A型肉毒毒素对Methoxamine和电场刺激引发兔离体主动脉收缩的作用及机理
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摘要
研究背景:我们前期研究证明(botulinum toxin type A,BTX-A)并不仅作用于骨骼肌的胆碱能神经木梢,同时也作用于substance P(SP),vasoactive intestinal peptide(VIP),calcitonin gene-related peptide(CGRP)调控的平滑肌和腺体。根据我们前期的研究推定神经毒素(neurotoxin)—BTX-A可干预位于血管周围交感神经末梢递质的释放,抑制神经源肿瘤血管收缩从而改善肿瘤灌注量和氧供。探究神经肉毒素—BTX-A有望作为抗肿瘤治疗一种有效佐剂。
目的:观察BTX-A对肾上腺素α受体激动剂Methoxamine(MOA)和电场刺激(electrical field stimulation,EFS)引发主动脉肌条收缩的作用。
方法:击兔头部致昏后迅速取出主动脉并分离结缔组织后制成0.5×3.0 cm螺旋形肌条,悬挂于37℃Krebs液[(mM)120 NaCl,5.9 KCl,25 NaHCO_3,17.5 Dextrose,2.5CaCl_2,1.2 MgCl_2,1.2 NaH_2PO_4,(pH 7.4)]内持续供给95%O_2和5%CO_2的混合气体的恒温平滑肌浴槽中,肌条一端固定在肌槽底部的玻璃弯钩上,另一端固定在张力传感器上,血管条被悬于两个铂金电极之间,其长轴与电极长轴平行,电极与电刺激器相连。血管条在2 g的前负荷下1 h后分别加药并记录张力变化。(1)MOA组:MOA5μM引发收缩30 min后分别加入等量的vehicle(对照,n=10)、BTX-A50 U/ml(n=10)或100 U/ml(n=10),30 min后再加入MOA 5μM。(2)EFS组:EFS 50 Hz,80 V,1 ms,60 s引发肌条收缩30 min后分别加入等量的vehicle(n=10)或BTX-A 50 U/ml(n=10),30 min后加入MOA5μM。
结果:(1)BTX-A 50 U/ml和100 U/ml分别导致MOA诱发肌条收缩张力下降80%(P＜0.01)和95%(P＜0.001),再次加入MOA引发收缩为vehicle的35%(P＜0.001)和3%(P＜0.001),该抑制作用呈剂量依赖关系;(2)BTX-A 50 U/ml导致EFS诱发的肌条收缩张力下降94%(P＜0.001),加入MOA引发收缩为vehicle的10%(P＜0.001)。
结论:肾上腺素α受体激动剂MOA和EFS引发兔主动脉肌条收缩,BTX-A抑制MOA和EFS引发动脉平滑肌收缩作用机理与抑制NA的释放和其受体有关。
Backgrand:The inhibitive effect of botulinum toxin-A(BTX-A) is not only on cholinergic release in voluntary muscle,but also substance P(SP),vasoactive intestinal peptide (VIP),calcitonin gene-related peptide(CGRP) in smooth muscle and glands in our previous studies.Our proposals according to the previous study are that BTX-A might effect on sympathetic release in blood vessel and inhibits the contraction of blood vessel and promotes perfusion and oxygen of blood in tumor.The investigation of BTX-A as a adjuvant is a new approach to treatment of tumor.
Objective:To investigate the inhibitory effect of BTX-A on rabbit aortic contractility-induced by methoxamine(MOA),an agonist of noradrenergicαreceptor,or electric field stimulation(EFS) in vitro,respectively.
Methods:MOA-and EFS-treated group were carried out in this study.0.5×3.0 cm spiral-shaped strip of rabbit aorta was suspended in incubation bath containing Krebs bicarbonate buffer[composed of(in mM)120 NaCl,5.9 KCl,25 NaHCO_3,17.5 Dextrose,2.5 CaCl_2,1.2 MgCl_2,1.2 NaH_2PO4,(pH 7.4)],constant 37℃within oxygenated with 95% O_2-5%CO_2.one end of the strip was fixed to a hook on the bottom of the bath,the other end was connected to an isometric force transducer.These strips were suspended between platinum electrodes placed adjacent and parallel to the long axis of the aortic strips.Electrodes were connected to an electric stimulator.The aortic strips were prepared to 2g loading tension and equilibrate for 60minutes,and subdivided randomly into MOA group and EFS group.Strips in MOA-treated group were administrated MOA 5μM for promoting contraction for 30 min, followed the equal volume of vehicle(n=10),BTX-A 50 U(n=10) and 100 U/ml(n=10) respectively addition for 30 min recording,and subsequently treated with MOA 5μM again. Other strips in the EFS-treated group were stimulated by 50 Hz,80 V,1 ms and 60 s electricity,followed vehicle(n=10) and BTX-A 50 U/ml(n=10) respectively addition for 30 min,and subsequently treated with MOA 5μM again.The contractile graph in motility of the aortic strips were simultaneously recorded with physiological experimental system.
Results:(1) BTX-A 50 U/ml and 100 U/ml decreased respectively 80%(P＜0.01) and 95%(P＜0.001) of the aortic contractile tension-induced by MOA.MOA repeated addition promoted respectively 35%(P＜0.001) and 3%(P＜0.001) of contractile tension of the strips-treated respectively with BTX-A 50 and 100 U/ml compared to the strips treated with Krebs solution.(2) BTX-A 50 U significantly reduced 94%(P＜0.001) of the aortic contractility-induced by EFS.MOA addition promoted only 10%(P＜0.001) of contractile tension of the strips treated with BTX-A 50 compared to the strips treated with Krebs solution.
