孤啡肽对大鼠左心室功能的影响及其机制研究
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摘要
神经肽是一类广泛存在于机体组织且参与多种器官生理功能调节的肽类物质,其对心血管功能的影响一直是研究的热点,孤啡肽(nociceptin, Orphanin FQ,OFQ)即是其中之一。孤啡肽是一种结构类似于κ阿片受体的内源性配体-强啡肽A的十七肽,但它与阿片类受体的亲和力很低,其特异性受体为ORL1受体,与阿片受体有很高的同源性,同属于G蛋白耦联受体超家族。在中枢及外周应用孤啡肽均可引起一定程度的血压下降和心率减慢,研究认为除与孤啡肽参与中枢和外周神经对心血管的调节有关外,还可能与其直接作用于心血管有关。目前在急性心肌缺血及心衰的研究中发现心肌与血浆中孤啡肽含量增高,提示孤啡肽可能参与上述病理过程,但是目前对其作用机制尚不清楚。孤啡肽是否对心功能有直接的调节作用?以及作用的机制如何?我们对此做了进一步的研究。
目的:研究孤啡肽对大鼠心脏功能的影响及其可能机制,以期进一步阐述对孤啡肽参与调节心脏生理功能的认识。
方法:本实验从四个方面进行研究
1.大鼠应用孤啡肽(静脉注射)的在体研究:健康大鼠分为对照组(静脉给予等体积生理盐水)、不同浓度孤啡肽1nM组、10nM组和50nM组,采用颈动脉插管逆行置入左心室,观察给药前后LVSP、LVDP、+dP/dtmax、-dP/dtmax、HR的变化。进一步选用孤啡肽拮抗剂UFP-101与孤啡肽配伍给药,观察上述指标的变化。
2.孤啡肽及其受体的免疫荧光化学标定实验:采用组织免疫荧光观察观察孤啡肽及其受体在大鼠心肌中的分布;并且采用急性分离大鼠心肌细胞使用Confocal方法观察孤啡肽受体的分布。
3.孤啡肽对心肌细胞的L型钙通道、内向整流钾通道及瞬时外向钾通道研究:采用膜片钳技术,观察不同浓度的孤啡肽对上述离子通道功能的影响,以探讨孤啡肽对心脏作用可能的机制。
4.孤啡肽对心肌细胞PKA活性的影响:提取分别经不同浓度OFQ处理的心肌细胞蛋白,采用PKA活性分析试剂盒测定其活化程度,以探讨孤啡肽作用可能的分子机制。
结果:
1.静脉给予孤啡肽引起大鼠LVSP、LVDP、+dP/dtmax、-dP/dtmax、HR有明显的剂量依赖性抑制(P<0.05),预先应用孤啡肽的拮抗剂UFP-101可以阻断此作用。
2.免疫荧光组织化学显示在大鼠心肌组织中有孤啡肽及其受体存在而confocal结果进一步证实心肌细胞分布有孤啡肽受体。
3.膜片钳实验结果显示,孤啡肽对心肌细胞L型钙电流有明显的抑制作用,但没有明显的剂量依赖性,以1nM孤啡肽的作用最为明显(抑制率为22.7%,P<0.05),UFP-101可以阻断此抑制作用。而孤啡肽对内向整流钾电流和瞬时外向钾电流均没有明显影响。
4.心肌细胞PKA活性分析显示,孤啡肽对心肌细胞的PKA没有明显影响。给予Forskolin处理心肌细胞可以明显增高PKA活性,而孤啡肽并不能抑制这种PKA活性的增高,提示可能孤啡肽对心肌细胞的影响并不是通过PKA机制。
结论:孤啡肽对大鼠心脏左心室收缩与舒张功能有明显的抑制作用,此作用可能是通过孤啡肽-孤啡肽受体作用,引起心肌细胞L型钙电流的抑制所致。进一步的研究显示孤啡肽对于心肌细胞的PKA活性没有影响,提示可能孤啡肽的这种作用不是通过影响cAMP-PKA通路介导的。对于心肌细胞的内向整流钾电流和瞬时外向钾电流并未见孤啡肽对其有明显影响。
Neuropeptides exist widely and could regulate physiological function of many organs. In recent years, the regulation of neuropeptides on cardiovascular system has becoming a hot spot of research, one of which is the regulation of OFQ (nociceptin, Orphanin FQ). OFQ is a heptadecapeptide whose primary structure is indeed similar to that of dynorphin A, but binds to classical opioid receptors with low affinity. The OFQ receptor is referred as opioid receptor-like 1(ORL1) receptor, which shares high structural homogeneity with the opioid receptors and also belong to G protein-coupled membrane receptors family. Both Intracerebroventricular and and intravenous administration of OFQ decreased the blood pressure and heart rate obviously. It is showed OFQ not only played a role in cardiovascular regulation via central or peripheral neverous mechanism, but also possibly had direct inhibition of cardiovascular system. The recent studies have showed OFQ increased markedly in myocardial tissue and blood plasma during acute myocardial ischemia and heart failure, which suggest OFQ may regulate the heart function directly and the mechanism need to be explored. Therefore we established the current study to investigate the effects of OFQ on heart function in vivo and explore the possible mechanism.
