CP -154,526和verapamil对促肾上腺皮质激素释放因子分泌水平的影响

目的 探讨促肾上腺皮质激素释放因子Ⅰ型受体( CRF -R1)拮抗剂CP - 154,526 (CP)和钙离子通道拮抗剂verapamil (VP)对幼年大鼠在缺氧缺血(HI)后并放置1天后血浆中促肾上腺皮质激素释放因子分泌水平的影响.方法 80只幼年大鼠随机分成8组,即对照组、假手术组、CP对照组、VP对照组、模型组(HI组)、H1+ CP组、HI+VP组和HI+ CP+ VP组.用放射免疫法测定各组幼年大鼠血浆中CRF水平.结果 与对照组比较,HI组、HI+ CP组和HI+ CP+ VP组血浆CRF水平都显著降低(P＜0.001、P＜0.001、P＜0.001)；与假手术组比较,HI组、HI+ CP组和HI+ CP+ VP组血浆CRF水平都显著降低(P＜0.001、P＜0.001、P＜0.001)；与CP对照组比较,HI组、HI+ CP组和HI+CP+ VP组血浆CRF水平都显著降低(P ＜0.001、P＜0.001、P＜0.001)；与VP对照组比较,HI组、HI+ CP组和HI+ CP+ VP血浆CRF水平都显著降低(P ＜0.001、P＜0.001、P＜0.001);与HI组比较,HI+ CP组和HI+ VP组血浆CRF水平显著增加(P＜0.05、P＜0.001)；与HI+ CP比较,HI+ VP组血浆CRF水平显著增加(P＜0.001)；与HI+ VP组比较,HI+ CP+ VP组血浆CRF水平显著降低(P＜0.001).结论 幼年大鼠在HI后并放置1天后血浆CRF水平都显著减少；可是,当幼年大鼠用CP或者VP预处理后,血浆CRF分泌水平在缺氧缺血下的减少能被逆转；当用CP和VP同时预处理后,血浆CRF分泌水平在缺氧缺血下的减少没有被改变.

Objective To investigate therapeutic action of verapamil on QT prolongation induced by arsenic trioxide (As2O3) in guinea pig and to further explore its possible mechanism. Methods Different doses of As2 O3 was infused intravenously to observe the changes of QT interval on the electrocardiogram (ECG) at different times in guinea pig. Patchclamp technique and laser scanning confocal microscopy were utilized to study the action of As2 O3 on action potential duration (APD),L-type calcium current (ICa-L ), rapid delayed rectifier potassium current (IKr) and intracellular calcium concentration ([Ca2+]i) of guinea pig myocytes. At the same time, verapamil was applied preliminarily to evaluate effects of verapamil on changes of the above index induced by As2O3. Results Intravenous administration of As2 O3 at the dose of 1.6mg/kg and 0.8mg/kg prolonged QT interval on ECG obviously in guinea pig hearts dose dependently and time dependently. QTc (corrected QT interval) was progressively prolonged in the 2-hour period of intravenous infusion of 1.6mg/kg As2O3 from (328.5 ± 30.9)ms of control to (388.4 ± 31.3)ms at 2h following As2O3 ( P ＜ 0.01) .When verapamil was pretreated for 5min, then 1.6mg/kg As2 O3 was added, the results showed that QTe was shorter in verapamil-treatment group (357.3±21.4)ms than that in As2O3 group (388.4±31.3)ms (P＜0.05) at 2h. Confocal experiments showed that in normal Tyrode solution, As2 O3 (1μmol/L and 10μmol/L) had no obvious effects on resting [Ca2+]i (P＞0.05) in guinea pig cardiomyocytes, however, 10μmol/L As2 O3 could markedly enhance [Ca2+]i increase induced by KCl 60mmol/L and the peak value increased from 903.4±369.4 to 1674.6±563.2 ( P＜0.05). The action of elevating [Ca2+]icould be blocked by 10μmol/L verapamil incompletely. The patch-clamp studies indicated that As2 O3 at concentration of 10μmol/L prolonged APD50 from (263.6 -±75.2)ms to (523.9±47.8)ms (P＜0.01) and APD90 from (277.5 ± 77.5)ms to (536.3 ±49.6)ms (P ＜0.01) ,and increased ICa-L from (- 6.0±1.5)pA/pF to (-8.7±2.0)pA/pF (P＜0.01) at 0mV and also reduced IKr from (6.7±1.8)pA/pF to (4.5±1.8)pA/pF (P＜0.05). However, 10μmol/L verapamil could modulate prolonging APD50 from (523.9 ± 47.8) ms to (340.4±83.8) ms ( P＜0.01) and APD90 from (536.3 ±49.6)ms to (348.9 ± 85.5)ms (P＜0.01) and correct increasing Ica-L induced by 10μmol/L As2O3 from (-8.7±2.0)pA/pF to ( - 6.6±1.4)pA/pF (P＜0.05) at 0mV. Conclusion As2O3 could induce prolongation of the QT interval on the ECG in guinea pig hearts and the ionic mechanism is associated with increasing Ica-L and inhibiting IKr/HERG. Verapamil may be useful in normalizing QT prolongation during As2 O3 therapy by decreasing Ica-L and [Ca2+]iof ventricular myocytes in guinea pig.