Conclusion:MOA and EFS promote rabbit aortic contraction.BTX-A inhibits respectively the contractile responses to MOA and EFS with a manner of dose-dependence through inhibiting noradrenergic release and receptor probably.
目的:观察BTX-A对肾上腺素α受体激动剂Methoxamine(MOA)和电场刺激(electrical field stimulation,EFS)引发主动脉肌条收缩的作用。
方法:击兔头部致昏后迅速取出主动脉并分离结缔组织后制成0.5×3.0 cm螺旋形肌条,悬挂于37℃Krebs液[(mM)120 NaCl,5.9 KCl,25 NaHCO_3,17.5 Dextrose,2.5CaCl_2,1.2 MgCl_2,1.2 NaH_2PO_4,(pH 7.4)]内持续供给95%O_2和5%CO_2的混合气体的恒温平滑肌浴槽中,肌条一端固定在肌槽底部的玻璃弯钩上,另一端固定在张力传感器上,血管条被悬于两个铂金电极之间,其长轴与电极长轴平行,电极与电刺激器相连。血管条在2 g的前负荷下1 h后分别加药并记录张力变化。(1)MOA组:MOA5μM引发收缩30 min后分别加入等量的vehicle(对照,n=10)、BTX-A50 U/ml(n=10)或100 U/ml(n=10),30 min后再加入MOA 5μM。(2)EFS组:EFS 50 Hz,80 V,1 ms,60 s引发肌条收缩30 min后分别加入等量的vehicle(n=10)或BTX-A 50 U/ml(n=10),30 min后加入MOA5μM。
结果:(1)BTX-A 50 U/ml和100 U/ml分别导致MOA诱发肌条收缩张力下降80%(P＜0.01)和95%(P＜0.001),再次加入MOA引发收缩为vehicle的35%(P＜0.001)和3%(P＜0.001),该抑制作用呈剂量依赖关系;(2)BTX-A 50 U/ml导致EFS诱发的肌条收缩张力下降94%(P＜0.001),加入MOA引发收缩为vehicle的10%(P＜0.001)。
结论:肾上腺素α受体激动剂MOA和EFS引发兔主动脉肌条收缩,BTX-A抑制MOA和EFS引发动脉平滑肌收缩作用机理与抑制NA的释放和其受体有关。
Backgrand:The inhibitive effect of botulinum toxin-A(BTX-A) is not only on cholinergic release in voluntary muscle,but also substance P(SP),vasoactive intestinal peptide (VIP),calcitonin gene-related peptide(CGRP) in smooth muscle and glands in our previous studies.Our proposals according to the previous study are that BTX-A might effect on sympathetic release in blood vessel and inhibits the contraction of blood vessel and promotes perfusion and oxygen of blood in tumor.The investigation of BTX-A as a adjuvant is a new approach to treatment of tumor.
Objective:To investigate the inhibitory effect of BTX-A on rabbit aortic contractility-induced by methoxamine(MOA),an agonist of noradrenergicαreceptor,or electric field stimulation(EFS) in vitro,respectively.
Methods:MOA-and EFS-treated group were carried out in this study.0.5×3.0 cm spiral-shaped strip of rabbit aorta was suspended in incubation bath containing Krebs bicarbonate buffer[composed of(in mM)120 NaCl,5.9 KCl,25 NaHCO_3,17.5 Dextrose,2.5 CaCl_2,1.2 MgCl_2,1.2 NaH_2PO4,(pH 7.4)],constant 37℃within oxygenated with 95% O_2-5%CO_2.one end of the strip was fixed to a hook on the bottom of the bath,the other end was connected to an isometric force transducer.These strips were suspended between platinum electrodes placed adjacent and parallel to the long axis of the aortic strips.Electrodes were connected to an electric stimulator.The aortic strips were prepared to 2g loading tension and equilibrate for 60minutes,and subdivided randomly into MOA group and EFS group.Strips in MOA-treated group were administrated MOA 5μM for promoting contraction for 30 min, followed the equal volume of vehicle(n=10),BTX-A 50 U(n=10) and 100 U/ml(n=10) respectively addition for 30 min recording,and subsequently treated with MOA 5μM again. Other strips in the EFS-treated group were stimulated by 50 Hz,80 V,1 ms and 60 s electricity,followed vehicle(n=10) and BTX-A 50 U/ml(n=10) respectively addition for 30 min,and subsequently treated with MOA 5μM again.The contractile graph in motility of the aortic strips were simultaneously recorded with physiological experimental system.
Results:(1) BTX-A 50 U/ml and 100 U/ml decreased respectively 80%(P＜0.01) and 95%(P＜0.001) of the aortic contractile tension-induced by MOA.MOA repeated addition promoted respectively 35%(P＜0.001) and 3%(P＜0.001) of contractile tension of the strips-treated respectively with BTX-A 50 and 100 U/ml compared to the strips treated with Krebs solution.(2) BTX-A 50 U significantly reduced 94%(P＜0.001) of the aortic contractility-induced by EFS.MOA addition promoted only 10%(P＜0.001) of contractile tension of the strips treated with BTX-A 50 compared to the strips treated with Krebs solution.
Conclusion:MOA and EFS promote rabbit aortic contraction.BTX-A inhibits respectively the contractile responses to MOA and EFS with a manner of dose-dependence through inhibiting noradrenergic release and receptor probably.
引文
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