Additional effects of endothelin receptor blockade and angiotensin converting enzyme inhibition in rats with chronic heart failure.
OBJECTIVE
To evaluate the acute effects of tezosentan, a new dual parenteral endothelin receptor antagonist, on hemodynamics in a rat model of chronic heart failure (CHF), and further investigated if the combination of tezosentan with the angiotensin converting enzyme (ACE) inhibitor, enalapril, had additive hemodynamic effect.


METHODS
Hemodynamics was measured in rats with CHF, induced by ligation of the left coronary artery.


RESULTS
At 3 to 5 weeks after myocardial infarction, rats developed CHF. This was evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP) with mean values of 23 to 26 mmHg, by a 30 % to 40 % reduction in left ventricular dp/dt(max) and by a more than 10 % decrease in mean arterial pressure (MAP) as compared to sham-operated rats. In CHF rats, acute intravenous administration of either tezosentan (10 mg . kg) or enalapril (1 mg . kg) markedly decreased MAP and LVEDP, without affecting heart rate or dp/dtmax. Tezosentan had additive effects on MAP and LVEDP when given with enalapril compared with tezosentan (P < 0.05) or enalapril (P < 0.05) alone. There were no significant changes in heart rate and dp/dtmax with the combination treatment compared with tezosentan- or enalapril-treated CHF rats.


CONCLUSIONS
Acute intravenous tezosentan improves cardiac hemodynamics and decreases LVEDP and afterload (MAP) without changes in heart rate and cardiac contractility dp/dtmax) in CHF rats. These favorable effects of tezosentan are similar to those of enalapril. Furthermore, the benefits of tezosentan are apparent in addition to ACE inhibition. Thus, tezosentan could be a useful therapeutic agent in the acute treatment of heart failure.
Qiu
C B
CB
Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China; Actelion Ltd, CH-4123 Allschwil, Switzerland. changbin.qiu@actelion.com
Qiu
C S
CS
Hess
P
P
Clozel
J P
JP
Clozel
M
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004357:Drug Synergism; D004656:Enalapril / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D006333:Heart Failure / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; C120582:tezosentan; D004656:Enalapril