Diastolic dysfunction and abnormality of the Na+/Ca2+ exchanger in single uremic cardiac myocytes

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease, possibly due to a specific 'uremic cardiomyopathy'. This study investigated the function of the Na+/Ca2+ exchanger in single cardiac myocytes from a model of early renal impairment. Mild uremia was induced by partial (5/6) nephrectomy in male Wistar rats. After 4 weeks, ventricular myocytes were isolated, loaded with the fluorescent Ca2+ indicator indo-1, and contractile function and calcium transients recorded following electrical pacing at 0.2 Hz. Relaxation from rapid cooling contractures (RCCs) was also studied. Cells from uremic animals ( U) were hypertrophied compared with controls (C), with a significant increase in width (14%; P<0.02) and cross-sectional area ( 13%; P<0.03). There was a significant increase in diastolic intracellular Ca2+ ratio in the uremic cells (C, 0.33 +/- 0.00 vs U, 0.37 +/- 0.02; P<0.02), although the amount of calcium released per twitch was similar. Uremic cells were slower to relax following RCCs, however when Na+/ Ca2+ exchange was inhibited using a Na+-free/ Ca2+- free solution, this difference was abolished. Under these conditions, there was little difference in the relaxation rate of control cells, indicating that the Na+/Ca2+ exchanger plays only a minor role in relaxation in normal rat myocytes. However in uremia, the data indicate that the Na+/Ca2+ exchanger actively interfered with relaxation, possibly by working in reverse rather than forward mode. These results indicate that myocyte relaxation and Ca2+ handling are abnormal in early uremia and may provide further evidence for the existence of a specific 'uremic cardiomyopathy'.