Published Online
on January 30, 2006

A more recent version of this article appeared on March 1, 2006

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Submitted on July 15, 2005
Revised on August 1, 2005

Central Role for the Cardiotonic Steroid Marinobufagenin in the Pathogenesis of Experimental Uremic Cardiomyopathy

David J. Kennedy; Sandeep Vetteth; Sankaridrug M. Periyasamy; Mohamed Kanj; Larisa Fedorova; Samer Khouri; M. Bashar Kahaleh; Zijian Xie; Deepak Malhotra; Nikolai I. Kolodkin; Edward G. Lakatta; Olga V. Fedorova; Alexei Y. Bagrov; and Joseph I. Shapiro^*

From the Departments of Medicine and Pharmacology (D.J.K., S.V., S.M.P., M.K., M.B.K., Z.X., D.M., J.I.S.), Medical University of Ohio, Toledo, Ohio; and Laboratory of Cardiovascular Science (N.I.K., E.G.L., O.V.F., A.Y.B.), National Institute on Aging, Baltimore, Md.

^* To whom correspondence should be addressed. E-mail: jshapiro{at}meduohio.edu.

Abstract--Patients with chronic renal failure develop a "uremic" cardiomyopathy characterized by diastolic dysfunction, cardiac hypertrophy, and systemic oxidant stress. Patients with chronic renal failure are also known to have increases in the circulating concentrations of the cardiotonic steroid marinobufagenin (MBG). On this background, we hypothesized that elevations in circulating MBG may be involved in the cardiomyopathy. First, we observed that administration of MBG (10 µg/kg per day) for 4 weeks caused comparable increases in plasma MBG as partial nephrectomy at 4 weeks. MBG infusion caused increases in conscious blood pressure, cardiac weight, and the time constant for left ventricular relaxation similar to partial nephrectomy. Decreases in the expression of the cardiac sarcoplasmic reticulum ATPase, cardiac fibrosis, and systemic oxidant stress were observed with both MBG infusion and partial nephrectomy. Next, rats were actively immunized against a MBG-BSA conjugate or BSA control, and partial nephrectomy was subsequently performed. Immunization against MBG attenuated the cardiac hypertrophy, impairment of diastolic function, cardiac fibrosis, and systemic oxidant stress seen with partial nephrectomy without a significant effect on conscious blood pressure. These data suggest that the increased concentrations of MBG are important in the cardiac disease and oxidant stress state seen with renal failure.

Key words: cardiomyopathy • sarcoplasmic reticulum • cardiotonic agents • fibrosis • renal failure • reactive oxygen species

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