附子心脏毒作用机制研究
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摘要
目的：观察附子急性毒性和长期毒性中心脏毒性反应表现和特点,研究附子心脏毒作用机制,为临床合理应用附子提供科学依据。
方法：1.按照国际ICH规范,在GLP实验室条件下,进行黑顺片、白附片和泥附子醇提物灌胃小鼠的LD50测定,黑顺片、白附片和泥附子水提物灌胃小鼠的最大耐受量测定,以及6个提取物灌胃大鼠的急性毒性试验,观察附子急性毒性反应中的心脏毒性反应表现和特点；2.按照国际ICH规范,在GLP实验室条件下,进行泥附子醇提物灌胃正常大鼠3个月长期毒性试验,观察附子长期毒性中心脏毒性反应表现和特点；3.采用细胞培养技术观察附子中乌头碱不同浓度作用30min对乳鼠原代培养心肌细胞形态、超微结构、膜稳定性、内环境、能量代谢的影响,探讨附子心脏毒性的机制。
结果：1.急性毒性试验结果：黑顺片醇提物灌胃小鼠的半数致死量(LD50)为5.783g/kg(相当于49.853g生药/kg),95%可信限为5.313～6.338g/kg(相当于45.804～54.636g生药/kg)；白附片醇提物灌胃小鼠的LDso为6.872g/kg(相当于42.550g生药/kg),95%可信限为6.173～7.724g/kg(相当于38.221～47.828g生药/kg)；泥附子醇提物灌胃小鼠的LD50为5.054g/kg(相当于22.168g生药/kg),95%可信限为4.798～5.361g/kg(相当于21.043～23.513g生药/kg)；黑顺片、白附片、泥附子水提物灌胃小鼠的最大给药量(MTD)分别为21.273、25.597、60.932g/kg,分别相当于48.80、59.00、92.80g生药/kg。黑顺片醇提物5.08g/kg、白附片醇提物6.06g/kg、泥附子醇提物4.56g/kg灌胃大鼠可引起动物死亡和明显的毒性反应,黑顺片水提物以21.27g/kg、白附片水提物25.60g/kg、泥附子水提物30.48g/kg灌胃大鼠不引起明显急性毒性反应。附子醇提物灌胃大鼠、小鼠的急性毒性反应以心脏毒性、神经毒性和消化系统毒性为主,其中心脏毒性反应特点为,先出现心率加快和心律不齐,体热,皮肤、尾、足垫发红,心前区搏动明显加快,逐渐转为体凉,唇爪、尾部、耳、足垫苍白,唇爪发绀,最后心前区搏动减弱,心率减慢,死亡。血液中CK可出现异常,心肌充血致心脏系数增大。
2.长期毒性试验结果：泥附子醇提物6.20g生药/kg灌胃大鼠3个月,不引起明显毒性反应,但早期给药时在给药后心前区搏动有所加快,心律紊乱,雄鼠耗食量降低,随后恢复正常；实验结束时血液学中MID升高,病理组织学检查显示有心脏损伤,主要表现心肌小片状或灶性坏死、溶解,伴随慢性炎细胞浸润及纤维结缔组织增生。部分动物肾脏有肾小管上皮细胞浊肿、轻度空泡性变及少量透明管型。
3.附子中乌头碱心脏毒作用机制研究结果：乌头碱对原代培养SD乳鼠心肌细胞作用30min的最小毒性浓度为O.2%,在0.2%、0.36%、0.63%、1.13%、2%范围内作用30mmin,可引起细胞搏动减弱、消失,细胞变形、体积变小、脱壁、固缩和死亡；电子显微镜观察可见胞浆内空洞形成,线粒体肿胀和粗面内质网扩张,随着浓度的增加线粒体肿胀数量和程度增加,出现嵴断裂和线粒体破裂,细胞核形态异常和染色质边迹,细胞膜不完整,至最高浓度时可见大量细胞碎片,核固缩,胞浆内大量空洞,无正常线粒体和内质网,细胞形态消失。乌头碱可使细胞漏出LDH增加,细胞内ACP活性升高,糖原含量降低,MDA含量升高,细胞内K+减少而Ca2+增加,Ca2+-ATP酶活力降低。
结论：1.附子急性心脏毒性反应表现特点为：先出现心率加快和心律不齐,皮肤、尾、足垫发红,体热,心前区搏动明显加快,逐渐转为体凉,唇爪、尾部、耳、足垫苍白,唇爪发绀,最后心前区搏动减弱,心率减慢,死亡。
2.附子慢性心脏毒性反应表现特点为：早期给药引起心率加快、心律不齐,但能在短时间内恢复,且随着给药时间的延长心脏毒性反应发生率下降,可引起慢性心脏损伤,病变以灶性坏死和溶解、纤维组织增生为主。
3.乌头碱是附子心脏毒性的重要物质基础,附子的心脏毒作用机制是通过破坏心肌细胞形态和超微结构,使细胞膜稳定性受损,细胞能量代谢异常,内环境紊乱,细胞增殖异常等达到,毒性强度随给药剂量增加和作用时间延长而增强,在一定范围内呈显著毒-量正相关性和时-毒正相关性。
Aim It is aimed to observe manifestations and feature of cardiotoxicity in acute toxicity and chronic toxicity of Radix Aconiti Lateralis Preparata (Fuzi) respectively, and to study the related mechanism of cardiotoxicity, for the purpose of providing scientific basis for safe and rational use of Fuzi in clinic.
Methods1. According to the international ICH standards, the medium lethal dose (LD50) tests of the ethanol extracts of Hei-Shun Pian (HS), Bai-Fu-Pian (BF), and Ni-Fuzi (NF) and the maximum tolerated dose(MTD) tests of aqueous extracts of the three slices were carried out on mice by gavage under the IVC experimental surrounding; meanwhile, the acute toxicity tests for the six extracts were also conducted on rats to observe cardiac toxicity.2. According to the international ICH