Acute effects of an endothelin-1 receptor antagonist bosentan at different stages of heart failure in conscious dogs.
OBJECTIVE
Inhibition by endothelin antagonist is a potential therapy in heart failure. However, the effect of endothelin inhibition during the development of heart failure has not been evaluated. The goal of our study was to examine the acute hemodynamic effects of the mixed endothelin receptor antagonist bosentan in the control state and at different stages of heart failure induced by right ventricular pacing (250 bpm) in conscious dogs.


METHODS
Nine dogs were chronically instrumented for the measurements of left ventricular pressure and its first derivative (dP/dt), cardiac output, left ventricular regional wall thickness and aortic pressure. Bosentan (3 mg/kg, i.v. bolus) and placebo were given at control, at 1 week of pacing (stage of left ventricular dysfunction with perserved cardiac output) and at 3 weeks of pacing (phase of heart failure with low cardiac output).


RESULTS
With the development of heart failure, baseline plasma endothelin level increased progressively. Placebo did not induce hemodynamic and plasma endothelin changes during the 30 min recording at any stage. At control, bosentan did not change hemodynamics. At 1 and 3 weeks of pacing, bosentan did not modify left ventricular myocardial function indices but reduced mean arterial pressure (by 7 +/- 2 and 8 +/- 1 mm Hg respectively, p < 0.005). Bosentan increased stroke volume at 3 weeks of pacing only.


CONCLUSIONS
Endothelin inhibition by endothelin antagonist bosentan, decreases aortic pressure in both early left ventricular dysfunction and in heart failure in contrast with the control state. In the phase of heart failure with low cardiac output, bosentan increases stroke volume. In the early left ventricular dysfunction, bosentan, by reducing arterial pressure, may limit the deterioration of cardiac function through a reduction of the workload imposed on the heart.
Choussat
R
R
INSERM U 400, Faculté de Médecine de Créteil, France.
Hittinger
L
L
Barbe
F
F
Maistre
G
G
Carayon
A
A
Crozatier
B
B
Su
J
J
D000818:Animals; D000077300:Bosentan; D002302:Cardiac Output / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D016232:Endothelins / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D011498:Protein Precursors / Q000097:blood; D013318:Stroke Volume / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D017725:Ventricular Pressure / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D013449:Sulfonamides; D014665:Vasodilator Agents; D000077300:Bosentan