Abstract. Patients with chronic renal failure frequently develop cardiac hypertrophy and diastolic dysfunction; however, the mechanisms by which this occurs are still unclear. Male Sprague-Dawley rats were subjected to 5/6 nephrectomy and studied for their isolated myocyte function, calcium cycling, and gene expression of proteins important in calcium homeostasis after 4 wk. Comparable rats subjected to suprarenal aortic banding for the same duration were used for comparison. Rats subjected to 5/6 nephrectomy and aortic banding developed comparable hypertension; however, rats subjected to 5/6 nephrectomy experienced a greater degree of cardiac hypertrophy and downregulation of cardiac sodium potassium ATPase (Na ϩ /K ϩ -ATPase) activity than rats subjected to aortic banding. Moreover, cells isolated from the 5/6 nephrectomy rat hearts displayed impaired contractile function and altered calcium cycling compared with cells isolated from control or aortic constriction rat hearts. The 5/6 nephrectomy rat heart cells displayed a prolonged time constant for calcium recovery following stimulation, which corresponded to decreases in homogenate sarcoplasmic reticulum calcium ATPase-2a (SERCA2a) activity, protein density, and mRNA for SERCA2a. In conclusion, chronic renal failure leads to alterations in cardiac gene expression, which produces alterations in cardiac calcium cycling and contractile function. These changes cannot be explained only by the observed increases in BP. jshapiro@mco.eduPatients with renal failure usually develop cardiac complications. In end-stage renal disease (ESRD) patients treated with hemodialysis in the United States, annual mortality rates exceed 20%, with more than 50% attributed to cardiac mortality (1). Although the term "uremic cardiomyopathy" had previously been used to refer to a dilated cardiomyopathy complicating renal failure, more recent studies suggest that the most common form of heart disease in renal failure patients is one characterized by diastolic dysfunction and left ventricular hypertrophy (2). Although a number of known factors have been implicated in the pathogenesis of the left ventricular hypertrophy and diastolic dysfunction, our understanding of these processes is still incomplete (3).For many years, it has been known that the sodium pump is abnormal in chronic renal failure and that circulating inhibitor(s) can be demonstrated in the serum of uremic patients (4 -6). We have observed that sodium pump inhibition initiates a signal cascade that can cause alterations in gene transcription and ultimately produce hypertrophy in cardiomyocytes grown in culture (7-9). We have also observed that sodium pump inhibitors, including those circulating in the serum of uremic patients, can acutely cause altered calcium cycling and cardiomyocyte relaxation through sodium pump inhibition (10). The following studies were performed to further examine how cardiac growth and function are chronically modified by the uremic milieu. Materials and Methods AnimalsMale Sprague-Dawley rats (200...

These data show that one or more substances are present in uremic sera that acutely cause increased force of contraction and impaired recovery of cardiac myocyte calcium concentration as well as impaired relaxation. As these effects are similar to that seen with ouabain and can be prevented by co-incubation with an antibody fragment to digitalis, which also attenuates the sodium pump inhibitory effect, we suggest that this (these) substance(s) circulating in uremic sera and inhibiting the sodium pump also causes the acute diastolic dysfunction seen in our system.