Inhibitors of Renin-angiotensin-aldosterone Signaling—Losartan, Enalapril, and Cardosten—Prevent Development of Infarction-induced Heart Failure in Rats

Kiss, Krisztina and Fekete, Veronika and Pálóczi, János and Sárközy, Márta and Murlasits, Zsolt and Pipis, Judit and Kheyfets, Irina A. and Dugina, Julia L. and Sergeeva, Svetlana A. and Epstein, Oleg I. and Csonka, Csaba and Csont, Tamás Bálint and Ferdinandy, Péter and Bencsik, Péter (2016) Inhibitors of Renin-angiotensin-aldosterone Signaling—Losartan, Enalapril, and Cardosten—Prevent Development of Infarction-induced Heart Failure in Rats. Alternative Therapies in Health and Medicine, 22 (2). pp. 10-17. ISSN 1078-6791

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Abstract

Context: The activation of the renin-angiotensin-aldosteron system (RAAS) plays an important role in the pathophysiology of congestive heart failure, which is the reason that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have become established therapies for heart failure. However, it is still not known whether preventive treatment with losartan or enalapril can reduce symptoms of infarction-induced heart failure. Ultra-low dose (ULD) drug therapy is thought to exert specific activity, with a lower chance of side effects. Objectives: The research team had hypothesized that preventive treatment with inhibitors of RAAS signaling—losartan, enalapril, and a preparation of a ULD antibody; ie, cardosten, which target the angiotensin type 1 (AT1 ) receptor, might alleviate pathological hypertrophy and/or functional decline in infarction-induced heart failure. Methods: The research team treated male Wistar rats orally for 30 days with 20 mg/kg of losartan, 10 mg/kg enalapril, 5 or 7.5 mL/kg of cardosten, or a control solution, started one day prior to permanent coronary occlusion. A sham-operated group functioned as a second control group. Settings: The study was conducted at the Department of Biochemistry of the Faculty of Medicine at the University of Szeged in Szeged, Hungary, in cooperation with the Pharmahungary Group, also in Szeged, Hungary, and with OOO “NPF” Materia Medica Holding Ltd. in Moscow, Russia. Outcome Measures: To determine cardiac functional parameters in vivo, the research team inserted a catheter into the left ventricle of the rats and measured the parameters of ventricular pressure, and cardiac output was determined by thermodilution. Morphological parameters were measured after heart isolation in transverse sections by a digital caliper. Results: Thirty days after permanent coronary ligation, both losartan and enalapril significantly decreased mean arterial blood pressure (MABP), attenuated the development of the left-ventricular anterior-wall and septum hypertrophy, and reduced scar thickness compared to the vehicle control group. The deterioration of cardiac output and the increase in total peripheral resistance (TPR) due to coronary ligation were significantly inhibited by both losartan and enalapril. The effects of cardosten were comparable with those of losartan and enalapril on cardiac morphology, left ventricular function, and TPR; however, it did not influence MABP. Moreover, in contrast to losartan and enalapril, cardosten did not decrease the rate of survival. Conclusions: The study was the first to have demonstrated that preventive treatment with losartan, enalapril, or cardosten can attenuate pathological hypertrophy in infarction-induced heart failure in rats.

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