Hayar A, Guyenet P G
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
Am J Physiol. 1999 Sep;277(3):H1069-80. doi: 10.1152/ajpheart.1999.277.3.H1069.
The rostral ventrolateral medulla (RVLM) controls sympathetic tone via excitatory bulbospinal neurons. It is also the main target of alpha2-adrenoceptor (alpha2-AR) agonists used for treatment of hypertension. In this study, we examined the synaptic mechanisms by which alpha2-AR agonists may inhibit the activity of RVLM bulbospinal neurons. We recorded selectively from RVLM bulbospinal neurons in brain stem slices of neonate rats (P5-P21) using the patch-clamp technique (holding potential -70 mV). alpha2-ARs were activated by norepinephrine (NE, 30 microM) in the presence of the alpha1-adrenoceptor blocker prazosin. NE induced modest outward currents (5-28 pA) in 70% of the cells that were blocked by barium and by the alpha2-AR antagonist 2-methoxyidazoxan. The magnitude of this current was not correlated with the tyrosine hydroxylase immunoreactivity of the neurons. Mono- and oligosynaptic excitatory postsynaptic currents (EPSCs) or monosynaptic inhibitory postsynaptic currents (IPSCs) were evoked by focal electrical stimulation. In all cells, NE decreased the amplitude of the evoked EPSCs in the absence or presence of barium (49 and 70%) and decreased the amplitude of the evoked IPSCs (64 and 59%). The effect of NE on EPSC amplitude was blocked by 2-methoxyidazoxan. Focal stimulation produced a 1- to 2-s EPSC afterdischarge (probably due to activation of interneurons) that was 53% inhibited by NE. In the presence of tetrodotoxin, NE decreased the frequency of miniature EPSCs by 74%. In short, alpha2-AR stimulation produces weak postsynaptic responses in RVLM bulbospinal neurons and powerful presynaptic inhibition of both glutamatergic and GABAergic inputs. Thus the inhibition of RVL bulbospinal neurons by alpha2-AR agonists in vivo results from a combination of postsynaptic inhibition, disfacilitation, and disinhibition.
延髓头端腹外侧区（RVLM）通过兴奋性延髓脊髓神经元控制交感神经张力。它也是用于治疗高血压的α2肾上腺素能受体（α2-AR）激动剂的主要作用靶点。在本研究中，我们研究了α2-AR激动剂抑制RVLM延髓脊髓神经元活动的突触机制。我们使用膜片钳技术（钳制电位-70 mV）在新生大鼠（P5-P21）的脑干切片中选择性记录RVLM延髓脊髓神经元。在α1肾上腺素能受体阻滞剂哌唑嗪存在的情况下，用去甲肾上腺素（NE，30 μM）激活α2-AR。NE在70%的细胞中诱导出适度的外向电流（5-28 pA），该电流被钡离子和α2-AR拮抗剂2-甲氧基咪唑克生阻断。该电流的大小与神经元的酪氨酸羟化酶免疫反应性无关。通过局部电刺激诱发单突触和多突触兴奋性突触后电流（EPSC）或单突触抑制性突触后电流（IPSC）。在所有细胞中，无论有无钡离子存在，NE均降低诱发的EPSC幅度（分别降低49%和70%），并降低诱发的IPSC幅度（分别降低64%和59%）。NE对EPSC幅度的作用被2-甲氧基咪唑克生阻断。局部刺激产生1至2秒的EPSC后放电（可能由于中间神经元的激活），该后放电被NE抑制53%。在存在河豚毒素的情况下，NE使微小EPSC的频率降低74%。简而言之，α2-AR刺激在RVLM延髓脊髓神经元中产生微弱的突触后反应，并对谷氨酸能和γ-氨基丁酸能输入产生强大的突触前抑制。因此，体内α2-AR激动剂对RVL延髓脊髓神经元的抑制作用是突触后抑制、去易化和去抑制共同作用的结果。
