Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing marinobufagenin.
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 delta 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.
Tian
Jiang
J
Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614-2598, USA.
Shidyak
Amjad
A
Periyasamy
Sankaridrug M
SM
Haller
Steven
S
Taleb
Mohamed
M
El-Okdi
Nasser
N
Elkareh
Jihad
J
Gupta
Shalini
S
Gohara
Sabry
S
Fedorova
Olga V
OV
Cooper
Christopher J
CJ
Xie
Zijian
Z
Malhotra
Deepak
D
Bagrov
Alexei Y
AY
Shapiro
Joseph I
JI
D000818:Animals; D002018:Bufanolides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D002192:Canrenone / Q000494:pharmacology; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004347:Drug Interactions; D004719:Endomyocardial Fibrosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology; D009392:Nephrectomy; D010042:Ouabain / Q000037:antagonists & inhibitors / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D011392:Proline / Q000493:pharmacokinetics; D051381:Rats; D051437:Renal Insufficiency / Q000150:complications; D013148:Spironolactone / Q000494:pharmacology*; D014316:Tritium; D014511:Uremia / Q000150:complications*
D002018:Bufanolides; D002316:Cardiotonic Agents; D000451:Mineralocorticoid Receptor Antagonists; D011347:Procollagen; D014316:Tritium; D013148:Spironolactone; C093896:marinobufagenin; D010042:Ouabain; D002192:Canrenone; D011392:Proline