Objective: The purpose of this study was to investigate the effects of OFQ by intravenous administration on heart function in rats and explore the possible mechanism from cardiac ion channels.
Methods: The study was carried out in a series of experiments:
1. In vivo research: Healthy adult male SD (weighing 250-280g) rats were used for this experiment. The rats were randomly divided into four groups: the control group (normal saline i.v.), 1nM group (1nmol/kg, i.v.), 10 nM group(10 nmol/kg, i.v.) and 50 nM group(50 nmol/kg, i.v.). For the measurement of left ventricular pressures, a polyethylene catheter (Epidural catheter) was inserted into the left carotid artery and gently pushed into the left ventricle of rat anesthetized with urethane. After Hemodynamics indexes came to a steady state, the LVSP, LVDP, +dP/dtmax, -dP/dtmax and HR were recorded.
2. Immunofluorescence assay: OFQ and ORL1 receptor in the myocardial tissue were observed through immunofluorescence histochemistry, and ORL1 receptor was also located in the isolated ventricular myocytes from SD rats with confolcal laser scanning microscopy.
3. Patch clamp experiment: Ventricular myocytes were isolated from SD rats by Langendorff perfusion of the heart with an enzyme-containing solution as previous described. L-Ca current (ICa-L), inward rectifyimg potassium current (Ik1) and transient outward potassium current (Ito) of ventricular myocytes were induced through the particular procedure and recorded with the whole-cell voltage-clamp technique, respectively. The effects of OFQ on ICa-L, Ik1 and Ito were investigated respectively. All experiments were performed at room temperature and solutions were gased with 100% oxygen.
4. Effect of OFQ on PKA activity assay: Peptides were extracted from the isolated ventricular myocytes treated with and without OFQ, and using the Assay kit for Non-Radioactive Detection of cAMP Dependent Protein Kinase, PKA activity was measured via gel electrophoresis.
Results:
1. LVSP, LVDP, +dP/dtmax, -dP/dtmax and HR were significantly decreased in a dose-dependent manner after intravenous administration with OFQ. There was significant difference among groups (P<0.05). The OFQ induced inhibitions of LVSP, LVDP, +dP/dtmax, -dP/dtmax and HR were completely blocked by pre treatment with UFP-101, an potent, specific antagonist.
2. Immunofluorescence Histochemistry showed OFQ and ORL1 receptor existed in the myocardial tissue, furthermore the ORL1 receptor was confirmed in isolated myocytes with confolcal laser scanning microscopy.
3. OFQ obviously inhibited ICa-L in rat ventricular myocytes but not in a dose-depended manner, and the inhibition elicited by OFQ can be reversed by pre treatment with UFP-101. There were no significant effect on Ik1 and Ito in rat ventricular myocytes treated with OFQ.
