Streptomycin inhibits electrophysiological changes induced by stretching of chronically infarcted rat hearts

Streptomycin inhibits electrophysiological changes induced by stretching of chronically infarcted rat hearts 链霉素抑制慢性心肌梗死大鼠心脏牵张时的电生理改变 1 first-author 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:ssjx0216@126.com †E-mail:ssjx0216@126.com ssjx0216@126.com 1 1 2 Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China Department of Chinese Medicine, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China Department of Chinese Medicine, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China Objective: 2 To investigate stretch-induced electrophysiological changes in chronically infarcted hearts and the effect of streptomycin (SM) on these changes in vivo . Methods: 2 Sixty Wistar rats were divided randomly into four groups: a control group ( n =15), an SM group ( n =15), a myocardial infarction (MI) group ( n =15), and an MI+SM group ( n =15). Chronic MI was obtained by ligating the left anterior descending branch (LAD) of rat hearts for eight weeks. The in vivo blockade of stretch-activated ion channels (SACs) was achieved by intramuscular injection of SM (180 mg/(kg∙d)) for seven days after operation. The hearts were stretched for 5 s by occlusion of the aortic arch. Suction electrodes were placed on the anterior wall of left ventricle to record the monophasic action potential (MAP). The effect of stretching was examined by assessing the 90% monophasic action potential duration (MAPD 90 ), premature ventricular beats (PVBs), and ventricular tachycardia (VT). Results: 2 The MAPD 90 decreased during stretching in both the control (from (50.27±5.61) ms to (46.27±4.51) ms, P < 0.05) and MI groups (from (65.47±6.38) ms to (57.47±5.76 ms), P < 0.01). SM inhibited the decrease in MAPD 90 during inflation ((46.27±4.51) ms vs. (49.53±3.52) ms, P < 0.05 in normal hearts; (57.47±5.76) ms vs. (61.87±5.33) ms, P < 0.05 in MI hearts). The occurrence of PVBs and VT in the MI group increased compared with that in the control group (PVB: 7.93±1.66 vs. 1.80±0.86, P < 0.01; VT: 7 vs. 1, P < 0.05). SM decreased the occurrence of PVBs in both normal and MI hearts (0.93±0.59 vs. 1.80±0.86 in normal hearts, P < 0.05; 5.40±1.18 vs. 7.93±1.66 in MI hearts, P < 0.01). Conclusions: 2 Stretch-induced MAPD 90 changes and arrhythmias were observed in chronically infarcted myocardium. The use of SM in vivo decreased the incidence of PVBs but not of VT. This suggests that SACs may be involved in mechanoelectric feedback (MEF), but that there might be other mechanisms involved in causing VT in chronic MI. 研究目的 2 以往研究发现链霉素作为牵张激活离子通道阻断剂，可抑制机械电反馈时心脏的电生理效应，但多为离体研究。由于慢性心肌梗死时心肌细胞间存在较为明确的牵拉，故本研究探讨了在大鼠体内应用链霉素是否可以抑制慢性心肌梗死大鼠心脏牵张诱导的电生理改变。 创新要点 2 首次探讨了在大鼠体内应用链霉素对慢性心梗时心脏机械电反馈现象的影响。 研究方法 2 60只Wistar大鼠随机分为4组：对照组（ n =15）、链霉素组（ n =15）、心梗组（ n =15）和心梗＋链霉素组（ n =15）。结扎左前降支（LAD）8周制备慢性心梗模型，术后肌注链霉素（180 mg/(kg∙d)）7天后，钳夹主动脉5秒牵张心脏，观察牵张效应包括90%单相动作电位时程（MAPD 90 ）、室性期前收缩（PVB）、室性心动过速（VT）等。 重要结论 2 研究结果发现牵张使得对照组（(50.27±5.61) ms vs. (46.27±4.51) ms, P < 0.05）和心梗组（(65.47±6.38) ms vs. (57.47±5.76) ms, P < 0.01）大鼠心脏MAPD90缩短。链霉素可抑制牵张引起的正常（(46.27±4.51) ms vs. (49.53±3.52) ms, P < 0.05）和梗死心肌（(57.47±5.76) ms vs. (61.87±5.33) ms, P < 0.05）MAPD90的缩短（见图1）。牵张后心梗组大鼠心肌PVB（7.93±1.66 vs. 1.80±0.86, P < 0.01）和VT（7 vs. 1, P < 0.05）的发生较对照组增多。链霉素可抑制正常（0.93±0.59 vs. 1.80±0.86, P < 0.05）和梗死心肌（5.40±1.18 vs. 7.93±1.66, P < 0.01）PVB的发生。以上结果表明，牵张诱导慢性梗死心肌出现MAPD 90 的改变并产生心律失常。在大鼠体内应用链霉素可降低PVB的发生但对VT无影响。因此，牵张激活离子通道可能参与到慢性心梗的机械电反馈中，同时可能有其他机制参与到牵张诱导的VT中。 