Takenaka K, Sasaki S, Uchida A, Fujita H, Nakamura K, Ichida T, Itoh H, Nakata T, Takeda K, Nakagawa M
Second Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
Am J Hypertens. 1996 Oct;9(10 Pt 1):964-72. doi: 10.1016/0895-7061(96)00171-9.
To determine whether central GABA (gamma-aminobutyric acid) B receptor stimulation would affect the sympathetic and cardiovascular activities, baclofen (a GABAB receptor agonist) was injected into lateral cerebral ventricles (intracerebroventricularly, ICV) in urethane-anesthetized normotensive rats. Intracerebroventricular injections of GABAA agonist (muscimol, 1 microgram) consistently decreased blood pressure and heart rate. In contrast ICV injections of baclofen (2 micrograms) increased blood pressure (BP) and heart rate with initial transient cardiovascular depression, and these effects of baclofen were abolished by ICV pretreatment with GABAB antagonist (saclofen, 100 micrograms). To determine whether the cardiovascular effects of ICV injections were elicited by activating GABA receptors in the hypothalamus, we injected baclofen or muscimol directly into various hypothalamic areas. Baclofen (100 and 800 ng) injected into the ventromedial hypothalamus (VMH) or posterior hypothalamus (PH) of normotensive rats produced dose-related decreases in sympathetic nerve activity, blood pressure, and heart rate. These effects of baclofen were larger in VMH injections than in PH injections. The depressor responses elicited by VMH injections of baclofen were abolished by intravenous pretreatment with alpha-blocker, but unaffected by parasympathetic blocker, further indicating that the depressor responses of baclofen (VMH) were not due to parasympathetic activation, but due to peripheral sympathetic depression. Muscimol (400 ng) and baclofen (800 ng) injected into VMH produced similar amplitude of sympathetic-depressant, depressor and bradycardic responses. In contrast, BP was increased by the same dose of baclofen injected into the hypothalamic depressor area (anterior hypothalamus, AH), but was unaffected by muscimol. Final experiments were performed to determine whether these sympathetic and cardiovascular effects to hypothalamic GABAB stimulations would be altered in hypertension. In spontaneously hypertensive rats (SHR), basal BP and heart rate were already higher than in normotensive controls (Wistar-Kyoto rat, WKY). Baclofen injected into VMH reduced sympathetic nerve activity, BP, and heart rate in both groups of rats, and these effects were significantly larger in SHR than in WKY. This enhanced depressor response induced by baclofen (VMH) in SHR persisted even after sinoaortic denervation, which indicates that the enhanced depressor response is not due to reduced peripheral baroreflex sensitivity in SHR. On the other hand, baclofen injected into AH increased BP and heart rate in both WKY and SHR, but the magnitude of these responses did not differ between two groups. In summary, GABA reduces sympathetic nerve activity, BP, and heart rate through both GABAA and B receptors in VMH. The GABAB system acts on the depressor area, AH, to further regulate the cardiovascular activities. In SHR, the GABAB-ergic system in VMH but not in AH is altered, and this might contribute to the development of hypertension.
为了确定中枢γ-氨基丁酸（GABA）B受体刺激是否会影响交感神经和心血管活动，在氨基甲酸乙酯麻醉的正常血压大鼠的侧脑室（脑室内，ICV）注射巴氯芬（一种GABAB受体激动剂）。脑室内注射GABAA激动剂（蝇蕈醇，1微克）持续降低血压和心率。相比之下，脑室内注射巴氯芬（2微克）会使血压（BP）和心率升高，最初伴有短暂的心血管抑制，而巴氯芬的这些作用可被脑室内预先注射GABAB拮抗剂（沙氯芬，100微克）消除。为了确定脑室内注射的心血管效应是否是通过激活下丘脑的GABA受体引起的，我们将巴氯芬或蝇蕈醇直接注射到下丘脑的各个区域。将巴氯芬（100和800纳克）注射到正常血压大鼠的腹内侧下丘脑（VMH）或下丘脑后部（PH）会使交感神经活动、血压和心率产生剂量相关的降低。巴氯芬在VMH注射中的这些作用比在PH注射中更大。VMH注射巴氯芬引起的降压反应可被静脉预先注射α受体阻滞剂消除，但不受副交感神经阻滞剂影响，这进一步表明巴氯芬（VMH）的降压反应不是由于副交感神经激活，而是由于外周交感神经抑制。将蝇蕈醇（400纳克）和巴氯芬（800纳克）注射到VMH产生的交感神经抑制、降压和心动过缓反应幅度相似。相比之下，将相同剂量的巴氯芬注射到下丘脑降压区域（下丘脑前部，AH）会使血压升高，但不受蝇蕈醇影响。进行了最后的实验以确定这些对下丘脑GABAB刺激的交感神经和心血管效应在高血压中是否会改变。在自发性高血压大鼠（SHR）中，基础血压和心率已经高于正常血压对照（Wistar-Kyoto大鼠，WKY）。将巴氯芬注射到VMH会降低两组大鼠的交感神经活动、血压和心率，并且这些作用在SHR中比在WKY中显著更大。即使在去窦主动脉神经支配后，巴氯芬（VMH）在SHR中诱导的增强的降压反应仍然持续，这表明增强的降压反应不是由于SHR中外周压力反射敏感性降低。另一方面，将巴氯芬注射到AH会使WKY和SHR的血压和心率升高，但两组之间这些反应的幅度没有差异。总之，GABA通过VMH中的GABAA和B受体降低交感神经活动、血压和心率。GABAB系统作用于降压区域AH以进一步调节心血管活动。在SHR中，VMH而非AH中的GABAB能系统发生改变，这可能导致高血压的发生。
