Background Plasma levels of endothelin-1 (ET-1) are increased in patients and animals with severe congestive heart failure (CHF). It remains unknown, however, whether ET-1 plays a direct and contributory role in the progression of CHF. Accordingly, the present project tested the hypothesis that chronic blockade of the ET A receptor would have direct and beneficial effects on left ventricular (LV) and myocyte function in a model of CHF. Methods and Results Global LV and isolated myocyte function were examined in rabbits in the following groups (12 per group): chronic rapid ventricular pacing (RVP; 400 bpm, 3 weeks), RVP and concomitant administration of the selective ET A receptor antagonist (PD 156707 24 mg/d), and sham controls. LV fractional shortening decreased after RVP (17±5 versus 42±3%) and end-diastolic dimension increased (2.36±0.44 versus 1.24±0.18 cm) compared with controls ( P <.05). With RVP plus ET A blockade, LV fractional shortening was increased (33±6%) and end-diastolic dimension decreased (2.02±0.30 cm) compared with RVP-only values ( P <.05). Plasma norepinephrine and endothelin increased twofold in the RVP group. In the RVP plus ET A blockade group, plasma endothelin increased threefold compared with RVP values. Isolated myocyte shortening velocity declined after RVP (42±13 versus 72±10 μm/s, P <.05) compared with controls but was normalized with RVP plus ET A blockade (77±16 μm/s). Myocyte inotropic response to extracellular Ca 2+ , β-receptor stimulation, and ET-1 was reduced in the RVP group and returned to control levels with RVP and concomitant ET A receptor blockade. Conclusions The results from this study suggest that chronically elevated ET-1 levels and subsequent activation of the ET A receptor play a direct and contributory role in the progression of the CHF process. Thus, specific ET A receptor blockade may provide a new and useful therapeutic modality in the setting of CHF.
Background —Release of growth hormone (GH), putatively through alterations in insulin growth factor-1 (IGF-1) levels, has been implicated to influence left ventricular (LV) myocardial structure and function. The objective of this study was to determine contributory mechanisms by which GH supplementation may influence LV function with the development of congestive heart failure (CHF). Methods and Results —Pigs were assigned to the following groups: (1) chronic pacing at 240 bpm for 3 weeks (n=10), (2) chronic pacing and GH supplementation (200 μg · kg −1 · d −1 , n=10), and (3) controls (n=8). GH treatment increased IGF-1 plasma levels by nearly 2.5-fold throughout the pacing protocol. In the untreated pacing CHF group, LV fractional shortening was reduced and peak wall stress increased. In the pacing CHF and GH groups, LV fractional shortening was higher and LV wall stress lower than untreated CHF values. Steady-state myocyte velocity of shortening was reduced with pacing CHF and was unchanged from CHF values with GH treatment. In the presence of 25 nmol/L isoproterenol, the change in myocyte shortening velocity was reduced in the untreated CHF group and increased in the GH-treated group. LV sarcoplasmic reticulum Ca 2+ -ATPase abundance was reduced with pacing CHF but was normalized with GH treatment. Conclusions —Short-term GH supplementation improved LV pump function in pacing CHF as a result of favorable effects on LV remodeling and contractile processes. Thus, GH supplementation may serve as a novel therapeutic modality in developing CHF.
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 function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF). Methods and Results 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 · kg −1 · d −1 ) and 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 receptor 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 3.45±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 values. 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 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 AT 1 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 AT 1 Ang II receptor blockade reduced plasma endothelin levels by >50% from rapid-pacing values. Conclusions 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 AT 1 Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.
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 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 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 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 AT 1 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 β-adrenergic response was reduced by >50% in both the rapid pacing group and the AT 1 Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca 2+ channel density and the relative abundance of sarcoplasmic reticulum Ca 2+ ATPase density were reduced 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 components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT 1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.
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