Arrhythmia Mechanoelectric feedback Monophasic action potential Myocardial infarction Streptomycin 心律失常 机械电反馈 单相动作电位 心肌梗死 链霉素 Introduction 1 There is a close relationship between malignant ventricular arrhythmias and myocardial infarction (MI) (Haugaa et al., 2010 2010 ), which leads to high cardiovascular mortality (Wang, 2012 2012 ). It is well recognized that mechanical restitution and regional inhomogeneity in contractility act as foci for arrhythmias (Thygesen and Uretsky, 2004 2004 ; Ashikaga et al., 2005 2005 ) through a process known as mechanoelectric feedback (MEF). In chronic MI, scar tissue is surrounded by normal or ischemic myocardium, and greater stretch occurs than in normal myocardium (Bertini et al., 2010 2010 ). Previous studies also verified that MEF can be increased by chronic MI (Kiseleva et al., 2000 2000 ), contributing to the appearance of arrhythmias. We inferred that electrophysiological changes induced by stretch in normal hearts, shortened action potential duration (APD), the occurrence of after-depolarization, and premature beats (Kiseleva et al., 2000 2000 ; Ravens, 2003 2003 ; Taggart and Lab, 2008 2008 ) might be observed in chronically infarcted myocardium. Many studies have demonstrated that stretch-activated ion channels (SACs) have a crucial role to perform in MEF, though details of the mechanism are unclear (Garan et al., 2005 2005 ; Lab, 2006 2006 ). Streptomycin (SM), a blocker of SACs, has been known to inhibit the activities of SACs in single cell, tissue, and intact preparations in various species (Lab, 2006 2006 ). It can decrease the occurrence of arrhythmias induced by changes in ventricular wall-stress in isolated rat hearts (Salmon et al., 1997 1997 ). Eckardt et al. ( 2001 2001 ) studied Langendorff-perfused rabbit hearts and found that SM (200 μmol/L) could inhibit the shortened repolarization induced by stretching. The dominant frequency of ventricular fibrillation (VF) induced by stretching decreases following SM treatment in rabbit hearts (Trapero et al., 2008 2008 ). SM also prevents stretch-related vulnerability to atrial fibrillation (Ninio and Saint, 2008 2008 ). In hearts from hypertensive rats, Kim et al. ( 2012 2012 ) recently found that 100 μmol/L SM could reduce stretch-induced ectopic heartbeats by increasing the threshold for stretch-induced arrhythmias. However, the effect of blocking of SACs with SM has seldom been observed in vivo , and results are often contradictory. Cooper and Kohl ( 2005 2005 ) reported that SM could not block chronotropy in the spontaneous pacemaking rate induced by stretching, and further questioned the in situ utility of SM for acute blocking of mechanosensitive mechanisms. Garan et al. ( 2005 2005 ) found that SM reduced ST segment elevation following impact in swine but did not reduce the frequency of VF. Using skeletal muscle, Yeung et al. ( 2005 2005 ) and Spangenburg and McBride ( 2006 2006 ) found that oral SM in vivo could block the activities of SACs in the rat and mouse, respectively. However, there has been no analogous study on myocardium. The aim of this study was to observe the effect of stretching on the monophasic action potential (MAP) and the effect of the application of SM in vivo on electrophysiological changes in chronically infarcted rat hearts. Materials and methods 1 Preparation of MI model 2 The study was performed in accordance with the rules of The Care and Use of Laboratory Animals issued by the US National Institute of Health (NIH Publication No. 85-23, revised in 1985). Sixty Wistar rats (regardless of their genders, 180–224 g) were chosen for the experiment. Each rat, anaesthetized by intraperitoneal injection using sodium pentobarbital (40–50 mg/kg) and heparin (1000 U/kg), was intubated and then connected to a respirator. Artificial respiration was provided during the whole surgical process (breathing rate 60 min −1 , tidal volume 30 ml/100 mg). Electrocardiograms (ECG; limb leads including I, II, III, aVR, aVL, aVF) were recorded from electrodes attached to the limbs of each rat. Briefly, MI was obtained by ligating the left anterior descending branch (LAD) of the coronary artery. First, the heart was exteriorized between the 3rd and 4th costal bones of the left sternal border. Second, the LAD was ligated between the pulmonary conus and the left auricle. Successful ligature of the LAD was verified by regional myocardial cyanosis and ST elevation in the ECG. Third, the heart was replaced and the cut was