降钙素基因相关肽对家兔离体窦房结电生理活动的影响

用常规微电极方法研究了降钙素基因相关肽(CGRP)对家兔窦房结起搏细胞的电生理作用, 并进一步探讨这种作用与钙电流的关系.结果: (1) 低浓度CGRP (1 nmol/L)对窦房结动作电位各参数无显著影响;中等浓度CGRP (10 nmol/L)可增加大舒张期电位、动作电位幅度、 0期大除极化速率和4期自动除极速率, 缩短窦性周期、动作电位复极化50%和90%时间, 这些作用经20 min达到高峰;高浓度CGRP (100 nmol/L)可引起窦房结节律失常.(2) 钙拮抗剂CdCl2和verapamil可削弱由CGRP (20 nmol/L)引起的窦房结细胞动作电位改变, 结果提示, CGRP在窦房结细胞的电生理效应中存在钙依赖机制.

细辛与verapamil镇痛协同作用的实验研究

目的研究细辛与verapamil的镇痛协同作用,为临床联合用药提供理论依据.方法采用醋酸扭体实验及热板法致痛实验观测其镇痛作用,并用神经盒、多媒体MS-302系统观察其对蟾蜍坐骨神经动作电位的影响.结果细辛及A-V复方制剂对醋酸致小鼠腹痛、热板法致小鼠足痛均有明显的镇痛作用并能抑制蟾蜍坐骨神经动作电位的传导.verapamil有弱的镇痛作用,无坐骨神经动作电位阻滞作用.A-V复方制剂的镇痛及抑制神经动作电位传导作用均大于其组分细辛和维拉帕米.结论细辛和verapamil有镇痛协同作用.

HTK液与Verapamil配伍对供心保存效果的实验研究

目的 通过建立Langendorff离体鼠心灌流模型,研究HTK液与Verapamil配伍对供心的保护效果.方法 30只SD大鼠(200～400g/只),随机分为实验组与对照组,实验组予以HTK液与Verapamil(5mg/L)配伍、对照组予以单纯HTK液作为停搏液,建立标准的Langendorff离体心脏灌注模型,4℃低温下保存大鼠心脏6h,予以37℃ K-H液复灌,心脏复跳,生理仪记录缺血前、复灌20min、40min、60min、80min时血流动力学标值,检测心脏复灌45min时冠脉流出液中心肌酶学指标,实验结束后各组留取样本以行常规病理切片及电镜切片观察微观结构变化.结果 实验组LVSP平均恢复率高于对照组,对照组LVEDP持续上升,实验组LVEDP相对稳定;对照组心肌酶均明显高于实验组(P＜0.05);病理切片显示对照组损伤较实验组明显.结论 HTK液联合Verapamil较单独使用HTK液作为心肌保护液,对心肌具有更明显的保护作用.

维拉帕米在大鼠肝微粒体中代谢产物的体外鉴定

AIM: To investigate the metabolism of verapamil at low concentrations in rat liver microsomes. METHODS: Liver microsomes of Wistar rats were prepared using ultracentrifuge method. The in vitro metabolism of verapamil was studied with the rat liver microsomal incubation at concentration of 1.0 μmol/L and 5.0 μmol/L. The metabolites were separated and assayed by liquid chromatography-ion trap mass spectrometry (LC/MSn), and further identified by comparison of their mass spectra and chromatographic behaviors with reference substances. RESULTS: Eight metabolites, including two novel metabolites (M4 and M8), were found in rat liver microsomal incubates. They were identified as O-demethyl-verapamil isomers (M1 - M4), N-dealkylated derivatives of verapamil (M5-M7), and N, O-didemethyl-verapamil (M8). CONCLUSION: O-Demethylation and N-dealkylation were the main metabolic pathways of verapamil at low concentrations in rat liver microsomes, and the relative proportion of them in verapamil metabolism changed with different substrate concentrations.