下丘脑室旁核内GABA在中枢高渗刺激诱发的心血管反应中的作用
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摘要
下丘脑室旁核(hypothalamic paraventricular nucleus,PVN)是神经内分泌活动和自主神经功能的整合中枢,具有调节体内电解质及体液平衡、应激反应、心血管活动等多项生理功能。虽然有研究表明PVN参与应激性心血管反应的调节,但其作用的具体神经化学机制尚不完全清楚,尤其是目前的研究很少将PVN内的神经递质释放情况和应激性心血管反应直接联系起来直观地揭示其神经化学机制。γ-氨基丁酸(γ-aminobutyric acid,GABA)是脑内重要的氨基酸类神经递质,PVN内不仅存在GABA能神经元的分布,也存在两种GABA受体,即GABA_A受体和GABA_B受体。虽然报道指出,PVN内的GABA可能参与心交感神经反射,但它在应激性心血管反应调节中的作用及其机制尚未见报道。
因此,本实验以高渗刺激为应激刺激,用电脑控制的代谢笼慢性记录清醒状态、自由活动大鼠的心血管活动变化的同时,利用脑部微量透析法和高效液相色谱法测定PVN局部细胞外液中的GABA浓度变化,并进一步利用两种GABA受体的阻断剂探讨PVN内GABA参与应激性心血管反应中枢调节的作用及其神经化学机制。
实验结果如下:
(1) PVN局部灌流0.6M盐水时,血压从(80.07±5.05)mmHg上升到(87.23±5.88)mmHg(P＜0.001),心率从(375.23±14.31)次/分增加到(441.39±12.68)次/分(P＜0.001),PVN区细胞外液中GABA水平也明显增加到刺激前的(561.96±173.96)%(P＜0.05)。
(2) PVN局部同时灌流GABA_A受体阻断剂Bicuculline和0.6M盐水,高渗刺激引起的血压的增加反应明显降低(P＜0.001),而心率的增加反应不受明显影响(P＞0.05)。
(3) PVN局部灌流含有GABA_B受体阻断剂Saclofen的0.6M盐水,高渗刺激引起的血压的增加反应显著降低(P＜0.001),而心率的增加反应不受明显影响(P＞0.05)。
(4) PVN局部灌流GABA_B受体激动剂Baclofen时,血压在高浓度组显著降低(P＜0.05),而心率未受明显影响(P＞0.05);PVN局部灌流GABA_A受体激动剂Muscimol时,血压和心率均未受明显影响(P＞0.05)。
结论:
中枢高渗刺激可引起PVN内GABA的释放,而后者通过GABA_A和GABA_B受体参与应激性血压升高反应。
The paraventricular nucleus of the hypothalamus (PVN) integrates neuroendocrine and autonomic activity to maintain physiological homeostasis and regulate the cardiovascular responses. Although several studies have shown that the PVN is involved in the regulation of cardiovascular responses induced by stressors, the neurochemical mediators in the PVN responsible for generation of the stress responses have not been fully elucidated. Moreover, most of these studies are performed in the anaesthetic state, and anesthesia is well known for its profound effect on cardiovascular and autonomic function. Therefore, in this study, to investigate the neurochemical mechanisms responsible for cardiovascular responses induced by central salt-loading, we directly perfused the PVN region with hypertonic saline (0.6M) by using an in vivo microdialysis technique. And then the extracellular concentrations ofγ-aminobutyric acid (GABA) in the PVN region were measured in free-moving conscious rats along with the blood pressure (BP) and heart rate(HR). In addition, to test whether the observed GABA release is involved in the cardiovascular responses, bicuculline(an antagonist of GABAa receptor) or salcofen(an antagonist of GABA_B receptor) were coadministered with hypertonic saline, and the cardiovascular responses were examined.
The results were as follows:
(1) Local perfusion of 0.6M saline in PVN region elicited significant increases in BP and HR from 80.07±5.05mmHg and 375±14 beats/min to the maximums of 87.23±5.88mmHg (P<0.001) and 441±12 beats/min (P<0.001), respectively. In addition, perfusion of 0.6M saline increased the extracellular GABA levels in the PVN region, which reached 561.96±173.96% (P < 0.05) of the basal level.
(2) Coadministration of bicuculline or salcofen with hypertonic saline significantly attenuated the increased response of BP (P<0.001, respectively).
(3) Direct perfusion of baclofen (an agonist of GABA_B receptor) in the PVN decreased BP, although the muscimol (an agonist of GABA_A receptor) did not affect the BP and HR.
Conclusion:
Local perfusion of hypertonic saline in the PVN region elicits a local release of GABA, which may act via GABA_A and GABA_B receptors to produce pressor response.
