Liguzinediol通过作用于肌浆网钙释放发挥正性肌力作用及其心脏安全性评价
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摘要
目的：
探索Liguzinediol (LZDO)对正常大鼠离体心脏正性肌力作用的机理,并评价其心脏安全性。
方法：
1.大鼠Langendorff离体心脏灌流：
采用常规大鼠Langendorff离体心脏灌流技术,记录左心室收缩功能。分析LZDO以及LZDO在α1、β、D1、H1受体阻滞剂,磷酸二酯酶、Na+-K+-ATP酶、Na+-ca2+交换抑制剂,L-型钙通道阻滞剂,兰尼碱受体、肌浆网钙泵抑制剂存在的条件下,对左心室收缩压(LVSP)、左心室舒张末期压(LVEDP)、左心室内压最大上升速率(+dp/dtmax)、左心室内压最大下降速率(-dp/dtmax)、心率(HR)的作用。
2. GPCR受体活性测定技术：
我们选取了与心肌收缩力有关的31个GPCR受体,分析LZDO对它们的作用。
3.大鼠心脏乳头肌动作电位记录：
采用常规大鼠离体乳头肌动作电位记录技术,记录乳头肌动作电位的各参数。分析LZDO对动作电位复极50%水平的时程(APD50)和90%水平的时程(APD90)的作用。
4.全细胞电流钳记录技术：
采用膜片钳全细胞电流钳技术,记录大鼠左心室单个肌细胞的动作电位的各参数。分析LZDO对动作电位复极50%水平的时程(APD50)和90%水平的时程(APD90)的作用。
5.全细胞电压钳记录技术：
应用膜片钳全细胞电压钳技术,分析LZDO对L-型钙电流的作用,探讨LZDO正性肌力作用的机制；分析LZDO对hNav1.5电流、hERG电流的作用,对其进行心脏安全性评价。
6.细胞内钙成像技术：
采用细胞内钙成像的方法研究LZDO对心肌细胞内钙释放的作用。
7.在体和离体心电图技术：
采用常规豚鼠在体和离体心电图技术,研究LZDO对豚鼠心电图的P-R间期和QTc间期的影响。
结果：
1. LZDO剂量依赖性地增加大鼠离体左心室收缩力,其正性肌力作用能被L-型钙通道阻滞剂、兰尼碱受体抑制剂、肌浆网钙泵抑制剂所完全阻断：LZDO能显著地增加左心室收缩压(LVSP)、左心室舒张末期压(LVEDP)、左室内压最大上升速率(+dp/dtmax)、左室内压最大下降速率(-dp/dtmax),但并不显著性地改变心率。在α1受体阻滞剂哌唑嗪(Prazosin1μM)、β受体阻滞剂普萘洛尔(Propranolol1μM)、多巴胺D1受体阻滞剂(SCH233901μM)、H1受体阻滞剂非索那定(Fexofenadine1μM)、磷酸二酯酶抑制剂IBMX(5μM)、Na+-K+-ATP酶抑制剂哇巴因(Ouabain1μM)、Na+-Ca2+交换抑制剂(KB-R79431μM)存在的条件下,LZDO100μM仍能显著地增加上述功能指标(P<0.05)。L-型钙通道阻滞剂尼莫地平(Nimodipine1μM)、L-型钙通道阻滞剂维拉帕米(Verapamil1μM)、兰尼碱受体抑制剂钉红(Ruthenium red5μM)、肌浆网钙泵抑制剂毒胡萝卜素(Thapsigargin2μM)能完全阻断LZDO100μM的正性肌力作用(P>0.05),显示LZDO的正性肌力作用是通过L-型钙通道、兰尼碱受体和肌浆网钙泵所介导的。
2. LZDO对GPCR受体无显著性的激活作用：
实验结果显示,LZDO100μM对31个GPCR受体无显著性的激活作用。
3. LZDO对正常大鼠乳头肌动作电位无显著性作用：
LZDO100μM对大鼠乳头肌动作电位的复极50%水平的时程(APD50)和90%水平的时程(APD90)无显著性作用(P>0.05)。
4. LZDO对正常大鼠心肌细胞动作电位无显著性作用：
LZDO100μM对大鼠左心室单个肌细胞动作电位的复极50%水平的时程(APD50)和90%水平的时程(APD90)无显著性作用(P>0.05)。
5. LZDO并不能增加正常大鼠左心室肌细胞的L-型钙电流,LZDO对hNav1.5电流与hERG电流均无显著性的抑制作用：
LZDO100μM对大鼠左心室单个肌细胞的L-型钙电流无显著性作用(P>0.05),显示LZDO的作用靶点不是L-型钙通道；LZDO(1,10,100,300μM)对hNav1.5电流无显著性的抑制作用；LZDO(1,10,100,300μM)对hERG电流无显著性的抑制作用。
6.LZDO显著性地增加正常大鼠左心室肌细胞内的钙释放量：
LZDO100μM可以显著性地增加大鼠左心室肌细胞内的钙释放量(P<0.05)；LZDO100μM可以恢复由咖啡因所引起的肌浆网钙衰竭现象,这说明LZDO的作用靶点不是兰尼碱受体。
7. LZDO对豚鼠在体和离体心脏心电图的P-R间期及QTc间期均无显著性的影响：
豚鼠在体给予LZDO1.7g.kg-1或豚鼠离体心脏灌流LZDO300μM后,P-R间期及QTc间期并没有显著性的改变(P>0.05)。
结论：
