二氧化硫在心血管活动调节中的作用及在脓毒症大鼠发病中的机制研究
发布时间：2019-05-18 12:58
【摘要】：目的： 1.探讨二氧化硫(sulfur dioxide, SO2)在麻醉大鼠孤束核(nucleus tractus solitarii, NTS)及头端延髓腹外侧区(rostral ventrolateral medulla, RVLM)的心血管效应及其机制 2.探讨内源性SO2在脓毒症大鼠肝、肾、心、脑及血清中的分布与水平变化。 3.探讨SO2对脓毒症大鼠动脉压力反射(areterial baroreflex, ABR)功能的影响及其机制。 方法： 1.SO2在NTS和RVLM产生的心血管效应：成年雄性Spargue-Dawley (SD)大鼠50只,其中25只大鼠在NTS单侧微量注射不同剂量SO2(2,20,200pmol)或人工脑脊液(artificial cerebrospinal fluid, aCSF),观察在NTS内注射SO2对大鼠血压和心率产生的影响。余25只大鼠在RVLM单侧微量注射不同剂量SO2(2,20,200pmol)或aCSF,观察在RVLM内注射SO2对大鼠血压和心率产生的影响。 2.SO2在RVLM产生心血管效应的机制：成年雄性SD大鼠43只,其中11只大鼠预先在RVLM注射aCSF或谷氨酸(Glu)促离子型受体非选择性拮抗剂犬尿喹啉酸(KYN,15nmol)观察其对二氧化硫在RVLM引起心血管效应的影响。32只大鼠预先在RVLM注射aCSF、ATP敏感性钾通道(KATP)阻断剂格列苯脲(Gli,40μmol)、L-型钙离子通道阻断剂尼卡地平(Nic,200pmol)、非选择性一氧化氮合酶(NOS)抑制剂NG硝基L精氨酸甲酯(L-NAME,15nmol)、选择性可溶性鸟苷酸环化酶(sGC)抑制剂1H-[1,2,4]E二唑[4,3-α]喹喔啉-1-酮(ODQ,250pmol),探讨RVLM内二氧化硫的离子通道及信号转导通路。 3.SO2在各组织及血清中的分布水平：用盲肠结扎穿刺(cecal ligation and puncture, CLP)法制作脓毒症大鼠模型。采用随机数表法将40只成年雄性SD大鼠,随机分为假手术组(n=8)和脓毒症模型组(n=32)。造模后3h、6h、12h及24h处死大鼠,取肝、肾、心、脑组织,并留取血清标本。采用酶联免疫吸附试验(ELISA)测定S02水平。 4.SO2对脓毒症大鼠ABR的影响：雄。性SD大鼠66只采用随机数表法随机分为11组：①假手术(SO)+生理盐水(Saline)+静脉注射(iv)组;②CLP+Saline+iv组;③SO+SO2+iv组;④CLP+SO2+iv组;⑤SO+aCSF+NTS组;⑥SO+SO2+NTS组;⑦CLP+aCSF+NTS组；⑧CLP+SO2+NTS组;⑨CLP+KYN+NTS组;⑩SO+aCSF+SO2+NTS组(预先双侧NTS注射aCSF,而后再在同一部位注射SO2)11SO+KYN+SO2+NTS组(预先在双侧NTS注射KYN,而后再在同一部位注射SO2)。分别在给药前、给药后5min和30min3个时间点测定大鼠ABR功能。 结果： 1.SO2在NTS和RVLM产生的心血管效应：NTS单侧微量注射SO2产生剂量依赖性降低血压和减慢心率的作用(P＜0.05)。RVLM单侧微量注射SO2产生剂量依赖性的升高血压和加快心率的作用(P＜0.05)。 2.SO2在RVLM产生心血管效应的机制：预先RVLM注射KYN能部分阻断SO2(20pmol)在RVLM引起的心血管效应(P＜0.05)。预先RVLM注射Gli、 Nic、 L-NAME或ODQ能有效阻断SO2(20pmol)在RVLM产生的升高血压、加快心率的效应(P＜0.05)。 3.SO2在各组织及血清中的分布水平：假手术组大鼠肝、肾、心脏、脑及血清中均含有一定量SO2,且以心脏组织中的含量最高。与假手术组比较,CLP造模后3h后大鼠肝、肾、心、脑及血清中SO2水平开始升高,12h有统计学意义,24h达到高水平。 4.SO2对脓毒症大鼠ABR的影响：①同一组内不同时相ABR值变化结果：与给药前相比,SO+SO2+iv组,CLP+SO2+iv组,SO+SO2+NTS组,CLP+SO2+NTS组,SO+aCSF+SO2+NTS组给药后5min和30min ABR值均明显降低(P＜0.05),而CLP+KYN+NTS组明显升高(P＜0.05)。②相同时相不同组间ABR值变化结果：给药前,CLP+Saline+iv组明显低于SO+Saline+iv组或SO+SO2+iv组(P0.05), CLP+aCSF+NTS组明显低于SO+aCSF+NTS组或SO+SO2+NTS组(P＜0.05)。给药后5min和30min, CLP+SO2+iv组明显低于CLP+Saline+iv组(P＜0.05)或SO+Saline+iv组(P0.05), CLP+SO2+NTS组明显低于CLP+aCSF+NTS组(P＜0.05)或SO+aCSF+NTS组(P005), CLP+KYN+NTS组明显高于CLP+aCSF+NTS组(P＜0.05),SO+KYN+SO2+NTS组明显高于SO+aCSF+SO2+NTS组(P＜0.05)。 结论： 1.SO2在NTS能够引起剂量依赖性降低血压和减慢心率的作用。SO2在RVLM能够引起剂量依赖性升高血压和加快心率的作用。 2.SO2可能通过激动部分RVLM内Glu受体参与中枢血压的调控,该机制可能与KATP和L-型钙通道开放有关。SO2在RVLM产生的升高血压、加快心率的效应主要与NO/cGMP信号转导通路有关。 3.SO2可在正常大鼠体内内源性产生,心脏组织中的SO2水平高于其他组织；CLP大鼠体内SO2水平高于正常，，可能参与脓毒症大鼠的发病机制。 4.体内8O2生成增加对脓毒症大鼠ABR功能有降低作用,该作用不仅通过外周静脉系统发挥作用,而且可能通过中枢NTS影响ABR功能；SO2对大鼠ABR功能的调节,可能与Glu促离子型受体激动有关。
[Abstract]:Purpose: 1. To study the cardiovascular effects of sulfur dioxide (SO _ 2) in the nucleus of the solitary tract (NTS) and the lateral medulla (RVLM) of the head-end of the anesthetized rats. Mechanism 2. To investigate the effect of endogenous SO2 in the liver of sepsis rats. The distribution and water of kidney, heart, brain and serum 3. To investigate the effect of SO2 on the function of arterial baroreflex (ABR) in septic rats in response to and Methods:1. The cardiovascular effects of SO2 in NTS and RVLM:50 of adult male Sprague-Dawley (SD) rats,25 of which were injected with different doses of SO2 (2,20,200 pmol) or artificial cerebrospinal fluid (aCSF) at one side of the NTS. The effects of pressure and heart rate on rat blood were observed in 25 rats at different dose of SO2 (2,20,200 pmol) or aCSF at one side of the RVLM. The effect of the pressure and heart rate.2. The mechanism of the effect of SO2 on the production of cardiovascular effects in the RVLM:43 adult male SD rats,11 of which were pre-injected with aCSF or glutamate (Glu) non-selective receptor in the RVLM. The effect of anti-agent (KYN, 15nmol) on