因此,本实验以高渗刺激为应激刺激,用电脑控制的代谢笼慢性记录清醒状态、自由活动大鼠的心血管活动变化的同时,利用脑部微量透析法和高效液相色谱法测定PVN局部细胞外液中的GABA浓度变化,并进一步利用两种GABA受体的阻断剂探讨PVN内GABA参与应激性心血管反应中枢调节的作用及其神经化学机制。
实验结果如下:
(1) PVN局部灌流0.6M盐水时,血压从(80.07±5.05)mmHg上升到(87.23±5.88)mmHg(P＜0.001),心率从(375.23±14.31)次/分增加到(441.39±12.68)次/分(P＜0.001),PVN区细胞外液中GABA水平也明显增加到刺激前的(561.96±173.96)%(P＜0.05)。
(2) PVN局部同时灌流GABA_A受体阻断剂Bicuculline和0.6M盐水,高渗刺激引起的血压的增加反应明显降低(P＜0.001),而心率的增加反应不受明显影响(P＞0.05)。
(3) PVN局部灌流含有GABA_B受体阻断剂Saclofen的0.6M盐水,高渗刺激引起的血压的增加反应显著降低(P＜0.001),而心率的增加反应不受明显影响(P＞0.05)。
(4) PVN局部灌流GABA_B受体激动剂Baclofen时,血压在高浓度组显著降低(P＜0.05),而心率未受明显影响(P＞0.05);PVN局部灌流GABA_A受体激动剂Muscimol时,血压和心率均未受明显影响(P＞0.05)。
结论:
中枢高渗刺激可引起PVN内GABA的释放,而后者通过GABA_A和GABA_B受体参与应激性血压升高反应。
The paraventricular nucleus of the hypothalamus (PVN) integrates neuroendocrine and autonomic activity to maintain physiological homeostasis and regulate the cardiovascular responses. Although several studies have shown that the PVN is involved in the regulation of cardiovascular responses induced by stressors, the neurochemical mediators in the PVN responsible for generation of the stress responses have not been fully elucidated. Moreover, most of these studies are performed in the anaesthetic state, and anesthesia is well known for its profound effect on cardiovascular and autonomic function. Therefore, in this study, to investigate the neurochemical mechanisms responsible for cardiovascular responses induced by central salt-loading, we directly perfused the PVN region with hypertonic saline (0.6M) by using an in vivo microdialysis technique. And then the extracellular concentrations ofγ-aminobutyric acid (GABA) in the PVN region were measured in free-moving conscious rats along with the blood pressure (BP) and heart rate(HR). In addition, to test whether the observed GABA release is involved in the cardiovascular responses, bicuculline(an antagonist of GABAa receptor) or salcofen(an antagonist of GABA_B receptor) were coadministered with hypertonic saline, and the cardiovascular responses were examined.
The results were as follows:
(1) Local perfusion of 0.6M saline in PVN region elicited significant increases in BP and HR from 80.07±5.05mmHg and 375±14 beats/min to the maximums of 87.23±5.88mmHg (P<0.001) and 441±12 beats/min (P<0.001), respectively. In addition, perfusion of 0.6M saline increased the extracellular GABA levels in the PVN region, which reached 561.96±173.96% (P < 0.05) of the basal level.
(2) Coadministration of bicuculline or salcofen with hypertonic saline significantly attenuated the increased response of BP (P<0.001, respectively).
(3) Direct perfusion of baclofen (an agonist of GABA_B receptor) in the PVN decreased BP, although the muscimol (an agonist of GABA_A receptor) did not affect the BP and HR.
Conclusion:
Local perfusion of hypertonic saline in the PVN region elicits a local release of GABA, which may act via GABA_A and GABA_B receptors to produce pressor response.
引文
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[2]Qing-Hua Jin,Yuto Ueda,Yuta Ishizuka.Cardiovascular changes induced by central hypertonic saline are accompanied by glutamate release in awake rats.Am.J.Physiology,2001,281:1224-1231.
[3]Swanson LW and Sawchenko PE.Hypothalamic integration:organization of the paraventricular and supraoptic nuclei.AnnuRev Neurosci.1983,6:269-324.
[4]Kannan H,Hayashida Y,and Yamashita H.Increase in renal sympathetic outflow by paraventricular nucleus stimulation in awake rats.Am J physiol regulatory integrative comp Physiol 1989,256:R1325-R1330.
[5]Malpas SC,Coote JH.Role of vasopressin in sympathetic response to paraventricular nucleus stimulation in anesthetized rats Am J Physiol.1994,266:R228-R230.
[6]Negoro H and Akaishi T.Interaction of hypertonic Nacl,hemorrhage and angiotensin Ⅱ in stimulating paraventricular neurosecretory cells in the rat.Exp Brain Res.1982,48:121-126.
[7]夏强,张荣宝.杏仁中央核在下丘脑室旁核心血管反应中的作用.浙江大学学报(医学版),2006,35:172-176.
[8]Y.Ishizuka,Y.Ishida,Q.-H.Jin,A.Shimokawa,H.Kannan.Abdominal vagotomy attenuates interleukin-1β-induced nitric oxide release in the paraventricular nucleus region in conscious rats.Brain Research 1998,789:157-161.
[9]Q.-H.Jin,T.Kunitake,Y.Ishizuka,H.Kannan.Increase in norepinephrine but not nitric oxide metabolite levels in the hypothalamic paraventricular nucleus region in response to air jet and swing rotation in freely moving conscious rats.Brain Research 2000,876:205-210.
[10]吴飞健,吴政星,陈其才.GABA:一种重用的中枢抑制性神经递质.高等函授学报(自然科学版),1997,1:4-8.
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