Spinale F G, de Gasparo M, Whitebread S, Hebbar L, Clair M J, Melton D M, Krombach R S, Mukherjee R, Iannini J P, O S J
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
Circulation. 1997 Oct 7;96(7):2385-96. doi: 10.1161/01.cir.96.7.2385.
The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF).
Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) AT1 Ang II receptor blockade (valsartan, 3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (4) ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). In the pacing group, LV fractional shortening (LVFS) fell (13.4+/-1.4% versus 39.1+/-1.0%) and end-diastolic dimension (LVEDD) increased (5.61+/-0.11 versus 3.45+/-0.07 cm) compared with control (P<.05). With AT1 Ang II blockade and rapid pacing, LVEDD and LVFS were unchanged from pacing-only values. ACEI reduced LVEDD (4.95+/-0.11 cm) and increased LVFS (20.9+/-1.9%) from pacing-only values (P<.05). ACEI and AT1 Ang II blockade reduced LVEDD (4.68+/-0.07 cm) and increased LVFS (25.2+/-0.9%) from pacing only (P<.05). Plasma norepinephrine and endothelin increased by more than fivefold with chronic pacing and remained elevated with AT1 Ang II blockade. Plasma norepinephrine was reduced from pacing-only values by more than twofold in the ACEI group and the combination group. ACEI and AT1 Ang II receptor blockade reduced plasma endothelin levels by >50% from rapid-pacing values.
These findings suggest that the effects of ACEI in the setting of CHF are not solely due to modulation of Ang II levels but rather to alternative enzymatic pathways and that combined ACEI and AT1 Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems 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抑制剂（ACEI）、单独使用AT1血管紧张素（Ang）II受体阻滞剂以及联合使用ACEI和AT1 Ang II受体阻滞剂对左心室功能、全身血流动力学和神经激素系统活性的影响。
将猪随机分为5组：（1）快速心房起搏（240次/分钟）3周（n = 9）；（2）ACEI（苯那普利拉，0.187 mg·kg⁻¹·d⁻¹）加快速起搏（n = 9）；（3）AT1 Ang II受体阻滞剂（缬沙坦，3 mg·kg⁻¹·d⁻¹）加快速起搏（n = 9）；（4）ACEI和AT1 Ang II受体阻滞剂（苯那普利拉/缬沙坦，0.05/3 mg·kg⁻¹·d⁻¹）加快速起搏（n = 9）；（5）假手术对照组（n = 10）。与对照组相比，起搏组左心室短轴缩短率（LVFS）下降（13.4±1.4%对39.1±1.0%），舒张末期内径（LVEDD）增加（5.61±0.11对3.45±0.07 cm）（P<0.05）。使用AT1 Ang II阻滞剂并快速起搏时，LVEDD和LVFS与仅快速起搏时的值无变化。ACEI使LVEDD从仅快速起搏时的值降低（4.95±0.11 cm），LVFS增加（20.9±1.9%）（P<0.05）。ACEI和AT1 Ang II阻滞剂使LVEDD从仅快速起搏时的值降低（4.68±0.07 cm），LVFS增加（25.2±0.9%）（P<0.05）。慢性起搏使血浆去甲肾上腺素和内皮素增加超过五倍，AT1 Ang II阻滞剂时仍保持升高。ACEI组和联合用药组血浆去甲肾上腺素较仅快速起搏时的值降低超过两倍。ACEI和AT1 Ang II受体阻滞剂使血浆内皮素水平较快速起搏时的值降低>50%。
这些发现表明，ACEI在CHF情况下的作用并非仅归因于对Ang II水平的调节，而是归因于其他酶促途径，并且联合使用ACEI和AT1 Ang II受体阻滞剂可能为CHF情况下的左心室泵功能和神经激素系统提供独特的益处。
