Hindawi Publishing Corporation Journal of Diabetes Research Volume 2013, Article ID 427693, 14 pages http://dx.doi.org/10.1155/2013/427693 Research Article RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes Ibrahim F. Benter, 1 Fawzi Babiker, 2 Ibrahim Al-Rashdan, 3 Mariam Yousif, 1 and Saghir Akhtar 1 1 Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait 2 Department of Physiology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait 3 Department of Medicine, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait Correspondence should be addressed to Fawzi Babiker; fawzi.b@hsc.edu.kw Received 25 April 2013; Revised 16 July 2013; Accepted 17 July 2013 Academic Editor: Daisuke Koya Copyright © 2013 Ibrahim F. Benter et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aims. We evaluated the efects of RU28318 (RU), a selective mineralocorticoid receptor (MR) antagonist, Captopril (Capt), an angiotensin converting enzyme inhibitor, and Losartan (Los), an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R-) induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I) followed by a period of 30 min of reperfusion (R). Drugs were administered for 30 min either before or ater ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple). Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly efective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an efective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most efective at improving −/ (a measure of diastolic function) when administered to diabetic hearts ater ischemia. 1. Introduction In addition to the circulatory renin-angiotensin-aldosterone system (RAAS), there is now a signiicant body of evidence supporting the concept of a “local tissue or cellular RAAS” that has important roles in the pathology of cardiovascular diseases [1]. he local production of aldosterone and the discovery of mineralocorticoid receptor (MR) expression in the heart have led to a greater understanding of the role of aldosterone/mineralocorticoid receptor activation in the cardiovascular diseases, including hypertension and heart failure [2, 3]. Aldosterone activates its mineralocorticoid receptor (MR) in the nondiabetic heart and can cause structural and electrical remodelling, ibrosis, oxidative stress, inlamma- tion, and arrhythmias [1, 4–7]. MR antagonists have shown signiicant beneit in patients with let ventricular dysfunc- tion and myocardial infarction [8]. For example, the recent Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure (EMPHASIS-HF) study has shown that eplerenone, an MR antagonist, has beneicial efects in patients with moderate heart failure (NYHA class II) [9]. However, beneicial efects of MR blockade in pathological states such as diabetes are unclear. It is well established that signaling network alterations in diabetes are such that potential therapies will need to be tailored for this pathological state [10–12]. Inhibitors of the renin-angiotensin-aldosterone system (RAAS), such