stitched. Sham-operated animals were operated following the procedure mentioned above, but without ligation of the LAD. The surviving rats were kept in a cage and fed with a full diet and water. Sham-operated animals were divided at random into two groups: a control group ( n =15) in which experiments were carried out after 8 weeks and an SM group ( n =15) in which after 7 weeks, the rats were injected intramuscularly with SM (Merro Pharmaceuticals Companies; 180 mg/(kg·d)) for 7 d. Experiments were then conducted. MI animals were also divided into two groups: an MI group ( n =15) in which experiments were carried out 8 weeks after ligature of the LAD and an MI+SM group ( n =15) in which, after ligation of the LAD for 7 weeks, the rats were injected intramuscularly with SM (180 mg/(kg·d)) for 7 d. Experiments were then conducted. Recording 2 Each animal was anaesthetized and ventilated as mentioned above. ECG was recorded during the whole experiment. The right common carotid artery was dissociated. A catheter was connected to a pressure transducer (YP500, Gaobeidian, China), which was inserted into the left ventricle (LV) via the right common carotid artery and aorta by catheterization to measure the pressure of the ventricle. The distance between the end of the catheter and the transducer was minimized to decrease system dampening. Thoracotomy was performed. The heart and aortic arch were revealed. A suction electrode, placed on the anterior wall of the LV, was used to detect LV MAP (Fu et al., 2007 2007 ). Protocols 2 After stabilization for 15 min, the heart was stretched by an occlusion of the aortic arch for 5 s, followed by unclamping of the aortic arch. The 90% monophasic action potential duration (MAPD 90 ), LV pressure, premature ventricular beats (PVBs), and ventricular tachycardia (VT) were monitored during 5 s of stretching. Data analysis 2 The measurement and analysis of MAPD 90 (in ms) were conducted according to the criteria of Fu et al. ( 2007 2007 ). Every five beats, one MAP was analyzed and then averages were calculated. Stretch-induced arrhythmias (SIAs) were defined according to the guidelines of the Lambeth Convention (Curtis et al., 2013 2013 ). Data were analyzed using SPSS 13.0 (Statistical Package for the Social Sciences 13.0, SPSS Company, USA) by an independent University-based statistician. Quantitative data, expressed as mean±standard deviation (SD), were compared with analysis of variance (ANOVA). A χ 2 test was used for qualitative data. P < 0.05 was considered statistically significant. Results 1 Effect of stretching on MAPD 90 2 During the occlusion of the aortic arch, the MAPD 90 decreased, compared with the basal condition in the control group ((50.27±5.61) ms vs. (46.27±4.51) ms, P < 0.05) and in the MI group ((65.47±6.38) ms vs. (57.47±5.76) ms, P < 0.01) (Fig. 1 1 ). The MAPD 90 increased significantly compared with the control groups after ligation of the LAD ((65.47±6.38) ms vs. (50.27±5.61) ms, P < 0.01) and during stretching ((57.47±5.76) ms vs. (46.27±4.51) ms, P < 0.01) (Fig. 1 1 ). MAPD 90 decreased in the control group during stretching ( * P < 0.05) and in the MI group ( ** P < 0.01), compared with that under basic conditions. SM had no influence on MAPD 90 in either normal or infarcted rat hearts under basic conditions, but SM did inhibit the decrease in MAPD 90 induced by stretching ( Δ P < 0.05, ΔΔ P < 0.01, compared with the control group; # P < 0.05, compared with the MI group). Data are expressed as mean±SD ( n =15) Effect of SM on MAPD 90 changes during stretching 2 After the treatment with SM, the MAPD 90 showed no significant changes from basal conditions either in normal ((50.27±5.61) ms vs. (50.33±3.62) ms, P> 0.05) or infarcted rat hearts ((65.47±6.38) ms vs. (63.20±6.32) ms, P > 0.05) (Fig. 1 1 ). However, SM inhibited the stretch-induced decrease in MAPD 90 during the occlusion of the aortic arch, both in the normal (compared with the basal conditions, (49.53±3.52) ms vs. (50.33±3.62) ms, P > 