitor AM-404 in order to augment tissue levels of endocannabinoids was without effect on CF or LVSP. We conclude that in the rat isolated heart with re-established vasoconstrictor tone, cannabinoids including anandamide elicit coronary vasodilation and a secondary increase in contractility via CB1 receptors and potassium channels.