伊贝沙坦联合培哚普利治疗对压力负荷性心肌肥厚大鼠心肌钙调神经磷酸酶及钙泵的影响

Effects of Irbesartan and Perindopril on Calcineurin and Sarcoplasmic Reticulum Ca^(2+)-ATPase in Pressure Overload-induced Cadiac Hypertrophy in Rats

目的初步探讨钙调神经磷酸酶、钙泵和血管紧张Ⅱ素在大鼠压力负荷性心肌肥厚中的变化及伊贝沙坦和培哚普利联合应用对它们的影响。方法40只雄性SD大鼠随机分为5组,每组8只。除假手术组外,其余4组大鼠采用腹主动脉部分结扎法造成压力负荷性心肌肥厚模型,术后1周分别用下列药物开始灌胃:假手术组生理盐水2mL/kg.d,对照组生理盐水2mL/kg.d,伊贝沙坦组(20mg/kg.d)、培哚普利组(2mg/kg.d)及联合用药组(培哚普利2mg/kg.d,伊贝沙坦20mg/kg.d)。用药6周后测量左室质量指数(LVMI)、血浆和心肌AngⅡ、心肌钙调神经磷酸酶及钙泵活性的变化。结果联合用药组LVMI((2.14±0.12)显著低于对照组(2.99±0.16)及单用伊贝沙坦(2.36±0.13)或培哚普利组(2.39±0.16)(P<0.05),伊贝沙坦组血浆AngⅡ(伊贝沙坦:630±50.7比假手术:309±29.9,对照:310±36.8,培哚普利:288±36.9,联合用药:327±46.1,P<0.05)及心肌AngⅡ(伊贝沙坦:7.15±0.50比假手术:3.11±0.93,对照:5.04±0.35,培哚普利:3.21±0.34,联合用药:3.31±0.36,P<0.05)显著高于其他组,各用药组钙调神经磷酸酶活性显著低于对照组(假手术:0.44±0.04,培哚普利:0.51±0.05,伊贝沙坦:0.51±0.03,联合用药:0.49±0.04比对照:0.61±0.03,P<0.05),对照组心肌肌浆网钙泵活性显著降低(对照:3.6±0.69比假手术:6.85±0.88,培哚普利:4.51±0.58,伊贝沙坦:4.45±0.55,联合用药:5.63±0.61,P<0.05),联合用药组可明显增加钙泵活性至正常。相关分析显示LVMI与CaN呈显著正相关(r=0.80,P<0.01),与钙泵活性呈负相关(r=-0.726,P<0.01)。结论伊贝沙坦升高心肌AngⅡ而培哚普利对其无影响,两者均能降低心肌钙调神经磷酸酶活性,升高心肌钙泵活性,联合应用更有利于改善心肌肥厚。

Objective To study the effects of irbesartan and perindopril combination treatment on the changes of calcineurin（CaN） , sarcoplasmic reticulum Ca^2＋-ATPase（ SR Ca^2＋ -ATPase） and plasma and myocardium angiotensin Ⅱ （AngⅡ ） in pressure overload-induced cardiac hypertrophy in rats. Methods Forty male adult Sprague Dawley rats were divided into 5 groups： sham operation group and aortic banding groups. One week after operation, rats were gavaged with normal saline, perindopril, irbesartan or combination of perindopril and irbesartan. LVMI, plasma and tissue AngⅡ , CaN and SR Ca^2＋ -ATPase activity were determined at the end of 6 week treatment. Results LVMI（control.2.99±0.16 vs combination：2. 14±0.12,Irbesartan：2.36±0. 13,Perindopril：2.39±0.16）mg/g（P〈0.05）, CaN （control：0.61±0. 03 vs sham：0.44±0. 04 ,Perindopril：0. 51±0.05, Irbesartan：0.51±0.03, combination：0.49±0.04）A410nm/mg·pr（P〈0.05） activity were remarkably decreased after drug intervention which was most remarkable in the combination group. The levels of Ang Ⅱ in plasma（Irbesartan：630±50.7 vs sham：309±29.9, control.. 310±36.8, Perindopril： 288±36.9, combination： 327±46.10）pg/mL（P〈0.05） and myocardium（Irbesartan： 7. 15 ±0.50 vs sham： 3.11±0. 93, control.. 5.04±0.35, Perindopril： 3.21±0.34, combination：3.31±0.36） pg/mL（P〈0.05） were remarkably increased in irbesartan group. SR Ca^2＋- ATPase activity were increased after drug intervention（control：3.6±0.69 vs sham：6.85 ±0.88, Perindopril：4. 51±0.58, Irbesartan：4. 45±0. 55, combination：5.63±0.61）mmol Pi/g protein ·h（P〈0. 05）, especially in the combination group. LVMI was positively correlated with CaN（r=0.80, P〈0.01）, negatively correlated with SR Ca^2＋-ATPase（r=-0. 726, P〈0.01）. Conclusion Irbesartan increased AngⅡ in myocardium while perindopril did not. Both irbesartan and perindopril decrease CaN activity, increase SR Ca^2＋-ATPase activity. Irbesartan and perindopril combination treatment was shown to have better effects on regression of ventricular hypertrophy.