Influence of congestive heart failure on endothelin levels and receptors in rabbits.
Congestive heart failure, both in man and in animals is associated with an increased plasma level of endothelin. To investigate further the potential role of the endothelin system, we designed a study to determine the effect of experimental congestive heart failure (CHF) on plasma and tissue immunoreactive-endothelin (irET) and on the density and affinity of endothelin-1 receptors in the heart and kidney. For this purpose, CHF was induced in rabbits by combined aortic valvular insufficiency and stenosis. When CHF was established, plasma and tissue irET levels were measured by radioimmunoassay and density and affinity of endothelin-1 receptors were measured by binding assay on tissue homogenates. Compared to control rabbits, plasma irET was significantly elevated in rabbits with CHF [1.04 +/- 0.15 vs. 0.04 +/- 0.01 fmol/ml, P < 0.001]. Tissue irET concentrations in ventricles and kidney were roughly 4 orders of magnitude higher than plasma concentrations. CHF decreased the tissue irET levels in left ventricle and kidney by 32 and 46%, respectively (P < 0.01), whereas CHF increased it by 58% in the right ventricle (P < 0.005). The density of ET-1 receptors was decreased in the right and left ventricles and in kidneys by 26, 36, and 61%, respectively (P < 0.05). Receptor affinity remained unchanged in response to CHF in both ventricles, whereas it increased in kidney [Kd (pM); 154 +/- 17 vs. 99 +/- 9, P < 0.01]. Thus, this study demonstrates that experimental CHF is not only characterized by elevated plasma irET levels but also by a decrease in tissue irET concentrations in the left ventricle and kidney, and by a down-regulation of ET-1 receptors both in the heart and kidney. Functional consequences of these changes need to be determined.
Löffler
B M
BM
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Roux
S
S
Kalina
B
B
Clozel
M
M
Clozel
J P
JP
D000818:Animals; D001022:Aortic Valve Insufficiency / Q000150:complications; D001024:Aortic Valve Stenosis / Q000150:complications; D015536:Down-Regulation; D016232:Endothelins / Q000032:analysis*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D006352:Heart Ventricles / Q000737:chemistry; D007668:Kidney / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011817:Rabbits; D017466:Receptors, Endothelin / Q000032:analysis*
D016232:Endothelins; D017466:Receptors, Endothelin