Avaliação dos efeitos de derivados aminoguanidínicos na hipertrofia cardíaca induzida em ratos

Abstract

Cardiovascular diseases can cause morphological and functional adaptations in the cardiovascular system. Aminoguanidine (AG) has been suggested as a potential therapeutic tool to combat cardiac hypertrophy and myocardial fibrosis. The use of AG was clinically unfeasible due to hepatotoxic risks. The objective of this study was to evaluate the effects of aminoguanidine derivatives (DAG) (PA83, LQM01 and LQM03) on the isoproterenolinduced cardiac hypertrophy model. The in vitro antioxidant capacity of DAG and AG was evaluated by the ability to sequestrate radicals DPPH•, ABTS•+, H2O2 and •NO. Trolox and quercetin were used as positive controls. The antiglycation capacity of DAG and AG was determined. Cardiac hypertrophy was induced in male Wistar rats (7 to 10 weeks of age) by administration of isoproterenol (ISO, 7 mg/kg, s.c.) for 15 days. At the same time, the animals were treated with DAG and AG in different doses (i.p.). The ratio between heart weight and body weight (HW/BW) and the ratio between left ventricular weight and body weight (LVW/BW) were determined and used as cardiac hypertrophy index. The total area of cardiac myocytes and deposition of tissue collagen were determined histologically. Among the derivatives tested, only PA83 and LQM01 had the ability to sequester the radical DPPH• (IC50/PA83 = 12.86 μg∙mL-1; IC50/LQM01 = 18.10 μg∙mL-1). However, as for the ability to sequester the ABTS•+ radical, all the derivatives were effective in neutralizing it, with PA83 and LQM01 being the most successful (IC50/PA83 = 8.52 μg∙mL-1; IC50/LQM01 = 7.50 μg∙mL-1). PA83 was the most efficient derivative in reducing the amount of •NO and H2O2 (23.5% and 87.9%, respectively). Regarding the anti-coagulant capacity, the LQM03 derivative was shown to be the most effective, being better than AG in the first 24 hours (58.6 ± 1.5% and 34.3 ± 1.1%, respectively). According to the cardiac hypertrophy index (HW/BW and LVW/BW) treatment with DAG and/or AG was not able to prevent cardiac hypertrophy (****p <0.0001). However, treatment with LQM03 derivative (30 mg/kg) was able to slightly attenuate the hypertrophic effects of isoproterenol on the myocardium when compared to CT group (**p <0.01). Regarding the total relative area of the cardiac myocytes, both treatment with AG (50 mg/kg) and LQM03 (30 mg/kg) presented a significant increase when compared to CT groups (****p <0.00001) and ISO (####p <0.0001). Treatment with AG and LQM03 did not prevent the relative increase of collagen deposition in the myocardium, with an increase of 58.7% in the group treated with AG (*p <0.05), whereas in the group treated with LQM03 was 140.6% (****p <0.0001). In the liver, LQM03 treatment resulted in a significant increase of approximately 12 fold in the relative amount of hepatic collagen when compared to the other groups (****p <0.0001). The molecular docking study showed that the derivatives exhibited higher affinity for MMP-2 and MMP-9 isoforms than AG. In addition, it was observed that among the derivatives, the PA 83 compound had the highest affinity for MMPs.From the results obtained, it is concluded that the PA83 derivative is the compound with the best antioxidant profile in vitro. However, compound LQM03 is the derivative with the best anti-binding ability. Although the LQM03 derivative showed an attenuating behavior of the hypertrophic effects of ISO on the myocardium, this compound causes an increase in the deposition of myocardial and hepatic collagen.