standards, the three-month chronic toxicity test of ethanol extract derived from NF were conducted on rats under IVC surrounding to study manifestations and feature of chronic cardiotoxicity of Fuzi.3. To explore the potential mechanism of Fuzi on cardiac toxicity, the primary cardiomyocytes were cultured in vitro and then exposed to medium containing aconitine with different concentrations. Morphologic changes were observed and parameters concerning cell membrane, internal environment or energy metabolism were detected.
Results1.The LD50values of ethanol extract of HS for mice intragastric administration was49.853g crude drug/kg with95%confidential interval about45.804～54.636g crude drug/kg. The LD50of ethanol extract of BF was42.550g crude drug/kg and its95%confidential interval was38.221-47.828g crude drug/kg. The LD50of ethanol extract of NF for mice intragastric administration is22.168g crude drug/kg and its95%confidential interval was21.043～23.513g crude drug/kg. The MTD of water extracts of HS, BF, NF for mice intragastric administration were21.273,25.597,60.932g/kg, equal to48.80,59.00,92.80g crude drug/kg, respectively. When ethanol extracts of HS, BF, NF were administrated to rats at doses of5.08,6.06, and4.56g/kg, severe toxic manifestations and even death were appeared in some rats; however, the three water extracts didn't induce toxic reactions and death on rats with oral doses of21.27,25.60,30.48g/kg respectively. Acute toxic syndromes on rats and mice focused on neurotoxicity, cardiotoxicity and the digestive system toxicity. The acute cardiotoxicity of Fuzi features as flollows:initially fast heart rate and precordial beat, arrhythmia, hot body, flush skin, tail and foot pad were observed, gradually the body tended cold with pale appearance or even cyanochroia on lips, claws, tail,ears and foot of pads, accompanied with weak beat on precordium and slow heart rate before death. The serum CK level and enlarged heart coefficient could be occurred in some rats.
2The three-month chronic toxic test on rats of ethanol extract from NF showed that no obvious toxic syndromes were observed during the whole experiments except slight accelerated precordial beat and arrhythmia during the initial period. However, the24h-food intake of male rats deCREAsed and the MI, MID levels in blood inCREAsed. Besides, the organ morphologic examination showed injuries in heart tissue, manifesting as patchy or focal necrosis or dissolved, chronic inflammatory cell infiltration and fibrous connective tissue proliferation. For some rats, cloudy swelling, mild degeneration and a small amount of transparent type were observed in renal bubular epithelial cells in kidney.