LZDO的正性肌力作用与其增强肌浆网的钙释放量有关,LZDO对L-型钙通道无直接作用,其作用靶点可能为肌浆网钙泵。LZDO并没有显著性地改变豚鼠在体与离体心电图的P-R间期及QTc间期,也没有显著性抑制hNav1.5和hERG电流,显示其良好的心脏安全性。LZDO具有独特的生物学机制,很有希望成为临床治疗心衰的有效药物。
Objectives:
The purpose in the present work was to investigate the mechanism underlying positive inotropic effect in rat isolated hearts and evaluate cardiac safety of Liguzinediol.
Methods:
1. Intraventricular pressure recording from isolated rat hearts:
Left ventricle contractile function was measured using the Langendorff non-recirculating mode of isolated rat hearts. Effects of LZDO and LZDO in presences of ai receptor, β receptor, dopamine D1, Hi receptor antagonist, Phosphodiesterase, Na+-K+ATPase, Na+-Ca2+exchange inhibitor, L-type calcium channel antagonist, Ryanodine receptor, or SR Ca2+ATPase inhibitor. Left ventricular systolic pressure (LVSP) and left ventricular end diastolic pressure (LVEDP) as major cardiac contractile function were calculated. Also, heart rate (HR), peak rate of rise of left ventricular pressure (+dp/dtmax), and peak rate of fall of left ventricular pressure (-dp/dtmax) of isolated rat hearts were measured.
2. The stimulatory activity assay on31GPCRs:
The stable cell lines expressing31GPCRs respectively were applied for the screening. LZDO was diluted to100μM and screened in duplication. The cells were validated with the reference compounds. Their EC50/IC50values were similar to the reported values and can be applied in the screening. During screening, the reference agonist for each GPCR was assayed as positive control and at concentration stimulating maximal activity. The activation activity of LZDO to each GPCR was normalized with the positive control and shown as%activation.
3. Recording of action potential from rat heart papillary muscle:
The action potential (AP) duration at50%level (APD50) and at90%level (APD90) from rat heart papillary muscle were recorded using conventional intracellular recording technique. Effects of LZDO on above parameters were analyzed.
4. Whole-cell current clamp recording:
The action potential (AP) duration at50%level (APD50) and at90%level (APD90) of rat left myocyte were recorded using patch clamp current clamp configuration. Effects of LZDO on above paremeters were analyzed.
