Eplerenone decreases inflammatory foci in spontaneously hypertensive rat hearts with minimal effects on blood pressure.
The blood pressure (BP)-lowering effects of mineralocorticoid receptor (MR) antagonists in salt-sensitive rat models of hypertension are well understood. However, studies in salt-independent models have yielded mixed results, and therefore, we measured the hemodynamic effects of MR blockade in spontaneously hypertensive rats. We treated spontaneously hypertensive rats for 8 weeks with 30-300 mg.kg.d eplerenone or 20 mg.kg.d losartan and monitored BP using radiotelemetry and performed histopathological analyses of the hearts. Eplerenone, in contrast to losartan, caused only a small reduction in systolic BP at the highest dose tested. Both reduced left ventricular wall thickness, although eplerenone was less effective than losartan. Only losartan decreased heart weight. We observed foci of cardiomyopathy characterized by combinations of infiltrating monocytes, necrotic myocytes, and interstitial fibrosis in hearts of control animals. The number of foci seemed to be decreased in hearts of losartan- and eplerenone-treated animals. In a second study, using quantitative histomorphometry, the number of foci was significantly reduced by 20 mg.kg.d losartan (by 68%) or by 300 mg.kg.d eplerenone (by 50%). Our data support the hypothesis that a direct BP-independent effect on the progression of cardiomyopathy in the heart may be one basis for the cardiac protection afforded by MR antagonism.
Brandish
Philip E
PE
Department of Molecular Endocrinology, Merck & Co, West Point, PA 19486, USA. philip_brandish@merck.com
Forest
Thomas W
TW
Chen
Hongxing
H
Gatto
Nicholas T
NT
Molon-Noblot
Sylvain
S
Zwierzynski
Izabela
I
Szczerba
Peter
P
Adamson
Gary E
GE
Ma
Bennett K
BK
Flores
Osvaldo A
OA
Hershey
James C
JC
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077545:Eplerenone; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D017673:Sodium Chloride, Dietary / Q000494:pharmacology / Q000627:therapeutic use; D013148:Spironolactone / Q000031:analogs & derivatives
D017673:Sodium Chloride, Dietary; D013148:Spironolactone; D000077545:Eplerenone; D019808:Losartan