the cardiovascular effects of sulfur dioxide on the RVLM was observed.32 rats were pre-injected with aCSF, ATP-sensitive potassium channel (KATP) blocking agent gliclazide (Gli,40. mu.mol), L-type calcium channel blocker nicardipine (N (c,200 pmol), non-selective nitric oxide synthase (NOS) inhibitor NG-nitro L-arginine methyl ester (L-NAME,15 nmol), selective soluble ornithine-acid cyclase (sGC) inhibitor 1H-[1,2,4] E dicyandiamide[4,3-1]-1-one-one (O DQ,250 pmol), and the content of sulfur dioxide in the RVLM was investigated. Ion channel and signal transduction pathway.3. Distribution of SO2 in the tissues and serum: Cecal ligation and puncture, C 40 adult male SD rats were randomly divided into the sham operation group (n = 8) using the random number table method. And the rats were sacrificed at 3 h,6 h,12 h and 24 h after the model, and the liver and kidney were taken. Serum samples were taken from the heart and brain tissue. Enzyme-linked immunosorbent assay (ELISA) was used ( ELISA) Determination of S02 level.4. The effects of 2 on the ABR in septic rats were: the male and sexual SD rats were randomly divided into 11 groups using the random number table method: sham operation (SO) + physiological saline (Saline) + intravenous (iv) group; TCLP + Saline + iv group; HSO + SO2 + iv group; TCLP + SO2 + iv group; HSO + aCSF + NTS group; HSO + SO2 + NTS group; TCLP + aCSF + NTS group; HSO + SO2 + NTS group; TCLP + KYN + NTS group; HSO + aCSF + SO2 + NTS group; Group (pre-bilateral NTS injection of aCSF followed by injection of SO2 at the same site) 11SO + KYN + SO2 + NTS group (pre-bilateral NTS injection of KYN And then SO2 at the same site),5 min and 30 mi after administration, respectively. n3 The results were as follows:1. The cardiovascular effects of SO2 in the NTS and the RVLM: the dose-dependent decrease of the single-side micro-injection of SO2 in the NTS The effect of low blood pressure and slow heart rate (P <0.05). The dose-dependent rise of the single-side micro-injection of SO2 in the RVLM The effect of SO2 on the heart rate (P <0.05).2. The mechanism of the production of cardiovascular effect in the RVLM: the pre-RVLM injection of the KYN can partially block the SO2 (20 pmol). Cardiovascular effect induced by RVLM (P <0.05). Pre-RVLM injection of Gli, Nic, L-NAME or ODQ can effectively block the production of SO2 (20 pmol) in the RVLM The distribution of SO2 in the tissues and serum: the liver, the kidney, the heart, the brain and the serum of the sham operation group. The content of SO2 in the heart tissue was the highest in the heart, and the level of SO2 in the liver, the kidney, the heart, the brain and the serum of the rats after 3 h after the CLP model was compared with the sham operation group. The effect of SO 2 on the ABR in the rats with sepsis was higher than that in the same group. The results of the change of ABR in the same group were as follows: the results of the change of ABR in the same group were: the results of the changes of the ABR in the group of SO + SO2 + iv, CLP + SO2 + iv, SO + SO2 + NTS group, CLP + SO2 + NTS group, the SO + aCSF + SO2 + NTS group, and the ABR of the group of SO + aCSF + SO2 + NTS decreased significantly (P <0.05). The changes of ABR were significantly lower in the group of CLP + KYN + NTS (P <0.05). The results of the change of ABR were significantly lower than that in the group of SO + Saline + iv or the SO + SO 2 + iv group (P0.05). The CLP + aCSF + NTS group was significantly lower than that of the SO + aCSF. + NTS group or SO + SO2 + NTS group (P <0.05). The CLP + SO2 + iv group was significantly lower than that of the CLP + Saline + iv group (P <0.05) or the SO + Saline + iv group (P <0.05), and the CLP + SO2 + NTS group was significantly lower than that of the CLP + aCSF + NTS group (P <0.05) or the SO + aCSF + NTS group (P005), and the CLP + KYN + NTS group was significantly higher than that of the CLP + aCSF + NTS group (P <0.05), and the SO + KYN + SO2 + NTS group was significantly higher. 