5. Whole-cell voltage clamp recording:
Whole-cell voltage clamp technique was used to analyze the effects of LZDO on L-type Ca2+current which underlies mechanism of LZDO's positive inotropic effect and hNav1.5、 hERG currents which serve for cardiac safety evaluation of LZDO.
6. Intracellular Ca2+imaging:
Intracellular Ca2+imaging was used to investigate the effect of LZDO on Ca2+transient.
7. In vivo and in vitro electrocardiogram (ECG) recording:
ECG was recorded by conventional guinea pig in vivo and in vitro ECG techniques, we analyzed the effects of LZDO on P-R and QTc intervals.
Results:
1. LZDO increased left ventricular contractility in the isolated rat heart in a dose-dependent manner. L-type calcium channel antagonist, Ryanodine receptor inhibitor or SR Ca2+-ATPase inhibitor completely blocked the positive inotropic effect of LZDO:
LZDO significantly enhanced LVSP, LVEDP,+dp/dtmax, and-dp/dtmax, but not heart rate. α1adrenergic receptor antagonist (Prazosin1μM), β adrenergic receptor antagonist (Propranolol1μM), Dopamine D1receptor antagonist (SCH233901μM), H1receptor antagonist (Fexofenadine1μM), Phosphodiesterase inhibitor (IBMX5μM), Na+-K+-ATPase inhibitor (Ouabain1μM) or Na+-Ca2+exchange inhibitor (KB-R79431μM) had no effect on blocking contractile function of LZDO100μM (P<0.05). Meanwhile, L-type calcium channel antagonist (Nimodipine1μM), L-type calcium channel antagonist (Verapamil1μM), Ryanodine receptor inhibitor (Ruthenium red5μM) or SR Ca2+-ATPase inhibitor (Thapsigargin2μM) completely blocked the contractile function of LZDO (P>0.05). It is suggested that the positive inotropic effect of LZDO was mediated by L-type calcium channel, Ryanodine receptor and SR Ca2+-ATPase.
2. The31GPCRs were not activated by LZDO:
Results showed that LZDO100μM did not activate31GPCRs which related to cardiac contractility.
3. LZDO did not significantly change APD50and APD90in rat heart papillary muscle:
LZDO100μM did not significantly change APD50and APD90in rat heart papillary muscle (P>0.05).
4. LZDO did not significantly change APD50and APD90in rat left ventricular myocyte:
LZDO100μM did not significantly change APD50and APD90in rat left ventricular myocyte (P>0.05).
5. LZDO failed to increase the L-type calcium current in rat left ventricular myocyte, LZDO did not significantly suppress the hNavl.5and hERG current:
LZDO100μM did not significantly change L-type calcium current in rat left ventricular myocyte (P>0.05), it is suggested that LZDO's target is not L-type calcium channel. LZDO (1,10,100,300μM) did not significantly suppress the hNavl.5and hERG current.
6. LZDO significantly enhanced intracellular Ca2+transient in rat left ventricular myocyte:
LZDO100μM significantly enhanced intracellular Ca2+transient in rat left ventricular myocyte (P<0.05), Moreover, LZDO100μM restored the sarcoplasmic reticulum depletion effect of caffeine on Ca2+transient.
7. LZDO did not significantly change P-R and QTc intervals of in vivo and in vitro guinea pig ECG:
LZDO1.7g-kg-1in vivo and LZDO300μM in vitro could not significantly prolong P-R and QTc intervals (P>0.05).
Conclusions:
The positive inotropic effect of LZDO in isolated rat hearts was mediated through an elevation of SR Ca2+transient. LZDO had no direct effect on L-type calcium channel and may act on SR Ca2+ATPase. LZDO did not significantly change P-R and QTc intervals of in vivo and in vitro guinea pig ECG Moreover, LZDO did not significantly suppress the hNav1.5and the hERG current. These data suggested LZDO had no prearrythmia effect. LZDO has a unique biological mechanism without proarrythmia effect that may prove effective in treating heart failure in clinic.
