Department of Foundational Sciences & Research, East Carolina School of Dental Medicine, Greenville, NC; and.
Department of Surgery/Hypertension and Vascular Research, Cardiovascular Sciences Center, Wake Forest University School of Medicine, Winston-Salem, NC.
J Cardiovasc Pharmacol. 2023 Jan 1;81(1):76-84. doi: 10.1097/FJC.0000000000001368.
The over-expression of Ren -2 d gene in (mRen2)27 rats leads to development of hypertension mediated by the renin-angiotensin-system axis and exaggerated sympathetic nerve activity. Exogenously applied angiotensin II (AngII) on the superior cervical ganglion evokes ganglionic compound action potentials (gCAP) and ganglionic long-term potentiation (gLTP). We studied the functional role of angiotensin receptors and expression of reactive oxygen species marker, nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) proteins in AngII-induced postganglionic transmission. Bath-applied AngII revealed that the indices of ganglionic transmission, synaptic strength of gCAP, and decay time for gLTP are remarkably prolonged in (mRen2)27 rats and were abolished by an angiotensin receptor blocker (ARB), suggesting postganglionic AngII Type 1 (AT 1 ) receptor localization and mediation. Receptor density for AT 1 was similar in (mRen2)27 and control animals, and quantitative reverse transcription polymerase chain reaction revealed that it is consistent with the mRNA profile. Furthermore, immunocytochemistry analysis showed similar AT 1 receptor distribution and signals. However, assessment of Type 2 (AT 2 ), Ang-(1-7)-MAS and NOX4-specific proteins showed that AT 2 receptor protein expression was 4-fold lower, consistent with a low mRNA profile. MAS receptor expression was 10-fold lower and NOX4 protein was 2-fold lower. Despite similarity in the densities of AT 1 receptor, the low levels of the components of the protective arm of the renin-angiotensin system at the ganglia may contribute to the differential superior cervical ganglion sensitivity to AngII. The lower NOX4 affects reactive oxygen species balance and possibly results in activation of downstream pathways to promote increased sympathetic nerve activity. We speculate that the significant diminution in AT 2, MAS, and NOX4 protein expressions may play an indirect role in the alteration and efficacy of gCAP and gLTP in hypertension.
(mRen2)27 大鼠中 Ren-2d 基因的过度表达导致肾素-血管紧张素系统轴介导的高血压和交感神经活性过度增强。外源性应用血管紧张素 II（AngII）于颈上神经节可诱发神经节复合动作电位（gCAP）和神经节长时程增强（gLTP）。我们研究了血管紧张素受体的功能作用以及活性氧物质标记物烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（NOX4）蛋白在 AngII 诱导的节后传递中的表达。在 (mRen2)27 大鼠中，浴用 AngII 揭示了节后传递的指标、gCAP 的突触强度和 gLTP 的衰减时间明显延长，并且被血管紧张素受体阻滞剂（ARB）所消除，表明节后 AngII 型 1（AT1）受体定位和介导。(mRen2)27 和对照动物中的 AT1 受体密度相似，定量逆转录聚合酶链反应显示其与 mRNA 谱一致。此外，免疫细胞化学分析显示了相似的 AT1 受体分布和信号。然而，对 2 型（AT2）、Ang-（1-7）-MAS 和 NOX4 特异性蛋白的评估表明，AT2 受体蛋白表达低 4 倍，与低 mRNA 谱一致。MAS 受体表达低 10 倍，NOX4 蛋白低 2 倍。尽管 AT1 受体密度相似，但神经节中肾素-血管紧张素系统保护臂的组成成分水平较低，可能导致颈上神经节对 AngII 的敏感性不同。较低的 NOX4 会影响活性氧物质的平衡，并可能导致下游途径的激活，从而促进交感神经活性的增加。我们推测，AT2、MAS 和 NOX4 蛋白表达的显著减少可能在改变和增强 gCAP 和 gLTP 在高血压中的作用中起间接作用。
