【作者】 王立平；

【导师】 赵华；

【作者基本信息】 吉林大学 ， 生理学， 2007， 硕士

【摘要】 我国高血压的发病率逐年增高,严重威胁人类健康,据有关数据统计,目前全国高血压病人已有约一亿人,由高血压引起的心脑肾疾病的死亡率,已占全国疾病死亡人数的百分之四十并呈逐年上升趋势。然而,临床上主要通过扩血管、利尿达到降压作用,一直不能从病因上治疗高血压。90年代从国外引进血管紧张素II受体阻断剂洛沙坦,但由于其价格的昂贵而限制了它的使用。因此,目前发现某种生物活性物质,对于从根本上治疗高血压具有重要意义。甾体激素成分之一孕烷醇酮(PGN)产生于内分泌组织及中枢神经系统,其受体在中枢神经系统具有广泛分布。自发现PGN可作用于神经细胞膜γ-氨基丁酸(GABA)受体后,它的快速中枢作用成为当前神经生物学领域研究的热点。已经发现PGN具有镇痛、抗焦虑、抗应激作用。我们以往的实验证明PGN可干预大鼠应激性高血压的形成,并对已形成高血压大鼠的血压具有降低作用,但对在应激性高血压发病中起重要作用的AngⅡ的升压作用的影响未见报道。本实验采用股动脉插管,神经核团定位、微量注射的方法,目的在于研究在侧脑室、室旁核、缰核微量注射孕烷醇酮(PGN)对AngⅡ引起升压反应的影响,以探明孕烷醇酮在高血压治疗中的作用及可能机制。结果如下:侧脑室、下丘脑室旁核、缰核分别给予外源性的AngⅡ均引起大鼠血压升高,提前在缰核、侧脑室、下丘脑室旁核微量注射孕烷醇酮(PGN)能够抑制AngⅡ的升压作用,而荷包牡丹碱(Bic)能够阻断孕烷醇酮的这种抑制作用。结果说明孕烷醇酮可通过抑制血管紧张素Ⅱ(AngⅡ)的升压效应达到降压作用,其作用是通过GABAA受体介导的。更多还原

