Matouk Asmaa I, Taye Ashraf, El-Moselhy Mohamed A, Heeba Gehan H, Abdel-Rahman Abdel A
*Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, NC; and †Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Egypt.
J Cardiovasc Pharmacol. 2017 Jan;69(1):23-33. doi: 10.1097/FJC.0000000000000438.
Although acute activation of the novel endocannabinoid receptor GPR18 causes hypotension, there are no reports on GPR18 expression in the heart or its chronic modulation of cardiovascular function. In this study, after demonstrating GPR18 expression in the heart, we show that chronic (2 weeks) GPR18 activation with its agonist abnormal cannabidiol (abn-cbd; 100 µg·kg·d; i.p) produced hypotension, suppressed the cardiac sympathetic dominance, and improved left ventricular (LV) function (increased the contractility index dp/dtmax and reduced LV end-diastolic pressure, LVEDP) in conscious rats. Ex vivo studies revealed increased: (1) cardiac and plasma adiponectin (ADN) levels; (2) vascular (aortic) endothelial nitric oxide synthase (eNOS) expression, (3) vascular and serum nitric oxide (NO) levels; (4) myocardial and plasma cyclic guanosine monophosphate (cGMP) levels; (5) phosphorylation of myocardial protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) along with reduced myocardial reactive oxygen species (ROS) in abn-cbd treated rats. These biochemical responses contributed to the hemodynamic responses and were GPR18-mediated because concurrent treatment with the competitive GPR18 antagonist (O-1918) abrogated the abn-cbd-evoked hemodynamic and biochemical responses. The current findings present new evidence for a salutary cardiovascular role for GPR18, mediated, at least partly, via elevation in the levels of adiponectin.
尽管新型内源性大麻素受体GPR18的急性激活会导致低血压，但尚无关于GPR18在心脏中的表达或其对心血管功能的慢性调节作用的报道。在本研究中，在证实心脏中存在GPR18表达后，我们发现，用其激动剂异常大麻二酚（abn-cbd；100 µg·kg·d；腹腔注射）对GPR18进行慢性（2周）激活会导致清醒大鼠出现低血压、抑制心脏交感神经优势，并改善左心室（LV）功能（增加收缩力指数dp/dtmax并降低左心室舒张末期压力，即LVEDP）。体外研究显示，在接受abn-cbd治疗的大鼠中：（1）心脏和血浆脂联素（ADN）水平升高；（2）血管（主动脉）内皮型一氧化氮合酶（eNOS）表达增加；（3）血管和血清一氧化氮（NO）水平升高；（4）心肌和血浆环磷酸鸟苷（cGMP）水平升高；（5）心肌蛋白激酶B（Akt）和细胞外信号调节激酶1/2（ERK1/2）磷酸化增加，同时心肌活性氧（ROS）减少。这些生化反应促成了血流动力学反应，并且是由GPR18介导的，因为同时使用竞争性GPR18拮抗剂（O-1918）可消除abn-cbd引起的血流动力学和生化反应。目前的研究结果为GPR18在心血管方面的有益作用提供了新证据，至少部分是通过脂联素水平升高介导的。
