MODULATION OF THE RENIN-ANGIOTENSIN PATHWAY THROUGH ENZYME-INHIBITIONAND SPECIFIC RECEPTOR BLOCKADE IN PACING-INDUCED HEART-FAILURE .2. EFFECTS ON MYOCYTE CONTRACTILE PROCESSES

Background The goal of this study was to determine the effects of ACE inhibition alone, AT(1) angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT(1) Ang II receptor blockade in a model of con gestive heart failure (CHF) on isolated LV myocyte function and fundam ental components of the excitation-contraction coupling process. Metho ds and Results Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n = 9), (2) concomitant ACE I (benazeprilat, 0.187 mg.kg(-1).d(-1)) and rapid pacing (n = 9), (3) concomitant AT(1) Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n = 9), (4) concomitant ACEI and AT(1) Ang II receptor b lockade (benazeprilat/valsartan, 0.05/3 mg.kg(-1).d(-1)) and rapid pac ing (n = 9), and (5) sham controls (n = 10). LV myocyte shortening vel ocity was reduced with chronic rapid pacing compared with control (27. 2 +/- 0.6 versus 58.6 +/- 1.2 mu/s, P < .05) and remained reduced with AT(1) Ang II receptor blockade and rapid pacing (28.0 +/- 0.5 mu m/s, P < .05). Myocyte shortening velocity increased with ACEI or combinat ion treatment compared with rapid pacing only (36.9 +/- 0.7 and 42.3 /- 0.8 mu m/s, respectively, P < .05). Myocyte beta-adrenergic respons e was reduced by > 50% in both the rapid pacing group and the AT(1) An g II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca2+ channel density and the rel ative abundance of sarcoplasmic reticulum Ca2+ ATPase density were red uced with rapid pacing and returned to control levels in the combined ACEI and AT(1) Ang II blockade group. Conclusions The unique findings of this study were twofold. First, basic defects in specific component s of the myocyte excitation-contraction coupling process that occur wi th CHF are reversible. Second, combined ACEI and AT(1) Ang II blockade may provide unique benefits on myocyte contractile processes in the s etting of CHF.