Endothelin-1 stimulates cardiomyocyte injury during mitochondrial dysfunction in culture

To understand the pathophysiological role of endothelin-1 in the failing he art, we constructed a cellular mitochondrial impairment model and demonstra ted the effect of endothelin-1. Primary cultured cardiomyocytes from neonat al rats were pretreated with rotenone, a mitochondrial complex I inhibitor, and the cytotoxic effect of endothelin-1 on the cardiomyocytes was demonst rated. Rotenone gradually decreased the pH of the culture medium with incub ation time and caused slight cell injury. Endothelin-1 markedly enhanced th e effect of rotenone that decreased the pH of the medium and enhanced cellu lar injury: The enhancement of the decrease in pH and cell injury induced b y endothelin-1 was counteracted by the endothelin ETA receptor antagonist B Q123 or by :maintaining the pH of the medium by the addition of 50 mM HEPES . Endothelin-1 markedly increased the uptake of 2-deoxyglucose and lactic a cid production when the cardiomyocytes were pretreated with rotenone. These findings suggest that the stimulation of glucose uptake and anaerobic glyc olysis followed by the increase in lactic acid accumulation in cardiomyocyt es under the condition of mitochondrial impairment may be involved, at leas t in part, in the cellular injury by endothelin-1. Moreover, these findings suggest the possibility that the effect of endothelin-1 on myocardium is r eversed by the condition of the mitochondria; and endogenous endothelin-1 m ay deteriorate cardiac failure with mitochondrial dysfunction. This may con tribute to clarify the beneficial effect of endothelin receptor blockade in improving heart failures. (C) 2001 Elsevier Science B.V. All rights reserv ed.