Sun Gwo-Ching, Tse Jockey, Hsu Yung-Ho, Ho Chiu-Yi, Tseng Ching-Jiunn, Cheng Pei-Wen
Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan.
Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
Antioxidants (Basel). 2021 Nov 8;10(11):1784. doi: 10.3390/antiox10111784.
Opioids, a kind of peptide hormone involved in the development of hypertension, cause systemic and cerebral inflammation, and affects regions of the brain that are important for blood pressure (BP) control. A cause-and-effect relationship exists between hypertension and inflammation; however, the role of blood pressure in cerebral inflammation is not clear. Evidence showed that AT1R and μOR heterodimers' formation in the NTS might lead to the progression of hypertension. In this study, we investigated the formation of the μOR/AT1R heterodimer, determined its correlation with μORs level in the NTS, and explored the role of TLR4-dependent inflammation in the development of hypertension. Results showed that Ang II increased superoxide and Iba-1 (microgliosis marker: ionized calcium-binding adaptor molecule (1) levels in the NTS of spontaneously hypertensive rats (SHRs). The AT1R II inhibitor, losartan, significantly decreased BP and abolished superoxide, Iba-1, TLR4 expression induced by Ang II. Furthermore, losartan significantly increased nNsOS phosphorylation. Administration of a μOR agonist or antagonist in the NTS of WKY and SHRs increased endogenous μ-opioids, triggered the formation of μOR/AT1R heterodimers and the TLR4-dependent inflammatory pathway, and attenuated the effect of depressor nitric oxide (NO). These results imply an important link between neurotoxicity and superoxides wherein abnormal increases in NTS endogenous μ-opioids promote the interaction between Ang II and μOR, the binding of Ang II to AT1R, and the activation of microglia. In addition, the interaction between Ang II and μOR enhanced the formation of the AT1R and μOR heterodimers, and inactivated nNOS-derived NO, leading to the development of progressive hypertension.
阿片类物质是一种参与高血压发展的肽类激素，可引起全身和脑部炎症，并影响对血压（BP）控制至关重要的脑区。高血压与炎症之间存在因果关系；然而，血压在脑部炎症中的作用尚不清楚。有证据表明，孤束核中AT1R和μOR异二聚体的形成可能导致高血压的进展。在本研究中，我们研究了μOR/AT1R异二聚体的形成，确定了其与孤束核中μOR水平的相关性，并探讨了TLR4依赖性炎症在高血压发展中的作用。结果显示，血管紧张素II增加了自发性高血压大鼠（SHR）孤束核中的超氧化物和Iba-1（小胶质细胞增生标志物：离子钙结合衔接分子（1））水平。AT1R II抑制剂氯沙坦显著降低血压，并消除了血管紧张素II诱导的超氧化物、Iba-1、TLR4表达。此外，氯沙坦显著增加nNsOS磷酸化。在WKY和SHR的孤束核中给予μOR激动剂或拮抗剂可增加内源性阿片类物质，触发μOR/AT1R异二聚体的形成和TLR4依赖性炎症途径，并减弱降压性一氧化氮（NO）的作用。这些结果表明神经毒性与超氧化物之间存在重要联系，其中孤束核内源性阿片类物质的异常增加促进了血管紧张素II与μOR之间的相互作用、血管紧张素II与AT1R的结合以及小胶质细胞的激活。此外，血管紧张素II与μOR之间的相互作用增强了AT1R和μOR异二聚体的形成，并使nNOS衍生的NO失活，导致进行性高血压的发展。
