Investigation of the effect of agomelatine on arterial blood pressure and cardiac remodeling in experimental hypertension model

Background and Aim: The mechanisms underlying the hypotensive effects of agomelatine and its effects on cardiac remodeling are not fully known. The aim of our study was to investigate the role of NO/cGMP, HSP90 and antioxidant mechanisms in the possible effects of agomelatine on arterial blood pressure and cardiac remodeling in an experimental hypertension model induced by NOS inhibition. Material and Methods: Thirty-two adult male Spraque-Dawley rats were divided into four groups as Control (C), Agomelatine (AGO), Hypertension (HT) and Hypertension+Agomelatine (HT+AGO). L-NAME 400 mg/L was added to the drinking water of HT and HT+AGO groups for 6 weeks. In the last two weeks of the experiment, agomelatine (40 mg/kg/day) was administered intraperitoneally to AGO and HT+AGO groups. Serum and left ventricular eNOS, cGMP and HSP90 levels were analyzed by ELISA and NO levels were analyzed by spectrophotometric method. In left ventricular tissue, ERK1/2 and p-ERK1/2 were analyzed by western blot and immunohistochemical methods, and MDA and GSH levels were analyzed by spectrophotometric method. In addition, left ventricular cardiomyocyte diameters were determined by Hematoxylin and Eosin staining. Results: Systolic blood pressure increased in the HT group compared to the K group from the first week (p<0.001) and decreased in the HT+AGO group compared to the HT group (p<0.001). Serum eNOS, NO and cGMP levels and left ventricular GSH levels were higher in the HT+AGO group compared to the HT group (all p<0.05). Serum HSP90 level was higher in the HT+AGO group compared to the K group (p<0.05). The p-ERK1/2/ERK1/2 ratio in left ventricular tissue was higher in the HT group compared to the K group (p<0.01), but lower in the HT+AGO group compared to the HT group (p<0.05). Left ventricular cardiomyocyte diameters were higher in HT and HT+AGO groups compared to K and AGO groups (all p<0.01). Conclusion: NO-cGMP pathway and increased HSP90 level play a role in the decreasing effect of agomelatine on arterial blood pressure. Agomelatine may produce antioxidant effect by increasing GSH level in cardiac tissue and antihypertrophic effect by decreasing ERK1/2 protein activation. However, these effects did not cause significant morphological changes in the left ventricle.