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

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 ETA 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 ETA 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 ETA 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 ETA blockade group, plasma endothelin increased threefold compared with RVP values. Isolated myocyte shortening velocity declined after RVP (42 +/- 13 versus 72 +/- 10 microns/s, P < .05) compared with controls but was normalized with RVP plus ETA blockade (77 +/- 16 microns/s). Myocyte inotropic response to extracellular Ca2+, beta-receptor stimulation, and ET-1 was reduced in the RVP group and returned to control levels with RVP and concomitant ETA receptor blockade. CONCLUSIONS: The results from this study suggest that chronically elevated ET-1 levels and subsequent activation of the ETA receptor play a direct and contributory role in the progression of the CHF process. Thus, specific ETA receptor blockade may provide a new and useful therapeutic modality in the setting of CHF.