3.The minimum toxic dosage of aconitine on cardiomyocyte was0.2%. When respectively exposed the mediums containing aconitine0.2%,0.36%,0.63%,1.13%,2%for30minutes, it could induce cell beat suppression, deformation, take-off the wall, pyknosis and death. Under the electronic microscope, severe celluar toxicities were observed as cavity in the cytoplasm, swelling of mitochondria and rough endoplasmic reticulum and even ridge breakage of mitochondria as the concentration of aconitine was inCREAsed, followed by nuclear morphological abnormaliites, chromatin boundary trace, incomplete cell membrane. In the largest dosage, cell debrises, pyknosis, lots of cavity in the cytoplasm could be seen without mitochondria and rough endoplasmic reticulum. Aconitine induced LDH leakage inCREAsed, ACP overactivity, glycogen deCREAse, MDA inCREAse, intercellular K+deCREAse and Ca2+inCREAse.
Conclusions1The acute cardiotoxicity of Fuzi features are as flollows:initially fast heart rate and precordial beat, arrhythmia, hot body, flush skin, tail and foot pad were observed, gradually the body tended cold with pale appearance or even cyanochroia on lips, claws, tail,ears and foot of pads, accompanied with weak beat on precordium and slow heart rate before death. The serum CK level and enlarged heart coefficient could be occurred in some rats.
2. The chronic cardiotoxicity of Fuzi features are as follows:slight accelerated precordial beat and arrhythmia during the initial period. However, the24h-food intake of male rats deCREAsed and the MI, MID levels in blood inCREAsed. Besides, the organ morphologic examination showed injuries in heart tissue, manifesting as patchy or focal necrosis or dissolved, chronic inflammatory cell infiltration and fibrous connective tissue proliferation.
3. Aconitine is the major toxic ingredient of Fuzi for its cardiotoxicity. The potential mechanism of cardiotoxicity is related to damage morphology,cell organelles, and cell membrane, induce oxidative damage, disturb internal environment and energy metabolism.
方法：1.按照国际ICH规范,在GLP实验室条件下,进行黑顺片、白附片和泥附子醇提物灌胃小鼠的LD50测定,黑顺片、白附片和泥附子水提物灌胃小鼠的最大耐受量测定,以及6个提取物灌胃大鼠的急性毒性试验,观察附子急性毒性反应中的心脏毒性反应表现和特点；2.按照国际ICH规范,在GLP实验室条件下,进行泥附子醇提物灌胃正常大鼠3个月长期毒性试验,观察附子长期毒性中心脏毒性反应表现和特点；3.采用细胞培养技术观察附子中乌头碱不同浓度作用30min对乳鼠原代培养心肌细胞形态、超微结构、膜稳定性、内环境、能量代谢的影响,探讨附子心脏毒性的机制。
