Original ArticleEplerenone Decreases Inflammatory Foci in Spontaneously Hypertensive Rat Hearts With Minimal Effects on Blood PressureBrandish, Philip E PhD*; Forest, Thomas W PhD†; Chen, Hongxing MS, MD‡; Gatto, Nicholas T PhD†; Molon-Noblot, Sylvain PhD†; Zwierzynski, Izabela BS§; Szczerba, Peter MS§; Adamson, Gary E BS¶; Ma, Bennett K PhD¶; Flores, Osvaldo A PhD*; Hershey, James C PhD*Author Information From the Departments of *Molecular Endocrinology and †Safety Assessment, Merck & Co, West Point, PA; ‡Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT; and Departments of §Laboratory Animal Resources and ¶Drug Metabolism, Merck & Co, West Point, PA. Received for publication September 25, 2008; accepted October 16, 2008. Merck & Co, funded the work in its entirety. This work was previously presented in the form of an abstract and poster at the Endocrine Society. There are no conflicts of interest. Reprints: Dr. Philip E. Brandish, PhD, Merck & Co, Inc, 770 Sumneytown Pike, West Point, PA 19486 (e-mail: [email protected]). Journal of Cardiovascular Pharmacology: January 2009 - Volume 53 - Issue 1 - p 44-51 doi: 10.1097/FJC.0b013e3181953e65 Buy Metrics Abstract 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−1·d−1 eplerenone or 20 mg·kg−1·d−1 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−1·d−1 losartan (by 68%) or by 300 mg·kg−1·d−1 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. © 2009 Lippincott Williams & Wilkins, Inc.