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Comparative Study
. 2017 Jul 25;18(8):1612.
doi: 10.3390/ijms18081612.

Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril

Fedor Simko  1   2   3 , Olga Pechanova  4 , Kristina Repova  5 , Silvia Aziriova  6 , Kristina Krajcirovicova  7 , Peter Celec  8   9 , Lubomira Tothova  10 , Stanislava Vrankova  11 , Lucia Balazova  12 , Stefan Zorad  13 , Michaela Adamcova  14
Affiliations
Comparative Study

Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril

Fedor Simko et al. Int J Mol Sci. .

Abstract

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.

Keywords: captopril; fibrosis; hypertension; lactacystin; melatonin; remodelling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Systolic blood pressure (SBP) (A) and relative left ventricular weight (LVW/BW) (B) in the control group (Ctrl), L-NAME (L-NAME)-, continuous 24 h/day light (24 h)-, lactacystin (Lac)-induced hypertension, and in lactacystin-hypertension influenced by captopril (Lac+C) or melatonin (Lac+M). * p < 0.05 vs. Ctrl, # p < 0.05 vs. Lac.
Figure 2
Figure 2
Aortic thickness (WT) (A) and cross sectional area (CSA) (B) in the control group (Ctrl), L-NAME (L-NAME)-, continuous 24 h/day light (24 h)-, lactacystin (Lac)-induced hypertension, and in lactacystin-hypertension influenced by captopril (Lac+C) or melatonin (Lac+M). * p < 0.05 vs. Ctrl, # p < 0.05 vs. Lac.
Figure 3
Figure 3
Hydroxyproline concentration in the LV in soluble (A) and insoluble (B) collagen, and total hydroxyproline (C) in the control group (Ctrl), L-NAME (L-NAME)-, continuous 24 h/day light (24 h)-, lactacystin (Lac)-induced hypertension, and in lactacystin-hypertension influenced by captopril (Lac+C) or melatonin (Lac+M). * p < 0.05 vs. Ctrl, # p < 0.05 vs. Lac.
Figure 4
Figure 4
Nitric oxide synthase (NOS) activity in the heart (A) and kidney (B) in the control group (Ctrl), L-NAME (L-NAME)-, continuous 24 h/day light (24 h)-, lactacystin (Lac)-induced hypertension and in lactacystin-hypertension influenced by captopril (Lac+C) or melatonin (Lac+M). * p < 0.05 vs. Ctrl, # p < 0.05 vs. Lac.
Figure 5
Figure 5
The parameters of oxidative status in plasma (A1–D1), left ventricle (LV) (A2–D2) and aorta (A3–D3) in the control group (Ctrl), L-NAME (L-NAME)-, continuous 24 h/day light (24 h)-, lactacystin (Lac)-induced hypertension and in lactacystin-hypertension influenced by captopril (Lac+C) or melatonin (Lac+M). * p < 0.05 vs. Ctrl.
Figure 5
Figure 5
The parameters of oxidative status in plasma (A1–D1), left ventricle (LV) (A2–D2) and aorta (A3–D3) in the control group (Ctrl), L-NAME (L-NAME)-, continuous 24 h/day light (24 h)-, lactacystin (Lac)-induced hypertension and in lactacystin-hypertension influenced by captopril (Lac+C) or melatonin (Lac+M). * p < 0.05 vs. Ctrl.
Figure 6
Figure 6
Cytoplasmatic (A) and nuclear (B) left ventricular NF-κB expression in the control group (Ctrl), L-NAME (L-NAME)-, continuous 24 h/day light (24 h)-, lactacystin (Lac)-induced hypertension, and in lactacystin-hypertension influenced by captopril (Lac+C) or melatonin (Lac+M). * p < 0.05 vs. Ctrl.
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