Endothelin-1 production is enhanced by rotenone, a mitochondrial complex Iinhibitor, in cultured rat cardiomyocytes

In chronic heart failure and acute myocardial infarction, the tissue level of endothelin (ET)-1 in the heart, as well as its plasma level, has been re ported to increase markedly. There is, however, little information about wh at in these pathologic conditions leads to increased production of ET-1, an d which type of cell in the heart produces ET-1. We examined the mRNA and p eptide expression of ET-1 using cultured rat neonatal cardiomyocytes, in wh ich mitochondrial dysfunction was induced by rotenone, a mitochondrial resp iratory chain complex I inhibitor. because one of the common features in fa iling or ischemic hearts is an alteration in energy metabolism due to mitoc hondrial dysfunction. Rotenone increased glucose use by the culture cells w ithin 12 h of addition without affecting cell viability, and depressed the mitochondrial membrane potential after 72 h, indicating the induction of mi tochondrial dysfunction in cardiomyocytes. Rotenone induced significant inc rease in the expression level of mRNA for ET-1 within 1 h of addition. In a ccordance with this finding, immunoreactive ET-1 in culture medium increase d 3 times after 24 h of incubation, suggesting active secretion of ET-1 fro m cultured cells treated with rotenone. Immunocytochemical analysis verifie d significant increase of ET-1 peptide in cardiomyocytes, confirming the pr oduction of ET-1 by cardiomyocytes. These results suggest that derangement of mitochondrial function in cardiomyocytes itself could lead to the increa sed production of ET-1 in cardiomyocytes, and that this mechanism may contr ibute to the increased production of ET-1 in failing and ischemic hearts.