探索Liguzinediol (LZDO)对正常大鼠离体心脏正性肌力作用的机理,并评价其心脏安全性。
方法：
1.大鼠Langendorff离体心脏灌流：
采用常规大鼠Langendorff离体心脏灌流技术,记录左心室收缩功能。分析LZDO以及LZDO在α1、β、D1、H1受体阻滞剂,磷酸二酯酶、Na+-K+-ATP酶、Na+-ca2+交换抑制剂,L-型钙通道阻滞剂,兰尼碱受体、肌浆网钙泵抑制剂存在的条件下,对左心室收缩压(LVSP)、左心室舒张末期压(LVEDP)、左心室内压最大上升速率(+dp/dtmax)、左心室内压最大下降速率(-dp/dtmax)、心率(HR)的作用。
2. GPCR受体活性测定技术：
我们选取了与心肌收缩力有关的31个GPCR受体,分析LZDO对它们的作用。
3.大鼠心脏乳头肌动作电位记录：
采用常规大鼠离体乳头肌动作电位记录技术,记录乳头肌动作电位的各参数。分析LZDO对动作电位复极50%水平的时程(APD50)和90%水平的时程(APD90)的作用。
4.全细胞电流钳记录技术：
采用膜片钳全细胞电流钳技术,记录大鼠左心室单个肌细胞的动作电位的各参数。分析LZDO对动作电位复极50%水平的时程(APD50)和90%水平的时程(APD90)的作用。
5.全细胞电压钳记录技术：
应用膜片钳全细胞电压钳技术,分析LZDO对L-型钙电流的作用,探讨LZDO正性肌力作用的机制；分析LZDO对hNav1.5电流、hERG电流的作用,对其进行心脏安全性评价。
6.细胞内钙成像技术：
采用细胞内钙成像的方法研究LZDO对心肌细胞内钙释放的作用。
7.在体和离体心电图技术：
采用常规豚鼠在体和离体心电图技术,研究LZDO对豚鼠心电图的P-R间期和QTc间期的影响。
结果：
1. LZDO剂量依赖性地增加大鼠离体左心室收缩力,其正性肌力作用能被L-型钙通道阻滞剂、兰尼碱受体抑制剂、肌浆网钙泵抑制剂所完全阻断：LZDO能显著地增加左心室收缩压(LVSP)、左心室舒张末期压(LVEDP)、左室内压最大上升速率(+dp/dtmax)、左室内压最大下降速率(-dp/dtmax),但并不显著性地改变心率。在α1受体阻滞剂哌唑嗪(Prazosin1μM)、β受体阻滞剂普萘洛尔(Propranolol1μM)、多巴胺D1受体阻滞剂(SCH233901μM)、H1受体阻滞剂非索那定(Fexofenadine1μM)、磷酸二酯酶抑制剂IBMX(5μM)、Na+-K+-ATP酶抑制剂哇巴因(Ouabain1μM)、Na+-Ca2+交换抑制剂(KB-R79431μM)存在的条件下,LZDO100μM仍能显著地增加上述功能指标(P<0.05)。L-型钙通道阻滞剂尼莫地平(Nimodipine1μM)、L-型钙通道阻滞剂维拉帕米(Verapamil1μM)、兰尼碱受体抑制剂钉红(Ruthenium red5μM)、肌浆网钙泵抑制剂毒胡萝卜素(Thapsigargin2μM)能完全阻断LZDO100μM的正性肌力作用(P>0.05),显示LZDO的正性肌力作用是通过L-型钙通道、兰尼碱受体和肌浆网钙泵所介导的。
2. LZDO对GPCR受体无显著性的激活作用：
实验结果显示,LZDO100μM对31个GPCR受体无显著性的激活作用。
3. LZDO对正常大鼠乳头肌动作电位无显著性作用：
LZDO100μM对大鼠乳头肌动作电位的复极50%水平的时程(APD50)和90%水平的时程(APD90)无显著性作用(P>0.05)。
4. LZDO对正常大鼠心肌细胞动作电位无显著性作用：
LZDO100μM对大鼠左心室单个肌细胞动作电位的复极50%水平的时程(APD50)和90%水平的时程(APD90)无显著性作用(P>0.05)。
5. LZDO并不能增加正常大鼠左心室肌细胞的L-型钙电流,LZDO对hNav1.5电流与hERG电流均无显著性的抑制作用：
LZDO100μM对大鼠左心室单个肌细胞的L-型钙电流无显著性作用(P>0.05),显示LZDO的作用靶点不是L-型钙通道；LZDO(1,10,100,300μM)对hNav1.5电流无显著性的抑制作用；LZDO(1,10,100,300μM)对hERG电流无显著性的抑制作用。
6.LZDO显著性地增加正常大鼠左心室肌细胞内的钙释放量：
LZDO100μM可以显著性地增加大鼠左心室肌细胞内的钙释放量(P<0.05)；LZDO100μM可以恢复由咖啡因所引起的肌浆网钙衰竭现象,这说明LZDO的作用靶点不是兰尼碱受体。
7. LZDO对豚鼠在体和离体心脏心电图的P-R间期及QTc间期均无显著性的影响：
豚鼠在体给予LZDO1.7g.kg-1或豚鼠离体心脏灌流LZDO300μM后,P-R间期及QTc间期并没有显著性的改变(P>0.05)。
结论：
LZDO的正性肌力作用与其增强肌浆网的钙释放量有关,LZDO对L-型钙通道无直接作用,其作用靶点可能为肌浆网钙泵。LZDO并没有显著性地改变豚鼠在体与离体心电图的P-R间期及QTc间期,也没有显著性抑制hNav1.5和hERG电流,显示其良好的心脏安全性。LZDO具有独特的生物学机制,很有希望成为临床治疗心衰的有效药物。
