Center for Biomedical Research, Faculty of Medicine, University of Banja Luka, 16 Save Mrkalja St, 78000, Banja Luka, Republic of Srpska, Bosnia and Herzegovina.
Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
Eur J Pharmacol. 2021 May 15;899:174023. doi: 10.1016/j.ejphar.2021.174023. Epub 2021 Mar 13.
Different subtypes of GABA (gamma-aminobutyric acid A) receptors, through their specific regional and cellular localization, are involved in the manifestation of various functions, both at the central and peripheral levels. We hypothesized that various non-neuronal GABA receptors are expressed on blood vessels, through which positive allosteric modulators of GABA receptors exhibit vasodilatory effects. This study involved two parts: one to determine the presence of α1-6 subunit GABA receptor mRNAs in the rat thoracic aorta, and the other to determine the vasoactivity of the various selective and non-selective positive GABA receptor modulators: zolpidem (α1-selective), XHe-III-074 (α4-selective), MP-III-022 (α5-selective), DK-I-56-1 (α6-selective), SH-I-048A and diazepam (non-selective). Reverse transcription-polymerase chain reaction (RT-PCR) analysis data demonstrated for the first time the expression of α1, α2, α3, α4 and α5 subunits in the rat thoracic aorta tissue. Tissue bath assays on isolated rat aortic rings revealed significant vasodilatory effects of diazepam, SH-I-048A, XHe-III-074, MP-III-022 and DK-I-56-1, all in terms of achieved relaxations (over 50% of relative tension decrease), as well as in terms of preventive effects on phenylephrine (PE) contraction. Diazepam was the most efficient ligand in the present study, while zolpidem showed the weakest vascular effects. In addition, diazepam-induced relaxations in the presence of antagonists PK11195 or bicuculline were significantly reduced (P < 0.001 and P < 0.05, respectively) at lower concentrations of diazepam (10 M and 3 × 10 M). The present work suggests that the observed vasoactivity is due to modulation of "vascular" GABA receptors, which after further detailed research may provide a therapeutic target.
不同亚型的 GABA（γ-氨基丁酸 A）受体通过其特定的区域和细胞定位参与了中枢和外周水平的各种功能的表现。我们假设，各种非神经元 GABA 受体存在于血管上，通过这些受体的 GABA 阳性变构调节剂表现出血管扩张作用。这项研究包括两个部分：一部分是确定大鼠胸主动脉中α1-6 亚基 GABA 受体 mRNA 的存在，另一部分是确定各种选择性和非选择性 GABA 受体阳性变构调节剂的血管活性：唑吡坦（α1 选择性）、XHe-III-074（α4 选择性）、MP-III-022（α5 选择性）、DK-I-56-1（α6 选择性）、SH-I-048A 和地西泮（非选择性）。逆转录-聚合酶链反应（RT-PCR）分析数据首次证明了α1、α2、α3、α4 和α5 亚基在大鼠胸主动脉组织中的表达。在分离的大鼠主动脉环的组织浴实验中，地西泮、SH-I-048A、XHe-III-074、MP-III-022 和 DK-I-56-1 均显示出显著的血管扩张作用，表现为实现的松弛度（相对张力降低超过 50%），以及对苯肾上腺素（PE）收缩的预防作用。在本研究中，地西泮是最有效的配体，而唑吡坦显示出最弱的血管作用。此外，在拮抗剂 PK11195 或印防己毒素存在的情况下，地西泮诱导的松弛作用在较低浓度的地西泮（10-5M 和 3×10-5M）下显著降低（P<0.001 和 P<0.05）。本工作表明，观察到的血管活性是由于“血管”GABA 受体的调制所致，进一步的详细研究可能为治疗靶点提供依据。
