Nebivolol to attenuate the effects of hyper-homocysteinaemia in rats
Introduction
Homocysteine (Hcy) is a sulphur-containing amino acid. The metabolism of Hcy involves two pathways: remethylation to methionine, which requires folate and vitamin B12, and trans-sulphuration to cystathionine, which requires vitamin B6 [1]. Different defects at different levels of this process may lead to hyperhomocysteinemia (hHcy). Genetic diseases, acquired pathologies or poor dietary habits can cause hHcy [1]. Normally, the fasting plasma level of Hcy is between 5 and 15 mmol/L. A level of 15–30 mmol/L is considered moderate, whereas levels of 30–100 mmol/L and 100–500 mmol/L are considered intermediate and severe hHcy, respectively [2].
The literature and the data about the relation between the homocysteine and atherosclerosis date back to 45 years. In 1969, depending on observations of vascular lesions among the children with hyperhomocysteinemia, Kilmer McCully proposed a hypothesis that homocysteine is atherogenic [3]. Since then numerous studies with a cumulative data have confirmed that an elevation of total plasma homocysteine (tHcy) is related to early atherosclerosis [4], [5]. Today it is well known that hHcy elicits a cascade of events that injure the vascular wall [2]. These include chemical modification of lipoproteins, alterations of vascular structure, endothelial dysfunction, impairment of cell repair and proliferation of vascular smooth muscle cells [6], [7]. Moreover, a rise in plasma Hcy levels was proposed to contribute to ischaemic changes and alter the structure and function of blood vessels through oxidative stress [2], [8]. Oxidative stress appeared to give rise to vascular diseases and atherosclerosis via reactive oxygen species (ROS), with injury occurring when the critical balance between free radicals and the synthesis of anti-oxidant defence was altered [9]. Of interest, high levels of methionine or low levels of folate both of which contribute hHcy, seemed to have an adverse effect on the oxidant/anti-oxidant status of the liver and renal tissues and cause injury to these tissues [10], [11].
Nebivolol is a racemic mixture of two stereoisomers: d-nebivolol and l-nebivolol and has high affinity and selectivity for β1-adrenoceptor binding sites [12]. In addition to its β1 receptor–blocking and nitric oxid (NO)-releasing effects, nebivolol can substantially inhibit vascular oxidative stress [12]. A previous study demonstrated that nebivolol significantly decreased levels of 8-iso- prostaglandin F2α (PGF2α) a marker of oxidative stress, in urine samples of healthy volunteers [13]. Moreover, nebivolol was shown to facilitate ROS scavenging in the rat aorta and to alleviate oxidative stress-induced impairment of endothelium-dependent vasorelaxation [14]. Besides, nebivolol was shown to prevent the development of atherosclerosis in cholesterol fed-rabbits [15].
There is a controversy in the literature about the usefulness of Hcy lowering therapy mainly with vitamin supplements to reduce the cardiovascular events [16], [17], [18], [19]. Recent meta-analysis suggested that folic acid supplementation may improve endothelial dysfunction as assessed by flow-mediated vasodilation in the brachial artery in patients with coronary heart disease [18]. However, most of the analysis are currently in favour of no benefit from vitamin supplements to reverse the unfavourable effects of Hcy on the endothelium [16], [17]. More effective agents are needed both to lower the serum Hcy levels and protect the endothelium from its harm.
Nebivolol with its anti-hypertensive, anti-oxidant and NO-releasing effects may provide a good tool to reverse the unfavourable affects of Hcy on the endothelium which promotes atherosclerosis. To the best of our knowledge, there is no information available on the potentially preventive effects of nebivolol against the hHcy-induced damage in the wall of the aorta. Moreover, there are no data about the nebivolol to improve hHcy-induced oxidative stress in different rat tissues. The purpose of this study was to investigate the prophylactic effect of nebivolol against oxidative stress in brain, heart, liver and kidney tissues. Moreover, we aimed to demonstrate the potential prophylactic effect of nebivolol against hHcy-induced changes in the wall of the aorta.
Section snippets
Animals and experimental protocol
Twenty-four healthy adult male Wistar rats (16 weeks old, weighing between 322 and 354 g) were used in the study. The animals were obtained from the Adnan Menderes University, Faculty of Medicine, Experimental Research Centre, Aydin, Turkey. They were placed in screen-bottomed stainless steel cages at 22–24 °C in a room with a 12/12 h light/dark cycle. The rats were randomly divided into four groups (n = 6 rats per group): a control group, nebivolol group, hHcy group and nebivolol + hHcy group.
Results
There was no significant difference between the groups by means of weights (nebivolol group: 340.2 ± 3.07 g, hHcy group: 336.8 ± 4.08 g, nebivolol + hHcy group: 334.7 ± 3.84 g, control group: 338.3 ± 2.3 g) (P > 0.05).
The Hcy levels of the hHcy group were significantly higher than those of the other groups (P < 0.001) (Fig. 1). The Hcy level of the nebivolol + hHcy group was lower than that of the hHcy group (12.8 ± 0.75 versus 37.13 ± 2.89 mmol/L) (P < 0.001). The Hcy level of the nebivolol
Discussion
In this study, we demonstrated that nebivolol may be useful in alleviating hHcy-induced oxidative stress in tissues, such as brain, heart, liver and kidney. We also showed that it may be useful in preventing hHcy-induced structural deterioration of the vascular wall of the aorta. To the best of our knowledge, this is the first report to demonstrate the potential usefulness of nebivolol treatment in alleviating hHcy.
In this study, we used the experimental model of Cao et al. to produce hHcy [29]
Conclusion
In conclusion, in this study, nebivolol seemed to have an attenuating effect of the oxidative stress in brain, kidney, liver and heart tissues and improving structural changes of the aorta in a hHcy-induced rat model. Moreover, nebivolol appeared to decrease Hcy. Thus, nebivolol may be useful in clinical scenarios where hHcy affects physiopathological pathways. Further experimental and clinical studies are needed.
Conflict of interest
The authors of this manuscript declare that they do not have any potential conflict of interest.
Acknowledgements
Part of this study was supported by the University of Adnan Menderes Scientific Research Projects Commission (TPF-12010).
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