0.05) and MI hearts (compared with the basal conditions, (61.87±5.33) ms vs. (63.20±6.32) ms, P > 0.05). SM partly reversed the decrease in MAPD 90 induced by stretching in the normal hearts ((49.53±3.52) ms vs. (46.27±4.51) ms, P < 0.05) and in the infarcted rat hearts ((61.87±5.33) ms vs. (57.47±5.76) ms, P < 0.05) (Fig. 1 1 ). Effect of SM on SIAs 2 The PVBs appeared during the occlusion of the aorta. The number of PVBs was counted during the 5 s of occlusion of the aorta. The incidence of PVBs in the control group was observed during stretching (1.80±0.86). After ligation of the LAD for eight weeks, the incidence showed a marked and significant increase (7.93±1.66 in the MI group vs. 1.80±0.86 in the control group, P < 0.01). SM obviously reduced the number of PVBs caused by the occlusion of the aorta (1.80±0.86 vs. 0.93±0.59 in normal hearts, P < 0.05; 7.93±1.66 vs. 5.40±1.18 in infarcted hearts, P < 0.01) (Table 1 1 ). Signal collecting systems recorded the MAP figures (Fig. 2 2 ). After ligation of the left anterior descending artery for eight weeks, the number of PVBs obviously increased during the occlusion of the aortic arch for 5 s ( ** P < 0.01). The occurrence of PVBs significantly decreased with the use of SM, both in normal ( * P < 0.05) and infarcted hearts ( Δ P < 0.01). Data are expressed as mean±SD ( n =15) Group Number of PVBs  Control 1.80±0.86  SM 0.93±0.59 *  MI 7.93±1.66 **  MI+SM 5.40±1.18 Δ Upper figure: left ventricular pressure (LVP); Middle figure: MAP; Lower figure: ECG. (a) The occurrence of premature ventricular beats (PVBs) (thick arrows) during stretching in normal hearts; (b) Streptomycin (SM) inhibited the appearance of PVBs induced by stretching; (c) The number of PVBs increased significantly after ligation of the left anterior descending artery for eight weeks, and ventricular tachycardia (arrows with open hole) also occurred; (d) The occurrence of arrhythmias (arrows with dotted line) was reduced by pretreatment with SM During the occlusion of the aortic arch for 5 s, the number of VT in the control group was 1, whereas it increased to 7 in the MI group. After treatment with SM, the number of VT decreased to 0 in the SM group and to 3 in the MI+SM group. The incidence of VT was higher than that in the control group ( P < 0.05). SM decreased the occurrence of VT, but there was no significant difference between incidence in the MI+SM group and the MI group ( P > 0.05) (Table 2 2 ). The number of hearts with VT increased with stretching after ligation of the left anterior descending artery for eight weeks ( * P < 0.05). SM decreased the occurrence of VT, but the difference was not significant ( P > 0.05) Group Number of hearts with VT Number of hearts without VT  Control 1 14  SM 0 15  MI 7 * 8  MI+SM 3 12 Discussion 1 The present study found that the application of SM in vivo could inhibit changes in MAPD 90 and decrease the incidence of PVBs induced by stretching of chronically infarcted rat hearts. However, SM did not reduce the occurrence of VT, indicating the involvement of SACs in the genesis of stretch-induced PVBs in chronic MI, but suggesting a more complicated situation for stretch-induced VT. Changes in MAPD 90 and arrhythmias induced by stretching 2 Changes in MAPD caused by transiently increasing LV pressure have been reported in the normal myocardium of many species (Reiter et al., 1997 1997 ; Takagi et al., 1999 1999 ; Lerman et al., 2001 2001 ). Consistent with the results of earlier studies, the MAPD 90 of the LV was shortened during transient aortic occlusion in this study. Furthermore, we found that the stretch-induced decrease in MAPD 90 in vivo also had happened in the chronic MI rat hearts. By using a slice from the LV after MI treatment for five weeks, Kiseleva et al. ( 2000 2000 ) found that the sensitivity of the membrane potential and depolarization to stretch increased. Fu et al. ( 2007 2007 ) verified that the phenomenon of MEF increased in acute myocardium infarction (AMI) as well. The