Hsu Julia Chu-Ning, Sekizawa Shinichi, Tochinai Ryota, Kuwahara Masayoshi
Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Life (Basel). 2021 Jul 20;11(7):720. doi: 10.3390/life11070720.
High blood pressure is a major risk factor of cerebro-cardiovascular outcomes. Blood pressure is partly regulated by the autonomic nervous system and its reflex functions; therefore, we hypothesized that pharmacological intervention in the brainstem that can regulate blood pressure could be a novel therapeutic strategy to control hypertension. We infused a group II metabotropic glutamate receptor (mGluR) antagonist (LY341495, 0.40 μg/day), using a mini-osmotic pump, into the dorsal medulla oblongata in young spontaneously hypertensive rats (SHRs), as this area is adjacent to the nucleus tractus solitarius (NTS), of which the neurons are involved in baroreflex pathways with glutamatergic transmission. Blood pressure was recorded for conscious rats with the tail cuff method. A 6-week antagonist treatment from 6 to 12 weeks of age slightly but significantly increased systolic blood pressure by >30 mmHg, compared to that in SHRs without treatment. Moreover, the effect continued even 3 weeks after the treatment ended, and concurred with an increase in blood catecholamine concentration. However, heart rate variability analysis revealed that LY341495 treatment had little effect on autonomic activity. Meanwhile, mRNA expression level of mGluR subtype 2, but not subtype 3 in the brainstem was significantly enhanced by the antagonist treatment in SHRs, possibly compensating the lack of mGluR signaling. In conclusion, mGluR2 signaling in the dorsal brainstem is crucial for preventing the worsening of hypertension over a relatively long period in SHRs, through a mechanism of catecholamine secretion. This may be a specific drug target for hypertension therapy.
高血压是心脑血管疾病的主要危险因素。血压部分受自主神经系统及其反射功能调节；因此，我们推测对脑干进行药物干预以调节血压可能是控制高血压的一种新的治疗策略。我们使用微型渗透泵，将一种II型代谢型谷氨酸受体（mGluR）拮抗剂（LY341495，0.40μg/天）注入年轻的自发性高血压大鼠（SHR）的延髓背侧，因为该区域与孤束核（NTS）相邻，孤束核的神经元参与具有谷氨酸能传递的压力反射通路。采用尾袖法记录清醒大鼠的血压。与未治疗的SHR相比，在6至12周龄时进行为期6周的拮抗剂治疗，收缩压略有但显著升高超过30mmHg。此外，即使在治疗结束后3周，这种效应仍然存在，并且与血液中儿茶酚胺浓度的增加一致。然而，心率变异性分析显示，LY341495治疗对自主神经活动影响很小。同时，拮抗剂治疗显著增强了SHR脑干中mGluR 2亚型而非3亚型的mRNA表达水平，可能是对mGluR信号缺失的一种补偿。总之，延髓背侧的mGluR2信号通过儿茶酚胺分泌机制，对于在相对较长时间内防止SHR高血压病情恶化至关重要。这可能是高血压治疗的一个特定药物靶点。