结果：1.急性毒性试验结果：黑顺片醇提物灌胃小鼠的半数致死量(LD50)为5.783g/kg(相当于49.853g生药/kg),95%可信限为5.313～6.338g/kg(相当于45.804～54.636g生药/kg)；白附片醇提物灌胃小鼠的LDso为6.872g/kg(相当于42.550g生药/kg),95%可信限为6.173～7.724g/kg(相当于38.221～47.828g生药/kg)；泥附子醇提物灌胃小鼠的LD50为5.054g/kg(相当于22.168g生药/kg),95%可信限为4.798～5.361g/kg(相当于21.043～23.513g生药/kg)；黑顺片、白附片、泥附子水提物灌胃小鼠的最大给药量(MTD)分别为21.273、25.597、60.932g/kg,分别相当于48.80、59.00、92.80g生药/kg。黑顺片醇提物5.08g/kg、白附片醇提物6.06g/kg、泥附子醇提物4.56g/kg灌胃大鼠可引起动物死亡和明显的毒性反应,黑顺片水提物以21.27g/kg、白附片水提物25.60g/kg、泥附子水提物30.48g/kg灌胃大鼠不引起明显急性毒性反应。附子醇提物灌胃大鼠、小鼠的急性毒性反应以心脏毒性、神经毒性和消化系统毒性为主,其中心脏毒性反应特点为,先出现心率加快和心律不齐,体热,皮肤、尾、足垫发红,心前区搏动明显加快,逐渐转为体凉,唇爪、尾部、耳、足垫苍白,唇爪发绀,最后心前区搏动减弱,心率减慢,死亡。血液中CK可出现异常,心肌充血致心脏系数增大。
2.长期毒性试验结果：泥附子醇提物6.20g生药/kg灌胃大鼠3个月,不引起明显毒性反应,但早期给药时在给药后心前区搏动有所加快,心律紊乱,雄鼠耗食量降低,随后恢复正常；实验结束时血液学中MID升高,病理组织学检查显示有心脏损伤,主要表现心肌小片状或灶性坏死、溶解,伴随慢性炎细胞浸润及纤维结缔组织增生。部分动物肾脏有肾小管上皮细胞浊肿、轻度空泡性变及少量透明管型。
3.附子中乌头碱心脏毒作用机制研究结果：乌头碱对原代培养SD乳鼠心肌细胞作用30min的最小毒性浓度为O.2%,在0.2%、0.36%、0.63%、1.13%、2%范围内作用30mmin,可引起细胞搏动减弱、消失,细胞变形、体积变小、脱壁、固缩和死亡；电子显微镜观察可见胞浆内空洞形成,线粒体肿胀和粗面内质网扩张,随着浓度的增加线粒体肿胀数量和程度增加,出现嵴断裂和线粒体破裂,细胞核形态异常和染色质边迹,细胞膜不完整,至最高浓度时可见大量细胞碎片,核固缩,胞浆内大量空洞,无正常线粒体和内质网,细胞形态消失。乌头碱可使细胞漏出LDH增加,细胞内ACP活性升高,糖原含量降低,MDA含量升高,细胞内K+减少而Ca2+增加,Ca2+-ATP酶活力降低。
结论：1.附子急性心脏毒性反应表现特点为：先出现心率加快和心律不齐,皮肤、尾、足垫发红,体热,心前区搏动明显加快,逐渐转为体凉,唇爪、尾部、耳、足垫苍白,唇爪发绀,最后心前区搏动减弱,心率减慢,死亡。
2.附子慢性心脏毒性反应表现特点为：早期给药引起心率加快、心律不齐,但能在短时间内恢复,且随着给药时间的延长心脏毒性反应发生率下降,可引起慢性心脏损伤,病变以灶性坏死和溶解、纤维组织增生为主。
3.乌头碱是附子心脏毒性的重要物质基础,附子的心脏毒作用机制是通过破坏心肌细胞形态和超微结构,使细胞膜稳定性受损,细胞能量代谢异常,内环境紊乱,细胞增殖异常等达到,毒性强度随给药剂量增加和作用时间延长而增强,在一定范围内呈显著毒-量正相关性和时-毒正相关性。
Aim It is aimed to observe manifestations and feature of cardiotoxicity in acute toxicity and chronic toxicity of Radix Aconiti Lateralis Preparata (Fuzi) respectively, and to study the related mechanism of cardiotoxicity, for the purpose of providing scientific basis for safe and rational use of Fuzi in clinic.
Methods1. According to the international ICH standards, the medium lethal dose (LD50) tests of the ethanol extracts of Hei-Shun Pian (HS), Bai-Fu-Pian (BF), and Ni-Fuzi (NF) and the maximum tolerated dose(MTD) tests of aqueous extracts of the three slices were carried out on mice by gavage under the IVC experimental surrounding; meanwhile, the acute toxicity tests for the six extracts were also conducted on rats to observe cardiac toxicity.2. According to the international ICH standards, the three-month chronic toxicity test of ethanol extract derived from NF were conducted on rats under IVC surrounding to study manifestations and feature of chronic cardiotoxicity of Fuzi.3. To explore the potential mechanism of Fuzi on cardiac toxicity, the primary cardiomyocytes were cultured in vitro and then exposed to medium containing aconitine with different concentrations. Morphologic changes were observed and parameters concerning cell membrane, internal environment or energy metabolism were detected.
