MODULATION OF THE RENIN-ANGIOTENSIN PATHWAY THROUGH ENZYME-INHIBITIONAND SPECIFIC RECEPTOR BLOCKADE IN PACING-INDUCED HEART-FAILURE .1. EFFECTS ON LEFT-VENTRICULAR PERFORMANCE AND NEUROHORMONAL SYSTEMS

Background The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT(1) angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT(1) Ang II receptor blockade on LV func tion, systemic hemodynamics, and neurohormonal system activity in a mo del of congestive heart failure (CHF). Methods and Results Pigs were r andomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm ) for 3 weeks (n=9), (2) ACEI (benazeprilat, 0.187 mg.kg(-1).d(-1)) an d rapid pacing (n=9), (3) AT(1) Ang II receptor blockade (valsartan, 3 mg.kg(-1).d(-1)) and rapid pacing (n=9), (4) ACEI and AT(1) Ang II re ceptor blockade (benazeprilat/valsartan, 0.05/3 mg.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 3.4 5+/-0.07 cm) compared with control (P<.05). With AT(1) Ang II blockade and rapid pacing, LVEDD and LVFS were unchanged from pacing-only valu es. ACEI reduced LVEDD (4.95+/-0.11 cm) and increased LVFS (20.9+/-1.9 %) from pacing-only values (P<.05). ACEI and AT(1) Ang II blockade red uced LVEDD (4.68+/-0.07 cm) and increased LVFS (25.2+/-0.9%) from paci ng only (P<.05). Plasma norepinephrine and endothelin increased by mor e than fivefold with chronic pacing and remained elevated with AT(1) A ng II blockade. Plasma norepinephrine was reduced from pacing-only val ues by more than twofold in the ACEI group and the combination group. ACEI and AT(1) Ang II receptor blockade reduced plasma endothelin leve ls by >50% from rapid-pacing values. Conclusions These findings sugges t 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 pathw ays and that combined ACEI and AT(1) Ang II receptor blockade may prov ide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.