浜嶴O + aCSF + SO2 + NTS group (P <0.05). Conclusion:1 . SO2 can cause dose-dependent reduction of blood pressure and slow heart rate in the NTS. SO2 may cause a dose-dependent rise in hypertension and an accelerated heart rate in the RVLM. Involved in the regulation of central blood pressure, which may be related to the opening of KATP and L-type calcium channels. SO2 is produced in the RVLM 3. SO2 can be generated endogenously in normal rats, and the level of SO2 in cardiac tissue is higher than that of other groups. In rats, the level of SO2 in rats was higher than that of normal, and may be involved in the pathogenesis of sepsis rats.4. The increase in the production of 8O2 in vivo has a lower effect on the function of the ABR in septic rats, which can not only play a role in the peripheral venous system, but also may influence AB by the central NTS.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R459.7
本文编号：2480029
[Abstract]:Purpose: 1. To study the cardiovascular effects of sulfur dioxide (SO _ 2) in the nucleus of the solitary tract (NTS) and the lateral medulla (RVLM) of the head-end of the anesthetized rats. Mechanism 2. To investigate the effect of endogenous SO2 in the liver of sepsis rats. The distribution and water of kidney, heart, brain and serum 3. To investigate the effect of SO2 on the function of arterial baroreflex (ABR) in septic rats in response to and Methods:1. The cardiovascular effects of SO2 in NTS and RVLM:50 of adult male Sprague-Dawley (SD) rats,25 of which were injected with different doses of SO2 (2,20,200 pmol) or artificial cerebrospinal fluid (aCSF) at one side of the NTS. The effects of pressure and heart rate on rat blood were observed in 25 rats at different dose of SO2 (2,20,200 pmol) or aCSF at one side of the RVLM. The effect of the pressure and heart rate.2. The mechanism of the effect of SO2 on the production of cardiovascular effects in the RVLM:43 adult male SD rats,11 of which were pre-injected with aCSF or glutamate (Glu) non-selective receptor in the RVLM. The effect of anti-agent (KYN, 15nmol) on the cardiovascular effects of sulfur dioxide on the RVLM was observed.32 rats were pre-injected with aCSF, ATP-sensitive potassium channel (KATP) blocking agent gliclazide (Gli,40. mu.mol), L-type calcium channel blocker nicardipine (N (c,200 pmol), non-selective nitric oxide synthase (NOS) inhibitor NG-nitro L-arginine methyl ester (L-NAME,15 nmol), selective soluble ornithine-acid cyclase (sGC) inhibitor 1H-[1,2,4] E dicyandiamide[4,3-1]-1-one-one (O DQ,250 pmol), and the content of sulfur dioxide in the RVLM was investigated. Ion channel and signal transduction pathway.3. Distribution of SO2 in the tissues and serum: Cecal ligation and puncture, C 40 adult male SD rats were randomly divided into the sham operation group (n = 8) using the random number table method. And the rats were sacrificed at 3 h,6 h,12 h and 24 h after the model, and the liver and kidney were taken. Serum samples were taken from the heart and brain tissue. Enzyme-linked immunosorbent assay (ELISA) was used ( ELISA) Determination of S02 level.4. The effects of 2 on the ABR in septic rats were: the male and sexual SD rats were randomly divided into 11 groups using the random number table method: sham operation (SO) + physiological saline (Saline) + intravenous (iv) group; TCLP + Saline + iv group; HSO + SO2 + iv group; TCLP + SO2 + iv group; HSO + aCSF + NTS group; HSO + SO2 + NTS group; TCLP + aCSF + NTS group; HSO + SO2 + NTS group; TCLP + KYN + NTS group; HSO + aCSF + SO2 + NTS group; Group (pre-bilateral NTS injection of aCSF followed by injection of SO2 at the same site) 11SO + KYN + SO2 + NTS group (pre-bilateral NTS injection of KYN And then SO2 at the same site),5 min and 30 mi after administration, respectively. n3 The results were as follows:1. The cardiovascular effects of SO2 in the NTS and the RVLM: the dose-dependent decrease of the single-side micro-injection of SO2 in the NTS The effect of low blood pressure and slow heart rate (P <0.05). The dose-dependent rise of the single-side micro-injection of SO2 in the RVLM The effect of SO2 on the heart rate (P <0.05).2. The mechanism of the production of cardiovascular effect in the RVLM: the pre-RVLM injection of the KYN can partially block the SO2 (20 pmol). Cardiovascular effect induced by RVLM (P <0.05). Pre-RVLM injection of Gli, Nic, L-NAME or ODQ can effectively block the production of SO2 (20 pmol) in the RVLM The distribution of SO2 in the tissues and serum: the liver, the kidney, the heart, the brain and the serum of the sham operation group. The content of SO2 in the heart tissue was the highest in the heart, and the level of SO2 in the liver, the kidney, the heart, the brain and the serum of the rats after 3 h after the CLP model was compared with the sham operation group. The effect of SO 2 on the ABR in the rats with sepsis was higher than that in the same group. The results of the change of ABR in the same group were as follows: the results of the change of ABR in the same group were: the results of the changes of the ABR in the group of SO + SO2 + iv, CLP + SO2 + iv, SO + SO2 + NTS group, CLP + SO2 + NTS group, the SO + aCSF + SO2 + NTS group, and the ABR of the group of SO + aCSF + SO2 + NTS decreased significantly (P <0.05). The changes of ABR were significantly lower in the group of CLP + KYN + NTS (P <0.05). The results of the change of ABR were significantly lower than that in the group of SO + Saline + iv or the SO + SO 2 + iv group (P0.05). The CLP + aCSF + NTS group was significantly lower than that of the SO + aCSF. + NTS group or SO + SO2 + NTS group (P <0.05). The CLP + SO2 + iv group was significantly lower than that of the CLP + Saline + iv group (P <0.05) or the SO + Saline + iv group (P <0.05), and the CLP + SO2 + NTS group was significantly lower than that of the CLP + aCSF + NTS group (P <0.05) or the SO + aCSF + NTS group (P005), and the CLP + KYN + NTS group was significantly higher than that of the CLP + aCSF + NTS group (P <0.05), and the SO + KYN + SO2 + NTS group was significantly higher. 浜嶴O + aCSF + SO2 + NTS group (P <0.05). Conclusion:1 . SO2 can cause dose-dependent reduction of blood pressure and slow heart rate in the NTS. SO2 may cause a dose-dependent rise in hypertension and an accelerated heart rate in the RVLM. Involved in the regulation of central blood pressure, which may be related to the opening of KATP and L-type calcium channels. SO2 is produced in the RVLM 3. SO2 can be generated endogenously in normal rats, and the level of SO2 in cardiac tissue is higher than that of other groups. In rats, the level of SO2 in rats was higher than that of normal, and may be involved in the pathogenesis of sepsis rats.4. The increase in the production of 8O2 in vivo has a lower effect on the function of the ABR in septic rats, which can not only play a role in the peripheral venous system, but also may influence AB by the central NTS.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R459.7
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