Concomitant Endothelin Receptor Subtype-A Blockade During the Progression of Pacing-Induced Congestive Heart Failure in Rabbits

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Abstract
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.