4. There was not obvious variation on PKA activity in rat ventricular myocytes treated with OFQ. The increase of PKA activity induced by Forskolin, a PKA activator, was not reversed by treatment with OFQ.
Conclusions: OFQ inhibited the Left ventricular systolic and diastolic function, which may result from inhibition of ICa-L induced by OFQ in rat ventricular myocytes. Furthermore research showed OFQ had no significant effect on PKA activity of ventricular myocytes, which suggest the effect of OFQ on the heart function may not be mediated by cAMP-PKA passway. There was no significant effect on Ik1 and Ito in rat ventricular myocytes by treatment with OFQ.
目的:研究孤啡肽对大鼠心脏功能的影响及其可能机制,以期进一步阐述对孤啡肽参与调节心脏生理功能的认识。
方法:本实验从四个方面进行研究
1.大鼠应用孤啡肽(静脉注射)的在体研究:健康大鼠分为对照组(静脉给予等体积生理盐水)、不同浓度孤啡肽1nM组、10nM组和50nM组,采用颈动脉插管逆行置入左心室,观察给药前后LVSP、LVDP、+dP/dtmax、-dP/dtmax、HR的变化。进一步选用孤啡肽拮抗剂UFP-101与孤啡肽配伍给药,观察上述指标的变化。
2.孤啡肽及其受体的免疫荧光化学标定实验:采用组织免疫荧光观察观察孤啡肽及其受体在大鼠心肌中的分布;并且采用急性分离大鼠心肌细胞使用Confocal方法观察孤啡肽受体的分布。
3.孤啡肽对心肌细胞的L型钙通道、内向整流钾通道及瞬时外向钾通道研究:采用膜片钳技术,观察不同浓度的孤啡肽对上述离子通道功能的影响,以探讨孤啡肽对心脏作用可能的机制。
4.孤啡肽对心肌细胞PKA活性的影响:提取分别经不同浓度OFQ处理的心肌细胞蛋白,采用PKA活性分析试剂盒测定其活化程度,以探讨孤啡肽作用可能的分子机制。
结果:
1.静脉给予孤啡肽引起大鼠LVSP、LVDP、+dP/dtmax、-dP/dtmax、HR有明显的剂量依赖性抑制(P<0.05),预先应用孤啡肽的拮抗剂UFP-101可以阻断此作用。
2.免疫荧光组织化学显示在大鼠心肌组织中有孤啡肽及其受体存在而confocal结果进一步证实心肌细胞分布有孤啡肽受体。
3.膜片钳实验结果显示,孤啡肽对心肌细胞L型钙电流有明显的抑制作用,但没有明显的剂量依赖性,以1nM孤啡肽的作用最为明显(抑制率为22.7%,P<0.05),UFP-101可以阻断此抑制作用。而孤啡肽对内向整流钾电流和瞬时外向钾电流均没有明显影响。
4.心肌细胞PKA活性分析显示,孤啡肽对心肌细胞的PKA没有明显影响。给予Forskolin处理心肌细胞可以明显增高PKA活性,而孤啡肽并不能抑制这种PKA活性的增高,提示可能孤啡肽对心肌细胞的影响并不是通过PKA机制。
结论:孤啡肽对大鼠心脏左心室收缩与舒张功能有明显的抑制作用,此作用可能是通过孤啡肽-孤啡肽受体作用,引起心肌细胞L型钙电流的抑制所致。进一步的研究显示孤啡肽对于心肌细胞的PKA活性没有影响,提示可能孤啡肽的这种作用不是通过影响cAMP-PKA通路介导的。对于心肌细胞的内向整流钾电流和瞬时外向钾电流并未见孤啡肽对其有明显影响。
Neuropeptides exist widely and could regulate physiological function of many organs. In recent years, the regulation of neuropeptides on cardiovascular system has becoming a hot spot of research, one of which is the regulation of OFQ (nociceptin, Orphanin FQ). OFQ is a heptadecapeptide whose primary structure is indeed similar to that of dynorphin A, but binds to classical opioid receptors with low affinity. The OFQ receptor is referred as opioid receptor-like 1(ORL1) receptor, which shares high structural homogeneity with the opioid receptors and also belong to G protein-coupled membrane receptors family. Both Intracerebroventricular and and intravenous administration of OFQ decreased the blood pressure and heart rate obviously. It is showed OFQ not only played a role in cardiovascular regulation via central or peripheral neverous mechanism, but also possibly had direct inhibition of cardiovascular system. The recent studies have showed OFQ increased markedly in myocardial tissue and blood plasma during acute myocardial ischemia and heart failure, which suggest OFQ may regulate the heart function directly and the mechanism need to be explored. Therefore we established the current study to investigate the effects of OFQ on heart function in vivo and explore the possible mechanism.
