心肌内向整流钾电流激动剂扎考比利对腹主动脉缩窄大鼠心功能和心肌纤维化的作用

The Effect of IK1 Channel Agonist Zacopride on Cardiac Function and Myocardial Fibrosis in Rats Subjected to Abdominal Aorta Constriction

目的:研究心肌内向整流钾电流(Ik1)激动剂扎考比利对腹主动脉缩窄后大鼠心功能及心肌纤维化的改善作用。方法:腹主动脉缩窄造成大鼠压力超负荷心室重构模型,将建模成功的80只大鼠通过随机数字表分为模型组、扎考比利组、氯座组、扎考比利+氯喹组(每组20只),后三组依次预防性给予扎考比利、気阻断剂氯座、扎考比利+氯喹。另设假手术组(n=10),开腹后只挂线,不结扎。连续给药8周后,采用血流动力学指标评价各组大鼠心功能,放射免疫学方法测定血浆B型利钠肽(BNP)和肿瘤坏死因子-α(TNF-α)水平,马松染色观察心肌间质胶原沉积,免疫组织化学法测定心肌组织I型、ID型胶原的表达并计算胶原I型/ ID型胶原比值,逆转录聚合酶链反应法检测心肌组织转化生长因子-β1 |( TGF-β1)、Smad3和Smad7信使RNA ( mRNA)表达。结果:与模型组相比,扎考比利组大鼠左心室收缩压(LVSP)、左心室压力上升最大速率(+dP/dtmax)、左心室压力下降最大速率(-dP/dtmax)均显著升高,左心室舒张末期压力(LVEDP)显著降低,血浆BNP和TNF-a水平显著降低,心肌间质胶原面积明显减小,I型、ID型胶原表达下降,且I型/ID型胶原比值显著降低,心肌组织TGF-P,.Smad3 mRNA表达明显降低,Smad7 mRNA表达明显升高,差异均有统计学意义(P均<0.05 )o氯座组和扎考比利+氯座组上述各项指标与扎考比利组相比,差异均有统计学意义(P均<0.05 ),变化趋势与扎考比利组和模型组比较的上述结果相反。结论:扎考比利能够明显改善腹主动脉缩窄后大鼠的心功能与心肌纤维化程度,其机制可能与TGF-pySmads信号通路有关。

Objectives: To investigate the effect of IK1 channel agonist zacopride on cardiac function and myocardial fibrosis in rats subjected to abdominal aorta constriction. Methods: Pressure overload was induced in male SD rats by the abdominal aorta constriction (AC). AC rats were intraperitoneally administered with saline, zacopride, chloroquine, or zacopride+chlorquine (n=20 each) for 8 weeks. Another 10 rats underwent similar surgical procedure without AC served as sham group. Cardiac function was assessed by hemodynamic analysis. The plasm contents of BNP and TNF-a were determined by radioimmunoassay. The collagen area was determined with Masson staining. Type I collagen and type III collagen were determined by immunohistochemistry and the ratio of collagen I/III was calculated. The myocardial mRNA expression of TGF-pb Smad3 and Smad7 was detected by RTPCR. Results: Compared with the saline treated Model group, zacopride improved cardiac function as presented bysignificantly increased LVESP and 士dP/dg^ values and significantly reduced LVEDP (all P<0.05). The plasm concentration of BNP ([28& 1±15.6] ng/L) and TNF-a ([48.9±2.3] ng/ml) were also significantly decreased in the zacopride group compared with the Model group ([412.4±19.6] ng/L,[59.8±4.7] ng/ml, all P<0.05). Collagen deposition was attenuated, collagen I and collagen III expression was downregulated and the ratio of collagen l/III was reduced in the zacopride group as compared with the Model group (all P<0.05). Moreover, the expression of TGF-卩]mRNA (1.89±0.16), Smad3 mRNA (3.65±0.76) were significantly decreased, Smad7 mRNA (1.79±0.33) was significantly increased in zacopride group than in Model group (3」2±0.21, 5.66±0.54, 1.01 ±0.0& all P<0.05). Above effects observed in zacopride group could be significantly blocked by cotreatment with chloroquine. Con elusions: Zacopride can improve the cardiac functio n and attenuate myocardial fibrosis in rats subjected to abdominal aorta constriction, these effects may be mediated through modulating the TGF■卩】/Smads signal pathway.