Endothelin type A receptor blockade attenuates aorto-caval fistula-induced heart failure in rats with angiotensin II-dependent hypertension

Objective: Evaluation of the effect of endothelin type A
(ETA) receptor blockade on the course of volume-overload
heart failure in rats with angiotensin II-dependent
hypertension.
Methods: Ren-2 renin transgenic rats (TGR) were used as
a model of hypertension. Heart failure was induced by
creating an aorto-caval fistula (ACF). Selective ETA receptor
blockade was achieved by atrasentan. For comparison,
other rat groups received trandolapril, an angiotensinconverting
enzyme inhibitor (ACEi). Animals first
underwent ACF creation and 2 weeks later the treatment
with atrasentan or trandolapril, alone or combined, was
applied; the follow-up period was 20 weeks.
Results: Eighteen days after creating ACF, untreated TGR
began to die, and none was alive by day 79. Both atrasentan
and trandolapril treatment improved the survival rate,
ultimately to 56% (18 of 31 animals) and 69% (22 of 32
animals), respectively. Combined ACEi and ETA receptor
blockade improved the final survival rate to 52% (17 of 33
animals). The effects of the three treatment regimens on the
survival rate did not significantly differ. All three treatment
regimens suppressed the development of cardiac
hypertrophy and lung congestion, decreased left ventricle
(LV) end-diastolic volume and LV end-diastolic pressure, and
improved LV systolic contractility in ACF TGR as compared
with their untreated counterparts.
Conclusion: The treatment with ETA receptor antagonist
delays the onset of decompensation of volume-overload
heart failure and improves the survival rate in hypertensive
TGR with ACF-induced heart failure. However, the addition
of ETA receptor blockade did not enhance the beneficial
effects beyond those obtained with standard treatment
with ACEi alone.
Keywords: endothelin system, hypertension, Ren-2 renin
transgenic rat, renin–angiotensin system, volume-overload
heart failure
Abbreviations: ACE, angiotensin-converting enzyme;
ACF, aorto-caval fistula; ACEi, angiotensin-converting
enzyme inhibitor; ANG II, angiotensin II; ANG 1–7,
angiotensin-(1–7); (þdP/dt)max, maximum rates of pressure
rise; (dP/dt)max, maximum rates of pressure fall; ESPVR,
end-systolic pressure–volume relationship; ETA, endothelin
type A; ET-1, endothelin 1; HanSD, Hannover Sprague-
Dawley rats; LV, left ventricle; LVEDP, left ventricle enddiastolic
pressure; LVEDV, left ventricle end-diastolic
volume; PRSW, preload recruitable stroke work; RAAS,
renin–angiotensin–aldosterone system; RV, right ventricle;
SNS, sympathetic nervous system; TGR, Ren-2 renin
transgenic rats; TPR, total peripheral resistance