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(Hypertension. 2009;54:1313.)
© 2009 American Heart Association, Inc.

Original Articles

Spironolactone Attenuates Experimental Uremic Cardiomyopathy by Antagonizing Marinobufagenin

Jiang Tian; Amjad Shidyak; Sankaridrug M. Periyasamy; Steven Haller; Mohamed Taleb; Nasser El-Okdi; Jihad Elkareh; Shalini Gupta; Sabry Gohara; Olga V. Fedorova; Christopher J. Cooper; Zijian Xie; Deepak Malhotra; Alexei Y. Bagrov; Joseph I. Shapiro

From the Departments of Medicine and Physiology and Pharmacology (J.T., A.S., S.M.P., S.H., M.T., N.E.-O., J.E., S.Gu., S.Go., C.J.C., Z.X., D.M., J.I.S.), University of Toledo College of Medicine, Toledo, Ohio; Laboratory of Cardiovascular Science (O.V.F., A.Y.B.), National Institute on Aging, Baltimore, Md.

Correspondence to Joseph I. Shapiro, Mail Stop #1186 HSC, 3000 Arlington Ave, Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614-2598. E-mail joseph.shapiro{at}utoledo.edu

Spironolactone has been noted to attenuate cardiac fibrosis. We have observed that the cardiotonic steroid marinobufagenin plays an important role in the diastolic dysfunction and cardiac fibrosis seen with experimental renal failure. We performed the following studies to determine whether and how spironolactone might ameliorate these changes. First, we studied rats subjected to partial nephrectomy or administration of exogenous marinobufagenin. We found that spironolactone (20 mg/kg per day) attenuated the diastolic dysfunction as assessed by ventricular pressure-volume loops and essentially eliminated cardiac fibrosis as assessed by trichrome staining and Western blot. Next, we examined the effects of spironolactone and its major metabolite, canrenone (both 100 nM), on marinobufagenin stimulation of rat cardiac fibroblasts. Both spironolactone and canrenone prevented the stimulation of collagen production by 1 nM marinobufagenin but not 100 nM marinobufagenin, as assessed by proline incorporation and procollagen 1 expression, as well as signaling through the sodium-potassium-ATPase, as evidenced by protein kinase C isoform translocation and extracellular signal regulated kinase 1/2 activation. Both spironolactone and canrenone also altered ouabain binding to cultured porcine cells in a manner consistent with competitive inhibition. Our data suggest that some of the antifibrotic effects of spironolactone may be attributed to antagonism of marinobufagenin signaling through the sodium-potassium-ATPase.

Key Words: cardiomyopathy • renal failure • cardiotonic steroids • collagen • fibrosis