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EXPERIMENTAL STUDIES

The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure

^a Division of Cardiothoracic Surgery, Charleston, South Carolina, USA
^* Bristol Myers Squibb Research Institute, Princeton, New Jersey, USA

Manuscript received December 11, 1997; revised manuscript received July 21, 1998, accepted July 24, 1998.

Address for correspondence: Dr. Francis G. Spinale, Cardiothoracic Surgery, Room 418 CSB, Medical University of South Carolina, Charleston, South Carolina 29425

Objectives. We sought to identify the effects of endothelin (ET) subtype-A (ET_A)) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility.

Background. Congested heart failure causes increased plasma levels of ET and ET_A receptor activation.

Methods. Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n = 7; 2) CHF/ET_A-High Dose: paced for 2 weeks then ET_A receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n = 6; 3) CHF/ET_A-Low Dose: pacing for 2 weeks then ET_A receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n = 6; and 4) Control: n = 8.

Results. Left ventricle fractional shortening decreased with CHF compared with control (12 ± 1 vs. 39 ± 1%, p < 0.05) and increased in the CHF/ET_A High and Low Dose groups (23 ± 3 and 25 ± 1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET_A receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET_A High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET_A blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32 ± 3 vs. 54 ± 3 µm/s, p < 0.05), was higher in the CHF/ET_A High Dose group (39 ± 1 µm/s, p < 0.05), and was similar to CHF values in the Low Dose group.

Conclusions. ET_A receptor activation may contribute to the progression of LV dysfunction with CHF.

Abbreviations and Acronyms   ß-receptor = beta-adrenergic receptor   CHF = congestive heart failure   ET = endothelin   ETA = endothelin receptor subtype A   LV = left ventricle

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