Schaich Chris L, Grabenauer Megan, Thomas Brian F, Shaltout Hossam A, Gallagher Patricia E, Howlett Allyn C, Diz Debra I
Department of Physiology and Pharmacology and Hypertension and Vascular Research Center, Wake Forest School of Medicine Winston-Salem, NC, USA.
Department of Physiology and Pharmacology and Hypertension and Vascular Research Center, Wake Forest School of MedicineWinston-Salem, NC, USA; Analytical Chemistry and Pharmaceutics, RTI InternationalResearch Triangle Park, NC, USA.
Front Physiol. 2016 Jun 9;7:207. doi: 10.3389/fphys.2016.00207. eCollection 2016.
CB1 cannabinoid receptors are expressed on vagal afferent fibers and neurons within the solitary tract nucleus (NTS), providing anatomical evidence for their role in arterial baroreflex modulation. To better understand the relationship between the brain renin-angiotensin system (RAS) and endocannabinoid expression within the NTS, we measured dorsal medullary endocannabinoid tissue content and the effects of CB1 receptor blockade at this brain site on cardiac baroreflex sensitivity (BRS) in ASrAOGEN rats with low glial angiotensinogen, normal Sprague-Dawley rats and (mRen2)27 rats with upregulated brain RAS expression. Mass spectrometry revealed higher levels of the endocannabinoid 2-arachidonoylglycerol in (mRen2)27 compared to ASrAOGEN rats (2.70 ± 0.28 vs. 1.17 ± 0.09 ng/mg tissue; P < 0.01), while Sprague-Dawley rats had intermediate content (1.85 ± 0.27 ng/mg tissue). Microinjection of the CB1receptor antagonist SR141716A (36 pmol) into the NTS did not change cardiac BRS in anesthetized Sprague-Dawley rats (1.04 ± 0.05 ms/mmHg baseline vs. 1.17 ± 0.11 ms/mmHg after 10 min). However, SR141716A in (mRen2)27 rats dose-dependently improved BRS in this strain: 0.36 pmol of SR141716A increased BRS from 0.43 ± 0.03 to 0.71 ± 0.04 ms/mmHg (P < 0.001), and 36 pmol of SR141716A increased BRS from 0.47 ± 0.02 to 0.94 ± 0.10 ms/mmHg (P < 0.01). In contrast, 0.36 pmol (1.50 ± 0.12 vs. 0.86 ± 0.08 ms/mmHg; P < 0.05) and 36 pmol (1.38 ± 0.16 vs. 0.46 ± 0.003 ms/mmHg; P < 0.01) of SR141716A significantly reduced BRS in ASrAOGEN rats. These observations reveal differential dose-related effects of the brain endocannabinoid system that influence cardiovagal BRS in animals with genetic alterations in the brain RAS.
CB1大麻素受体在迷走神经传入纤维和孤束核（NTS）内的神经元上表达，为其在动脉压力反射调节中的作用提供了解剖学证据。为了更好地理解脑肾素-血管紧张素系统（RAS）与NTS内内源性大麻素表达之间的关系，我们测量了背侧延髓内源性大麻素组织含量，以及在该脑区阻断CB1受体对低胶质血管紧张素原的ASrAOGEN大鼠、正常的Sprague-Dawley大鼠和脑RAS表达上调的（mRen2）27大鼠心脏压力反射敏感性（BRS）的影响。质谱分析显示，与ASrAOGEN大鼠相比，（mRen2）27大鼠内源性大麻素2-花生四烯酸甘油水平更高（2.70±0.28对1.17±0.09 ng/mg组织；P<0.01），而Sprague-Dawley大鼠的含量处于中间水平（1.85±0.27 ng/mg组织）。向NTS微量注射CB1受体拮抗剂SR141716A（36 pmol）对麻醉的Sprague-Dawley大鼠的心脏BRS没有影响（基线时为1.04±0.05 ms/mmHg，10分钟后为1.17±0.11 ms/mmHg）。然而，在（mRen2）27大鼠中，SR141716A剂量依赖性地改善了该品系的BRS：0.36 pmol的SR141716A使BRS从0.43±0.03增加到0.71±0.04 ms/mmHg（P<0.001），36 pmol的SR141716A使BRS从0.47±0.02增加到0.94±0.1 ms/mmHg（P<0.01）。相比之下，0.36 pmol（1.50±0.12对0.86±0.08 ms/mmHg；P<0.05）和36 pmol（1.38±0.16对0.46±0.003 ms/mmHg；P<0.01）的SR141716A显著降低了ASrAOGEN大鼠的BRS。这些观察结果揭示了脑内源性大麻素系统在影响脑RAS基因改变动物的心血管迷走神经BRS方面存在剂量相关的差异效应。
