Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with NG-nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction.

Department of Physiology Faculty of Medicine Charles University 50003 Hradec Kralove Czech Republic

Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences 84505 Bratislava Slovakia

Institute of Molecular Biomedicine Faculty of Medicine Comenius University 81108 Bratislava Slovakia

Institute of Normal and Pathological Physiology Slovak Academy of Sciences 81371 Bratislava Slovakia

Institute of Pathophysiology Faculty of Medicine Comenius University Sasinkova 4 81108 Bratislava Slovakia

Institute of Pathophysiology Faculty of Medicine Comenius University Sasinkova 4 81108 Bratislava Slovakia 3rd Clinic of Internal Medicine Faculty of Medicine Comenius University 83305 Bratislava Slovakia Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences 84505 Bratislava Slovakia

Institute of Pathophysiology Faculty of Medicine Comenius University Sasinkova 4 81108 Bratislava Slovakia Institute of Molecular Biomedicine Faculty of Medicine Comenius University 81108 Bratislava Slovakia

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