Objectives:
The purpose in the present work was to investigate the mechanism underlying positive inotropic effect in rat isolated hearts and evaluate cardiac safety of Liguzinediol.
Methods:
1. Intraventricular pressure recording from isolated rat hearts:
Left ventricle contractile function was measured using the Langendorff non-recirculating mode of isolated rat hearts. Effects of LZDO and LZDO in presences of ai receptor, β receptor, dopamine D1, Hi receptor antagonist, Phosphodiesterase, Na+-K+ATPase, Na+-Ca2+exchange inhibitor, L-type calcium channel antagonist, Ryanodine receptor, or SR Ca2+ATPase inhibitor. Left ventricular systolic pressure (LVSP) and left ventricular end diastolic pressure (LVEDP) as major cardiac contractile function were calculated. Also, heart rate (HR), peak rate of rise of left ventricular pressure (+dp/dtmax), and peak rate of fall of left ventricular pressure (-dp/dtmax) of isolated rat hearts were measured.
2. The stimulatory activity assay on31GPCRs:
The stable cell lines expressing31GPCRs respectively were applied for the screening. LZDO was diluted to100μM and screened in duplication. The cells were validated with the reference compounds. Their EC50/IC50values were similar to the reported values and can be applied in the screening. During screening, the reference agonist for each GPCR was assayed as positive control and at concentration stimulating maximal activity. The activation activity of LZDO to each GPCR was normalized with the positive control and shown as%activation.
3. Recording of action potential from rat heart papillary muscle:
The action potential (AP) duration at50%level (APD50) and at90%level (APD90) from rat heart papillary muscle were recorded using conventional intracellular recording technique. Effects of LZDO on above parameters were analyzed.
4. Whole-cell current clamp recording:
The action potential (AP) duration at50%level (APD50) and at90%level (APD90) of rat left myocyte were recorded using patch clamp current clamp configuration. Effects of LZDO on above paremeters were analyzed.
