Li Guichu, Wang Xu, Abdel-Rahman Abdel A
Department of Pharmacology, Brody School of Medicine, Greenville, North Carolina 27858-4353, USA.
J Cardiovasc Pharmacol. 2005 Jul;46(1):52-62. doi: 10.1097/01.fjc.0000162773.54915.52.
We tested the hypothesis that the I1 receptor mediates the reduction in rostral ventrolateral medulla (RVLM) neuronal norepinephrine (NE; index of sympathetic activity) that leads to hypotension independent of other brainstem areas or the alpha2-adrenergic receptor. To this end, we developed a model that permitted measurement of real-time changes in neuronal NE in the RVLM or nucleus tractus solitarius (NTS) along with blood pressure and heart rate in the conscious SHR in response to localized microinjections of selective I1 (rilmenidine) or alpha2-adrenergic (alpha-methylnorepinephrine; alpha-MNE) agonist versus the mixed I1/alpha2 agonist clonidine. To further support the hypothesis, we investigated the effects of localized selective alpha2- (SK&F86466) or I1 (efaroxan) blockade on the reductions in neuronal NE and blood pressure elicited by intra-RVLM rilmenidine. In the latter experiment, changes in RVLM neuronal c-Fos (another marker of sympathetic neural activity) were also investigated. Intra-RVLM rilmenidine (40 nmol) or clonidine (1 nmol) similarly reduced RVLM NE and blood pressure; these responses were approximately 2-fold greater than those elicited by the pure alpha2-adrenergic agonist alpha-MNE (10 nmol). By contrast, intra-NTS rilmenidine or clonidine had no effect on NTS NE or blood pressure versus significant reductions in both parameters by alpha-MNE. Intra-RVLM rilmenidine decreased c-Fos expression, and these responses were abolished by efaroxan but not by SK&F 86466. These findings suggest: (1) in the RVLM, I1-receptor signaling suppresses cardiovascular neuron activity, which leads to lowering of blood pressure; (2) although the alpha2-adrenergic receptor in the RVLM serves a similar role, it does not exert a tonic neuronal inhibitory effect and is not essential, as a downstream signaling entity, for the I1-evoked neurobiological effects in the brainstem. The potential confounding effects of anesthetics on the I1 and/or alpha2 receptor-mediated neuronal and cardiovascular responses were circumvented in the present study.
I1受体介导延髓头端腹外侧区（RVLM）神经元去甲肾上腺素（NE；交感神经活动指标）的减少，进而导致低血压，且该过程独立于其他脑干区域或α2 - 肾上腺素能受体。为此，我们建立了一个模型，用于测量清醒自发性高血压大鼠（SHR）在局部微量注射选择性I1（利美尼定）或α2 - 肾上腺素能（α - 甲基去甲肾上腺素；α - MNE）激动剂与I1/α2混合激动剂可乐定后，RVLM或孤束核（NTS）中神经元NE的实时变化以及血压和心率。为进一步支持该假说，我们研究了局部选择性α2 - （SK&F86466）或I1（依酚氯铵）阻断对RVLM内注射利美尼定引起的神经元NE减少和血压降低的影响。在后者的实验中，还研究了RVLM神经元c - Fos（交感神经活动的另一个标志物）的变化。RVLM内注射利美尼定（40 nmol）或可乐定（1 nmol）同样降低了RVLM中的NE和血压；这些反应比纯α2 - 肾上腺素能激动剂α - MNE（10 nmol）引起的反应大约大2倍。相比之下，NTS内注射利美尼定或可乐定对NTS中的NE或血压没有影响，而α - MNE则显著降低了这两个参数。RVLM内注射利美尼定降低了c - Fos表达，这些反应被依酚氯铵消除，但未被SK&F 86466消除。这些发现表明：（1）在RVLM中，I1受体信号传导抑制心血管神经元活动，从而导致血压降低；（2）尽管RVLM中的α2 - 肾上腺素能受体起类似作用，但它不发挥持续性神经元抑制作用，并且作为下游信号实体，对于脑干中I1诱发的神经生物学效应并非必不可少。本研究规避了麻醉剂对I1和/或α2受体介导的神经元和心血管反应的潜在混杂效应。
