The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure.
OBJECTIVE
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 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/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.
Saad
D
D
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
Mukherjee
R
R
Thomas
P B
PB
Iannini
J P
JP
Basler
C G
CG
Hebbar
L
L
O
S J
SJ
Moreland
S
S
Webb
M L
ML
Powell
J R
JR
Spinale
F G
FG
D000818:Animals; D002304:Cardiac Pacing, Artificial; D018450:Disease Progression; D065128:Endothelin Receptor Antagonists; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D018377:Neurotransmitter Agents / Q000097:blood; D044022:Receptor, Endothelin A; D013552:Swine; D013997:Time Factors; D016277:Ventricular Function, Left
D065128:Endothelin Receptor Antagonists; D018377:Neurotransmitter Agents; D044022:Receptor, Endothelin A