【Abstract】 Object:To investigate the effects of Pregnanolone on blood pressure increased by AngⅡin brain areas of the rats and the effect of Bic on this process.Methods: 1. Femoral arteries of Wistar rats were intubated , lateral ventricle、Habenular nucleus、paraventricular nucleus were located. 2. To observe the changes of blood pressure of the lateral ventricle, PVN and Hb after the microinjection of AngⅡ, microinjection of PGN following AngⅡand the microinjection of PGN and AngⅡafter the pretreatment by Bic respectively.Result: 1. Arterial blood pressure was increased 2.06±0.28Kpa after microinjection of AngⅡinto lateral cerebral ventricle and increased 0.58±0.32 Kpa) after micro-injection of PGN and AngⅡinto lateral cerebral ventricle. The change of them has significantly difference (p<0.001), and the arterial blood pressure induced by micro-injection of AngⅡwas inhibited 71.84% by PGN. Arterial blood pressure was increased 1.49±0.16 Kpa after the micro-injection of Bic、PGN and AngⅡ, which was significantly greater than that induced by the micro-injection of PGN and AngⅡ. The inhibitory effect induced by PGN on the blood pressure was blocked 61.49﹪by Bic .2. Arterial blood pressure was increased 2.90±0.28 Kpa (p<0.001)after micro-injection of AngⅡinto PVN and increased 0.81±0.25 Kpa after micro-injection of PGN and AngⅡinto PVN.The change of them has significantly difference (p<0.001), and the arterial blood pressure induced by micro-injection of AngⅡwas inhibited 72.07﹪by PGN. Arterial blood pressure was increased 1.76±0.56 Kpa after micro-injection of Bic、PGN and AngⅡ,Which was greater than micro-injection of PGN and AngⅡ. The inhibitory effect induced by PGN on the blood pressure was blocked 45.45﹪by Bic .3.Arterial blood pressure was increased 2.62±0.47 Kpa(p<0.001) after micro-injection of AngⅡinto Hb and increased1.37±0.30Kpa after micro-injection of PGN and AngⅡ.The change has significantly difference (p<0.001), and the arterial blood pressure induced by micro-injection of AngⅡwas inhibited 47.71﹪by PGN. Arterial blood pressure was increased 2.02±0.24 Kpa after micro-injection of Bic、PGN and AngⅡ,Which was greater than micro-injection of PGN and AngⅡ(p<0.01) . The inhibitory effect induced by PGN was blocked 52.00﹪by Bic.Discussion: 1 .The effect of micro-injection of PGN into lateral cerebral ventricle on blood pressure increased by AngⅡand the effect of Bic on it.As the social developing quickly, the rhythm of life speeding up, the pressure on the people all around the world becomes bigger and bigger. SIH can be induced under the excitably psychical and physiological circumstance and there is a creasing incidence of the hypertensive disease year by year. At the same time, and hypertension can also induce many disease which will threat people’s health, degrade the quality of life, even threat people’s lives, so SIH is one of dangerous factors which induce the death of people. According to some data, we know that there are about a hundred million hypertensive people in our country at present. Fatality of Cardiac、cerebullar and nephric diseases induced by hypertension is 40﹪in all the diseases in our country, and it will increase year by year. We have not found a basic medicative method clinically. American use Losartan to cure hypertension. Losartan, but it is expensive. Thus, it’s our responsibility to seek to find an efficacious and economic pharmaceutical which will play an important role in clinic. PGN is one of hormones of neurosteroid in the central nervous system generally and has a lot of functions, such as mitigat、analgesia and anti-stress. Since 90’s the receptor of cellular membrane of PGN was found, people have thought highly of PGN. GABA is one important inhibitive transmitter in the CNS and it is one part of anti-stress system. GABA and GABA receptors in some cardiovascular center take part in the modulation of cardiovascular activity. Some data indicated that PGN activated GABAA receptor, caused hyperpolarization of membrane and then inhibited the activity of neuron. Many studies indicated that the contents of AngⅡincreased in blood and brain tissue under stress. AngⅡhad different functions in different organs but under stress it finally made BP up. It is well known that AngⅡis one important kind of excitable hormone and it can speed up the function of vasoconstriction, the secretion of aldosterone and release of bradykinin. The previous experiments in our laboratory certificated PGN could reduce the level of hypertension of the SIH rats by reducing the content of AngⅡof the SIH rats and inhibiting cardiovascular effects induced by AngⅡ. But if PGN can inhibit the effect of BP increasing induced by AⅡhas not been certificated. In these experiments, the BP increased 2.06±0.28 Kpa (p<0.001) after injecting AngⅡinto lateral cerebral ventricle. The result is the same as the previous experiments. Arterial blood pressure after the micro-injection of PGN and AngⅡsteped up 0.58±0.32 Kpa which was significantly greater than the difference induced by micro-injection of AngⅡ(p<0.001). the effect on arterial blood pressure induced by micro-injection of AngⅡwas inhibited 71.84﹪by PGN. it demonstrated PGN could inhibit the effect of blood pressure increased induced by AngⅡin lateral cerebral ventricle. After the micro-injection of Bic、PGN and AngⅡ, BP steped up1.49±0.16 Kpa which significantly greater than the difference induced by micro-injection of PGN and AngⅡ(p<0.001). The effect induced by PGN was blocked 61.49﹪. These suggested that Bic could turnover the effect of PGN which inhibited the effect of AngⅡon the BP. 2.The effect of micro-injection of PGN into PVN and Hb on blood pressure increased by AngⅡand the effect of Bic on it.The procedure of formation of SIH refer to PVN and Hb which are the region of defence reaction of SIH and exist there AngⅡand AngⅡreceptors. PVN is a nucleus of heterogeneity and not only has the function of neuroendocrine but also take part in the control of vegetative nervous activity. it’s one of cerebullar region in the regulation of the cardiovascular activity. the parvocellular neuron of PVN have correlation with the center of autonomic nerve in brainstem and dominate preganglionic neuron of adrenergic nerve. Recently, scholars in the world pay attention extremely to the function of control in cardiovascular activity. Bains etc. (1992)reported that the micro-injection of AngⅡinduced to heighten the BP. Electric stimulation caused boost pressure or depressurization, but the pathway and mechanism of cardiovascular effects have not been clear.Recently some studies reported feritin in the blood plasm and activity of AngⅡcaused by stress had more remarkably than in the control animals.The synthesized and released of AVP in PVN take part in the formation of SIH. RAS is activated after stress and concentration of AngⅡsteps up in the plasma. PVN synthesizes and releases more AVP which has the effect on it’s receptors. That is one of reaction paths through which AngⅡtakes part in BP increasing induced by stress.The antagonist of AngⅡReceptor or inhibitor of ACE used in center can obviously cut down the BP of spontaneous hypertensive rat. The content of AⅡincreases obviously in PVN、medulla oblongata and etc. icv captopril can obviously cut down BP and set point of carotid sinus reflex in SIH rat. Hb also has the system like that. as we know, Hb plays an important role in the central accommodation of cardiovascular activity. electric stimulated Hb or excited Hb by chemical method can step up BP and speed up heart rate of animals .Hb not only takes part in accommodation of BP but also takes part in the formation of spontaneously hypertensive and SIH .The experiments approach the effect of micro-injection of PGN into PVN and Hb on hypertension induced by AngⅡand the effect of Bic on it. The result indicated the BP step up after micro-injection of AngⅡinto PVN and Hb, PGN can antagonize the effect of AngⅡand Bic can turnover the effect of PGN. The procedure of formation of SIH refers to PVN and Hb which are both the regions of defence reaction of SIH. The experiments demonstrate that BP step up induced by micro-injection of AngⅡ, PGN can inhibit the effect induced by micro-injection of AngⅡas a negative modulator and Bic can turnover the effect of PGN. the results demonstrate the effect of PGN that cut down the BP in center is induced by GABA receptors .The ionic mechanisms and the neuropotential changes of the effect of PGN on cutting BP down need to be studied deeply in the future .Conclusion: 1. PGN can inhibit blood pressure increasing induced by micro-injection of AngII into lateral cerebral ventricle、PVN and Hb. It illustrate that PGN can inhibit the form of SIH under the whole condition and reduce the BP of hypertensive rats through inhibiting the blood pressure increasing caused by AngII, which maybe involve in the effect of PVN and Hb.2 Bic as the antagon of GABAA acceptor can inhibit the effect of PGN on the blood pressure induced by AngII. It illustrate that the effect of PGN may be mediated by GABAA acceptor.更多还原