Effects of Uremic Compounds on Cultured Myocytes: a Model for Uremic Myocardiopathy
Respiration is a central factor of metabolism in almost all tissues; thus, all pharmacological effects also concern the energy metabolism in a direct or an indirect manner. A system which allows determination of oxygen consumption and simultaneously application of the methods of light microscopy is therefore of general pharmacological interest, irrespective of the cell type under investigation. We present the application of such a test system to the study of myocardial cell responses after exposition to uremic compounds.
Congestive heart failure is the most common cause of mortality in patients of maintenance hemodialysis. However, no unambiguous evidence of specific uremic damage to the myocardium has yet been provided. Therefore, we exposed fetal mouse cardiac myocytes in culture to “uremic” conditions and investigated the responses in oxygen consumption and contractility using a microperfusion system. The uremic state was achieved by perfusion of the cultures with sera obtained from chronic hemodialysis patients, immediately before dialysis after the long interval. Cultured myocytes were spontaneously contractile with a constant beating frequency during perfusion with serum-free medium. During perfusion with high concentrations of uremic sera (5%–20%) contractions ceased completely within 9–10 min; with sera from healthy controls spontaneous contractions continued for at least 50 min. Perfusion of the cardiomyocyte cultures with urea (10–500 mM), creatinine (5–20 mM), or combinations of both compounds also inhibited cellular contractility. Application of 10 mM urea and of “uremic” sera (> 5%) increased cellular steady-state respiration while high concentrations of urea (50–500 mM) and creatinine (5–20 mM) provoked a concentration-dependent decrease in steady-state oxygen consumption. Obviously, changes in osmolarity did not contribute to these effects. We conclude that the sera of patients on maintenance hemodialysis contain factors which adversely affect myocyte contractility and respiration in culture. High urea and creatinine concentrations are assumed to contribute to this effect. The in vitro test system seems to be a useful assay for testing further substances suspected to be “uremic toxins” with respect to their impact on the myocardium.
KeywordsHPLC Depression Urea Creatinine Respiration
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