5. Whole-cell voltage clamp recording:
Whole-cell voltage clamp technique was used to analyze the effects of LZDO on L-type Ca2+current which underlies mechanism of LZDO's positive inotropic effect and hNav1.5、 hERG currents which serve for cardiac safety evaluation of LZDO.
6. Intracellular Ca2+imaging:
Intracellular Ca2+imaging was used to investigate the effect of LZDO on Ca2+transient.
7. In vivo and in vitro electrocardiogram (ECG) recording:
ECG was recorded by conventional guinea pig in vivo and in vitro ECG techniques, we analyzed the effects of LZDO on P-R and QTc intervals.
Results:
1. LZDO increased left ventricular contractility in the isolated rat heart in a dose-dependent manner. L-type calcium channel antagonist, Ryanodine receptor inhibitor or SR Ca2+-ATPase inhibitor completely blocked the positive inotropic effect of LZDO:
LZDO significantly enhanced LVSP, LVEDP,+dp/dtmax, and-dp/dtmax, but not heart rate. α1adrenergic receptor antagonist (Prazosin1μM), β adrenergic receptor antagonist (Propranolol1μM), Dopamine D1receptor antagonist (SCH233901μM), H1receptor antagonist (Fexofenadine1μM), Phosphodiesterase inhibitor (IBMX5μM), Na+-K+-ATPase inhibitor (Ouabain1μM) or Na+-Ca2+exchange inhibitor (KB-R79431μM) had no effect on blocking contractile function of LZDO100μM (P<0.05). Meanwhile, L-type calcium channel antagonist (Nimodipine1μM), L-type calcium channel antagonist (Verapamil1μM), Ryanodine receptor inhibitor (Ruthenium red5μM) or SR Ca2+-ATPase inhibitor (Thapsigargin2μM) completely blocked the contractile function of LZDO (P>0.05). It is suggested that the positive inotropic effect of LZDO was mediated by L-type calcium channel, Ryanodine receptor and SR Ca2+-ATPase.
2. The31GPCRs were not activated by LZDO:
Results showed that LZDO100μM did not activate31GPCRs which related to cardiac contractility.
3. LZDO did not significantly change APD50and APD90in rat heart papillary muscle:
LZDO100μM did not significantly change APD50and APD90in rat heart papillary muscle (P>0.05).
4. LZDO did not significantly change APD50and APD90in rat left ventricular myocyte:
LZDO100μM did not significantly change APD50and APD90in rat left ventricular myocyte (P>0.05).
5. LZDO failed to increase the L-type calcium current in rat left ventricular myocyte, LZDO did not significantly suppress the hNavl.5and hERG current:
LZDO100μM did not significantly change L-type calcium current in rat left ventricular myocyte (P>0.05), it is suggested that LZDO's target is not L-type calcium channel. LZDO (1,10,100,300μM) did not significantly suppress the hNavl.5and hERG current.
6. LZDO significantly enhanced intracellular Ca2+transient in rat left ventricular myocyte:
LZDO100μM significantly enhanced intracellular Ca2+transient in rat left ventricular myocyte (P<0.05), Moreover, LZDO100μM restored the sarcoplasmic reticulum depletion effect of caffeine on Ca2+transient.
7. LZDO did not significantly change P-R and QTc intervals of in vivo and in vitro guinea pig ECG:
LZDO1.7g-kg-1in vivo and LZDO300μM in vitro could not significantly prolong P-R and QTc intervals (P>0.05).
Conclusions:
The positive inotropic effect of LZDO in isolated rat hearts was mediated through an elevation of SR Ca2+transient. LZDO had no direct effect on L-type calcium channel and may act on SR Ca2+ATPase. LZDO did not significantly change P-R and QTc intervals of in vivo and in vitro guinea pig ECG Moreover, LZDO did not significantly suppress the hNav1.5and the hERG current. These data suggested LZDO had no prearrythmia effect. LZDO has a unique biological mechanism without proarrythmia effect that may prove effective in treating heart failure in clinic.
引文
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