Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure.
The effects of endothelin (ET) receptor blockade on energy utilization in heart failure (HF) are unknown. We administered ET type A (ETA), ET type B (ETB), and ETA/ETB antagonists to isolated hearts from Dahl salt-sensitive (DS) rats with HF and controls. Contractile efficiency was assessed as slope-1 of myocardial O consumption (VO2)-pressure-volume area relation. In HF, ETA and ETA/ETB but not ETB blockade decreased the contractility index (Emax)(-15 +/- 3% and -17 +/- 2%, P < 0.05), excitation-contraction (E-C) coupling VO2 (-39 +/- 4% and -37 +/- 5%, P < 0.01), and efficiency (-15 +/- 4% and -17 +/- 2%, P < 0.05). Despite decreased efficiency, ETA and ETA/ETB blockade decreased total VO2 (-24 +/- 3% and -22 +/- 2%, P < 0.05). Na+/H+ exchanger inhibition decreased Emax and E-C coupling VO2 similar to ETA and ETA/ETB blockade, but did not alter efficiency. In HF, endogenous ET-1 maintains contractility at expense of increased VO2 through ETA receptor activation, likely mediated by Na+/H+ exchange.
Noguchi
Teruo
T
Cardiology Unit, University of Vermont, Burlington, 05401, USA.
Chen
Zengyi
Z
Bell
Stephen P
SP
Nyland
Lori
L
LeWinter
Martin M
MM
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000077300:Bosentan; D002303:Cardiac Output, Low / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D004452:Echocardiography; D065128:Endothelin Receptor Antagonists; D004734:Energy Metabolism / Q000187:drug effects; D006334:Heart Function Tests; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017923:Sodium-Hydrogen Exchangers; D013449:Sulfonamides; C039465:5-dimethylamiloride; D000584:Amiloride; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)