Nonselective ETA/ETB-receptor blockade increases systemic blood pressure of Bio 14.6 cardiomyopathic hamsters.
To examine the role of endothelin ETA and ETB receptors in congestive heart failure due to cardiomyopathy, the effect of chronic treatment with selective ETA- and ETB-receptor antagonists (atrasentan and A-192621, respectively), alone and in combination, was assessed on functional and biochemical parameters of 52-week-old Bio 14.6 cardiomyopathic hamsters. Compared with control animals, cardiomyopathic hamsters treated for 9 weeks with atrasentan showed no variation in MAP; however, selective ETB- and combined nonselective ETA- and ETB-receptor antagonists increased systemic blood pressure. After selective ETB-receptor blockade, plasma endothelin levels were augmented. Importantly, this increase was highly enhanced (more than 8-fold) by concomitant ETA-receptor antagonism. Furthermore, the left ventricle:body weight ratio of cardiomyopathic hamsters treated with A-192621, alone or in combination with atrasentan, was significantly increased. On the other hand, decreased left ventricular end-diastolic pressure was observed in cardiomyopathic hamsters after selective ETA- or combined nonselective ETA/ETB-receptor antagonism, while only selective ETA-receptor blockade reduced left ventricular endothelin levels. Our results suggest that, in congestive heart failure, ETB receptors are essential to limit circulating endothelin levels, which may argue for improved cardiac benefits after long-term treatment with highly selective ETA-receptor antagonists.
Honoré
Jean-Claude
JC
Department of Pharmacology, Faculty of Medicine and Health Sciences, Universite de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H5N4, Canada.
Carrier
Emilie
E
Fecteau
Marie-Hélène
MH
Tirapelli
Carlos R
CR
Bkaily
Ghassan
G
D'Orleans-Juste
Pedro
P
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D009202:Cardiomyopathies / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D006224:Cricetinae; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008647:Mesocricetus; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects
C120508:A 192621; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009566:Nitrates; D009573:Nitrites; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000077868:Atrasentan