Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure.
OBJECTIVE
We examined the effects of chronic type A endothelin receptor (ETA) blockade in a dog model of pacing-induced cardiomyopathy.


METHODS
Eight dogs received an ETA antagonist, LU 135252 (50 mg/kg orally daily) and nine dogs received a matching placebo starting at day three of pacing and continued for the remainder of the three weeks of pacing.


RESULTS
In the placebo group, the mean pulmonary artery pressure and left ventricular end diastolic pressure increased from 16 +/- 3 and 8 +/- 2 mmHg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mmHg, respectively, at two weeks (both p < 0.001 versus baseline). Cardiac output declined from 3.5 +/- 0.7 to 1.9 +/- 0.6 l/min (p < 0.001). In the treatment group, LU 135252 attenuated the increase in mean pulmonary artery and left ventricular end diastolic pressure (16 +/- 3 and 9 +/- 1 mmHg at baseline 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 pulmonary vascular resistance increased only in the placebo group. Left ventricular end-diastolic volume increased to a similar degree. However, LU 135252 attenuated the increase in plasma norepinephrine level (placebo, 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).


CONCLUSIONS
Our results suggest that endothelin-1 plays a role in the hemodynamic perturbations in canine pacing-induced cardiomyopathy. The favourable hemodynamic effects without concomitant aggravation of neurohormonal activation suggests that ETA receptor blockade may be beneficial in the treatment of heart failure.
Moe
G W
GW
Terrence Donnelly Heart Centre, St Michael's Hospital, University of Toronto, Ontario, Canada.
Albernaz
A
A
Naik
G O
GO
Kirchengast
M
M
Stewart
D J
DJ
D000284:Administration, Oral; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004452:Echocardiography; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009638:Norepinephrine / Q000097:blood; D010666:Phenylpropionates / Q000008:administration & dosage* / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use; D011897:Random Allocation; D044022:Receptor, Endothelin A; D014655:Vascular Resistance / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan; D009320:Atrial Natriuretic Factor; D009638:Norepinephrine