BENEFICIAL-EFFECTS OF LONG-TERM SELECTIVE ENDOTHELIN TYPE-A RECEPTOR BLOCKADE IN CANINE EXPERIMENTAL HEART-FAILURE

Objectives: We examined the effects of chronic type A endothelin recep tor (ETA) blockade in a dog model of pacing-induced cardiomyopathy. Me thods: Eight dogs received an ETA antagonist, LU 135252 (50 mg/kg oral ly daily) and nine dogs received a matching placebo starting at day th ree of pacing and continued for the remainder of the three weeks of pa cing. Results: In the placebo group, the mean pulmonary artery pressur e and left ventricular end diastolic pressure increased from 16+/-3 an d 8+/-2 mmHg, respectively, at baseline to 40+/-11 and 34+/-7 mmHg, re spectively, at two weeks (both p<0.001 versus baseline). Cardiac outpu t declined from 3.5+/-0.7 to 1.9+/-0.6 l/min (p<0.001). In the treatme nt group, LU 135252 attenuated the increase in mean pulmonary artery a nd left ventricular end diastolic pressure (16+/-3 and 9+/-1 mmHg at b aseline to 29+/-3 and 27+/-3 mmHg, respectively, at two weeks (p<0.001 ), and the decline in cardiac output (3.2+/-0.3 to 2.6+/-0.8 l/min, p< 0.01; p<0.05 versus placebo for the three parameters). Systemic and pu lmonary vascular resistance increased only in the placebo group. Left ventricular end-diastolic volume increased to a similar degree. Howeve r, LU 135252 attenuated the increase in plasma norepinephrine level (p lacebo, 1.2+/-0.5 to 3.7+/-1.9 pmol/l; treatment, 0.8+/-0.3 to 2.4+/-0 .6 pmol/l; both p<0.001 versus baseline; p<0.05 versus placebo). Concl usion: Our results suggest that endothelin-l plays a role in the hemod ynamic perturbations in canine pacing-induced cardiomyopathy. The favo urable hemodynamic effects without concomitant aggravation of neurohor monal activation suggests that ETA receptor blockade may be beneficial in the treatment of heart failure. (C) 1998 Elsevier Science B.V. All rights reserved.