Selective endothelin-A versus combined endothelin-A/endothelin-B receptor blockade in rat chronic heart failure.
BACKGROUND
The relative efficacy of endothelin-A (ET(A)) receptor blockade versus combined ET(A)-ET(B) receptor blockade in chronic heart failure (CHF) is still largely unknown.


RESULTS
We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ET(A) antagonist ABT-627 (5 mg x kg(-1) x d(-1)), the ET(B) antagonist A-192621 (30 mg x kg(-1) x d(-1)) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ET(A) blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ET(B) blockade). ET(A) and combined ET(A)-ET(B) blockade reduced systolic blood pressure to the same extent, whereas ET(B) blockade had no effect. In contrast, only combined ET(A)-ET(B) blockade significantly reduced heart rate. Both ET(A) and combined ET(A)-ET(B) blockade, but not ET(B) blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastolic and end-systolic volumes. However, all treatments (including ET(B) blockade) decreased LV collagen accumulation.


CONCLUSIONS
The chronic blockade of both ET(A) and ET(B) receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ET(A) receptor blockade alone. However, only combined ET(A)-ET(B) receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ET(A) or mixed ET(A)-ET(B) antagonists in CHF remains to be determined.
INSERM E9920, (IFRMP no 23) Rouen University Medical School, Rouen, France.
P
P
Mulder
H
H
Boujedaini
V
V
Richard
G
G
Derumeaux
J P
JP
Henry
S
S
Renet
J
J
Wessale
T
T
Opgenorth
C
C
Thuillez
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016277:Ventricular Function, Left / Q000187:drug effects
C120508:A 192621; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D003094:Collagen; D000077868:Atrasentan