Results1.The LD50values of ethanol extract of HS for mice intragastric administration was49.853g crude drug/kg with95%confidential interval about45.804～54.636g crude drug/kg. The LD50of ethanol extract of BF was42.550g crude drug/kg and its95%confidential interval was38.221-47.828g crude drug/kg. The LD50of ethanol extract of NF for mice intragastric administration is22.168g crude drug/kg and its95%confidential interval was21.043～23.513g crude drug/kg. The MTD of water extracts of HS, BF, NF for mice intragastric administration were21.273,25.597,60.932g/kg, equal to48.80,59.00,92.80g crude drug/kg, respectively. When ethanol extracts of HS, BF, NF were administrated to rats at doses of5.08,6.06, and4.56g/kg, severe toxic manifestations and even death were appeared in some rats; however, the three water extracts didn't induce toxic reactions and death on rats with oral doses of21.27,25.60,30.48g/kg respectively. Acute toxic syndromes on rats and mice focused on neurotoxicity, cardiotoxicity and the digestive system toxicity. The acute cardiotoxicity of Fuzi features as flollows:initially fast heart rate and precordial beat, arrhythmia, hot body, flush skin, tail and foot pad were observed, gradually the body tended cold with pale appearance or even cyanochroia on lips, claws, tail,ears and foot of pads, accompanied with weak beat on precordium and slow heart rate before death. The serum CK level and enlarged heart coefficient could be occurred in some rats.
2The three-month chronic toxic test on rats of ethanol extract from NF showed that no obvious toxic syndromes were observed during the whole experiments except slight accelerated precordial beat and arrhythmia during the initial period. However, the24h-food intake of male rats deCREAsed and the MI, MID levels in blood inCREAsed. Besides, the organ morphologic examination showed injuries in heart tissue, manifesting as patchy or focal necrosis or dissolved, chronic inflammatory cell infiltration and fibrous connective tissue proliferation. For some rats, cloudy swelling, mild degeneration and a small amount of transparent type were observed in renal bubular epithelial cells in kidney.
3.The minimum toxic dosage of aconitine on cardiomyocyte was0.2%. When respectively exposed the mediums containing aconitine0.2%,0.36%,0.63%,1.13%,2%for30minutes, it could induce cell beat suppression, deformation, take-off the wall, pyknosis and death. Under the electronic microscope, severe celluar toxicities were observed as cavity in the cytoplasm, swelling of mitochondria and rough endoplasmic reticulum and even ridge breakage of mitochondria as the concentration of aconitine was inCREAsed, followed by nuclear morphological abnormaliites, chromatin boundary trace, incomplete cell membrane. In the largest dosage, cell debrises, pyknosis, lots of cavity in the cytoplasm could be seen without mitochondria and rough endoplasmic reticulum. Aconitine induced LDH leakage inCREAsed, ACP overactivity, glycogen deCREAse, MDA inCREAse, intercellular K+deCREAse and Ca2+inCREAse.
Conclusions1The acute cardiotoxicity of Fuzi features are as flollows:initially fast heart rate and precordial beat, arrhythmia, hot body, flush skin, tail and foot pad were observed, gradually the body tended cold with pale appearance or even cyanochroia on lips, claws, tail,ears and foot of pads, accompanied with weak beat on precordium and slow heart rate before death. The serum CK level and enlarged heart coefficient could be occurred in some rats.
2. The chronic cardiotoxicity of Fuzi features are as follows:slight accelerated precordial beat and arrhythmia during the initial period. However, the24h-food intake of male rats deCREAsed and the MI, MID levels in blood inCREAsed. Besides, the organ morphologic examination showed injuries in heart tissue, manifesting as patchy or focal necrosis or dissolved, chronic inflammatory cell infiltration and fibrous connective tissue proliferation.
3. Aconitine is the major toxic ingredient of Fuzi for its cardiotoxicity. The potential mechanism of cardiotoxicity is related to damage morphology,cell organelles, and cell membrane, induce oxidative damage, disturb internal environment and energy metabolism.
引文
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