contraction force of ischaemic and infarcted myocardium was lower than that of surrounding normal myocardium after MI. So, stretch exists between the normal and ischemic myocardia. Likewise, stretch also exists between the infarcted and ischemic myocardia in chronic MI. In the present study, more PVBs and VT occurred in infarcted myocardium with occlusion of the aorta, which is consistent with previous results (Horner et al., 1996 1996 ). Effects of the application of SM in vivo on MAPD 90 2 In single cardiomyocytes (Belus and White, 2003 2003 ) and multicellular preparations (Eckardt et al., 2000 2000 ; Spangenburg and McBride, 2006 2006 ), SM has been verified to be an effective blocker of SACs. This study confirmed that the stretch-induced decrease in MAPD 90 in chronic MI could be pharmacologically inhibited by an SAC blocker. SM had no effect on the MAPD 90 under basic conditions, but effectively inhibited the shortening of the MAPD 90 induced by transient aortic occlusion in both normal and chronically infarcted hearts. Based on these results and the characteristics of MEF, we inferred that: (1) in chronic MI, the activities of SACs were involved in the stretch-induced changes in the MAPD 90 ; (2) treatment with SM in vivo can inhibit the activities of SACs. Effects of the application of SM in vivo on SIAs 2 SM showed different effects on PVBs and VT. SM decreased the occurrence of PVBs caused by stretching. The Ca 2+ cycle and the activities of SACs are the main mechanisms of SIAs (Lab, 1996 1996 ). In short, the activities of SACs during stretching caused an increase in intracellular Ca 2+ ([Ca 2+ ] i ), which leads to after-depolarization and subsequent triggered activity (Fu et al., 2007 2007 ). The mechanism of the anti-arrhythmia effect of SM might be that by blocking SACs, it inhibits the increase in [Ca 2+ ] i . On the other hand, SM did not alter the occurrence of VT induced by aortic occlusion. There may have been several possible reasons for this: (1) the lack of a significant difference in this study may have been because of the small sample size; (2) absorption efficiency may have varied among different tissues following the application of SM in vivo , causing our results to differ from those of previous studies (Yeung et al., 2005 2005 ; Spangenburg and McBride, 2006 2006 ); (3) besides SACs, a more complicated mechanism may be involved in stretch-induced VT. Conclusions 1 Stretch-induced MAPD 90 changes and arrhythmias via MEF were observed in chronically infarcted myocardium. The use of SM in vivo decreased the incidence rate of PVBs but not VT, suggesting the involvement of SACs in MEF but that there might be other mechanisms involved in the formation of VT in chronically infarcted myocardium. The results of our study revealed increased MEF in chronic MI and the effectiveness of SM in vivo in minimizing certain electrophysiological changes during stretching. 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DOI: 10.1631/jzus.B1201010 http://doi.org/10.1631/jzus.B1201010 . Progress and challenges in the cardiovascular field EW Yeung , NP Whitehead , TM Suchyna , 等 . Effects of stretch-activated channel blockers on [Ca 2+ ] i and muscle damage in the mdx mouse . J Physiol , 2005 . 562 ( Pt 2 ): 367 - 380 . 15528244 DOI: 10.1113/jphysiol.2004.075275 http://doi.org/10.1113/jphysiol.2004.075275 . Effects of stretch-activated channel blockers on [Ca2+]i and muscle damage in the mdx mouse The authors thank Prof. Shu-xue LI (Heilongjiang University of Traditional Chinese Medicine, Harbin, China) for some reviews on technology. Compliance with ethics guidelines Jun-xian CAO, Lu FU, Qian-ping GAO, Rong-sheng XIE, and Fan QU declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed. 10.1631/jzus.B1300297 Project supported by the National Natural Science Foundation of China (No. 81301343) 2013-11-21 2014-05-22 2014-04-15 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2014 2014 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 06 15