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

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.

Lisinopril reverses behavioural alterations in spontaneously hypertensive rats

“…In SHR+LIS group, the behavioural changes may be related to the sympatholytic action of ACE-inhibition. In this and a number of our previous experiments (Simko et al 2009(Simko et al , 2015(Simko et al , 2017Hrenak et al 2013), ACE inhibition prominently reduced SBP but also exerted a number of protective effects on the cardiovascular system, supposedly via neurohumoral inhibition on various levels. ACE-inhibitors not only reduce angiotensin II formation, but also have a sympatholytic action via the attenuation of the release of norepinephrine from sympathetic nerve endings (Crozier et al 1989, Simko andSimko 1999;Simko et al 2003).…”

Histone Deacetylase Inhibition has Cardiac and Vascular Protective Effects in Rats With Pressure Overload Cardiac Hypertrophy

“…This gradually decreases ventricular compliance together with cardiac hypertrophy in the left ventricle (LV) and endothelial dysfunction, ultimately exceeds the limit of compensation, and eventually leads to heart failure (Iyer et al 2010). Thus, there is a continuous effort to identify substances that can prevent or reverse cardiac remodeling in heart disease (Simko et al 2017).…”

Ivabradine does not Impair Anxiety-Like Behavior and Memory in Both Healthy and L-NAME-Induced Hypertensive Rats

“…The situation in the L-NAME model is complex. L-NAME is a non-specific inhibitor of nitric oxide synthase resulting in endothelial dysfunction with decreased NO production in various organs including the brain (Bernatova et al 1999), hypertension development, and fibrotic remodeling of the left ventricle, kidney, or aorta (Pechanova et al 1997, Bernatova et al 2000, Simko et al 2004, Simko et al 2005, Simko et al 2017. Especially the prominent proteosynthetic and proliferative effects of L-NAME administration in the brain, reflected by increased concentrations of ribonucleic and deoxyribonucleic acids in the brain tissue (Bernatova et al 1999), suggest the potential of behavioral changes in this model.…”