This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin system (RAS). The results were compared with standard pharmacological blockade of the RAS using angiotensin-converting enzyme inhibitor (ACEi). The rationale for employing EET-A as a new treatment approach is based on our findings that apart from increased RAS activity, untreated ACF TGR also shows kidney and left ventricle (LV) tissue deficiency of EETs. Untreated ACF TGR began to die 17 days after creating ACF and were all dead by day 84. The treatment with EET-A alone or ACEi alone improved the survival rate: in 156 days after ACF creation, it was 45.5% and 59.4%, respectively. The combined treatment with EET-A and ACEi appeared to improve the final survival to 71%; however, the difference from either single treatment regimen did not reach significance. Nevertheless, our findings support the notion that targeting the cytochrome P-450-dependent epoxygenase pathway of arachidonic acid metabolism should be considered for the treatment of HF.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

Department of Biochemistry University of Texas Southwestern Medical Center Dallas TX 75390 USA

Department of Cardiology University Hospital Motol and 2nd Faculty of Medicine Charles University 150 06 Prague Czech Republic

Department of Internal Medicine 1 Cardiology University Hospital Olomouc and Palacký University 1 P Pavlova 185 6 Nová Ulice 779 00 Olomouc Czech Republic

Department of Pathophysiology 2nd Faculty of Medicine Charles University 150 06 Prague Czech Republic

Department of Renal and Body Fluid Physiology Mossakowski Medical Research Institute Polish Academy of Sciences 02 106 Warsaw Poland

Drug Discovery Center Medical College of Wisconsin Wauwatosa WI 53226 USA

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