Objective: The purpose of this study was to investigate the effects of OFQ by intravenous administration on heart function in rats and explore the possible mechanism from cardiac ion channels.
Methods: The study was carried out in a series of experiments:
1. In vivo research: Healthy adult male SD (weighing 250-280g) rats were used for this experiment. The rats were randomly divided into four groups: the control group (normal saline i.v.), 1nM group (1nmol/kg, i.v.), 10 nM group(10 nmol/kg, i.v.) and 50 nM group(50 nmol/kg, i.v.). For the measurement of left ventricular pressures, a polyethylene catheter (Epidural catheter) was inserted into the left carotid artery and gently pushed into the left ventricle of rat anesthetized with urethane. After Hemodynamics indexes came to a steady state, the LVSP, LVDP, +dP/dtmax, -dP/dtmax and HR were recorded.
2. Immunofluorescence assay: OFQ and ORL1 receptor in the myocardial tissue were observed through immunofluorescence histochemistry, and ORL1 receptor was also located in the isolated ventricular myocytes from SD rats with confolcal laser scanning microscopy.
3. Patch clamp experiment: Ventricular myocytes were isolated from SD rats by Langendorff perfusion of the heart with an enzyme-containing solution as previous described. L-Ca current (ICa-L), inward rectifyimg potassium current (Ik1) and transient outward potassium current (Ito) of ventricular myocytes were induced through the particular procedure and recorded with the whole-cell voltage-clamp technique, respectively. The effects of OFQ on ICa-L, Ik1 and Ito were investigated respectively. All experiments were performed at room temperature and solutions were gased with 100% oxygen.
4. Effect of OFQ on PKA activity assay: Peptides were extracted from the isolated ventricular myocytes treated with and without OFQ, and using the Assay kit for Non-Radioactive Detection of cAMP Dependent Protein Kinase, PKA activity was measured via gel electrophoresis.
Results:
1. LVSP, LVDP, +dP/dtmax, -dP/dtmax and HR were significantly decreased in a dose-dependent manner after intravenous administration with OFQ. There was significant difference among groups (P<0.05). The OFQ induced inhibitions of LVSP, LVDP, +dP/dtmax, -dP/dtmax and HR were completely blocked by pre treatment with UFP-101, an potent, specific antagonist.
2. Immunofluorescence Histochemistry showed OFQ and ORL1 receptor existed in the myocardial tissue, furthermore the ORL1 receptor was confirmed in isolated myocytes with confolcal laser scanning microscopy.
3. OFQ obviously inhibited ICa-L in rat ventricular myocytes but not in a dose-depended manner, and the inhibition elicited by OFQ can be reversed by pre treatment with UFP-101. There were no significant effect on Ik1 and Ito in rat ventricular myocytes treated with OFQ.
4. There was not obvious variation on PKA activity in rat ventricular myocytes treated with OFQ. The increase of PKA activity induced by Forskolin, a PKA activator, was not reversed by treatment with OFQ.
Conclusions: OFQ inhibited the Left ventricular systolic and diastolic function, which may result from inhibition of ICa-L induced by OFQ in rat ventricular myocytes. Furthermore research showed OFQ had no significant effect on PKA activity of ventricular myocytes, which suggest the effect of OFQ on the heart function may not be mediated by cAMP-PKA passway. There was no significant effect on Ik1 and Ito in rat ventricular myocytes by treatment with OFQ.
引文
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