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(Circulation. 1997;96:2397-2406.)
© 1997 American Heart Association, Inc.

Articles

Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure

II. Effects on Myocyte Contractile Processes

Francis G. Spinale, MD, PhD; Rupak Mukherjee, PhD; Julie P. Iannini, BS; Steve Whitebread, BS; Latha Hebbar, MD; Mark J. Clair, BS; D. Mark Melton, BS; Montgomery H. Cox, BS; Patrick B. Thomas, BS; ; Marc de Gasparo, MD

From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, and the Pharmaceutical Division, Novartis, Basel, Switzerland (S.W., M. de G.).

Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery and Physiology, Medical University of South Carolina, Charleston, SC 29425.

Background 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.

Methods and Results 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 · kg^-1 · 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 · kg^-1 · 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 µm/s, P<.05) and remained reduced with AT₁ Ang II receptor blockade and rapid pacing (28.0±0.5 µm/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 µm/s, respectively, P<.05). Myocyte ß-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.

Conclusions 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.

Key Words: heart failure • angiotensin • calcium channels • cardiovascular disease • myocardium

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