Spinale F G, Mukherjee R, Iannini J P, Whitebread S, Hebbar L, Clair M J, Melton D M, Cox M H, Thomas P B, de Gasparo M
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
Circulation. 1997 Oct 7;96(7):2397-406. doi: 10.1161/01.cir.96.7.2397.
The goal of this study was to determine the effects of ACE inhibition alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process.
Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) concomitant AT1 Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n=9), (4) concomitant ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). LV myocyte shortening velocity was reduced with chronic rapid pacing compared with control (27.2+/-0.6 versus 58.6+/-1.2 microm/s, P<.05) and remained reduced with AT1 Ang II receptor blockade and rapid pacing (28.0+/-0.5 microm/s, P<.05). Myocyte shortening velocity increased with ACEI or combination treatment compared with rapid pacing only (36.9+/-0.7 and 42.3+/-0.8 microm/s, respectively, P<.05). Myocyte beta-adrenergic response was reduced by >50% in both the rapid pacing group and the AT1 Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca2+ channel density and the relative abundance of sarcoplasmic reticulum Ca2+ ATPase density were reduced with rapid pacing and returned to control levels in the combined ACEI and AT1 Ang II blockade group.
The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.
本研究的目的是确定在充血性心力衰竭（CHF）模型中，单独使用血管紧张素转换酶（ACE）抑制剂、单独使用血管紧张素Ⅱ1型（AT1）受体阻滞剂以及联合使用ACE抑制剂和AT1受体阻滞剂对离体左心室心肌细胞功能和兴奋 - 收缩偶联过程基本成分的影响。
将猪随机分为五组：（1）快速心房起搏（240次/分钟）3周（n = 9）；（2）同时使用ACE抑制剂（苯那普利拉，0.187 mg·kg⁻¹·d⁻¹）并进行快速起搏（n = 9）；（3）同时使用AT1受体阻滞剂（缬沙坦，3 mg/kg/d）并进行快速起搏（n = 9）；（4）同时使用ACE抑制剂和AT1受体阻滞剂（苯那普利拉/缬沙坦，0.05/3 mg·kg⁻¹·d⁻¹）并进行快速起搏（n = 9）；（5）假手术对照组（n = 10）。与对照组相比，慢性快速起搏可降低左心室心肌细胞缩短速度（27.2±0.6对58.6±1.2μm/s，P<0.05），并且在使用AT1受体阻滞剂并进行快速起搏时仍保持降低（28.0±0.5μm/s，P<0.05）。与仅进行快速起搏相比，使用ACE抑制剂或联合治疗可增加心肌细胞缩短速度（分别为36.9±0.7和42.3±0.8μm/s，P<0.05）。在快速起搏组和AT1受体阻滞剂组中，心肌细胞β-肾上腺素能反应均降低>50%，使用ACE抑制剂可改善25%，联合治疗可增加至54%。快速起搏会降低L型钙通道密度和肌浆网钙ATP酶密度的相对丰度，而在联合使用ACE抑制剂和AT1受体阻滞剂组中可恢复至对照水平。
本研究的独特发现有两点。第一，CHF时发生的心肌细胞兴奋 - 收缩偶联过程特定成分的基本缺陷是可逆的。第二，在CHF情况下，联合使用ACE抑制剂和AT1受体阻滞剂可能对心肌细胞收缩过程具有独特的益处。
