Participação dos canais para cálcio nos efeitos cardiovasculares induzidos pelo indol-3-carbinol em ratos

Abstract

Cardiovascular diseases (CVD) represent the leading cause of death, hospitalizations, and outpatient care worldwide. The main modifiable risk factor for the development of CVD is systemic arterial hypertension (SAH), a clinical condition characterized by persistent elevation of blood pressure (BP). Alkaloids have demonstrated several medicinal benefits and may be useful for treating SAH. In this context, the present study aimed to evaluate the cardiovascular effects induced by indole-3-carbinol (I3C), an indole alkaloid found in cruciferous vegetables, seeking evidence of the mechanism of action. In the acute protocol, I3C was administered intravenously (5, 10, 30, and 50 mg/kg) in Wistar rats, and BP and heart rate (HR) were measured. In in vitro assays, I3C (10-6-10-2 M) was added to superior mesenteric artery rings with or without functional endothelium pre-contracted with phenylephrine (PHE) or depolarizing solution (60 mM KCl). Also, the effects of I3C on the contractions induced by CaCl2 were evaluated in the absence or presence of the compound and in another protocol, and the vessels were exposed to pre-contraction with S(-)-Bay K 8644, a Cav1.2 channel activator. In the in silico study, docking and molecular dynamics were performed to evaluate the interaction of I3C with the Cav1.2 channel. For the evaluation of the treatment with I3C, the animals were divided into three groups: normotensive control Wistar Kyoto (WKY-CTL), hypertension (SHR-CTL), and hypertension treated with I3C at a dose of 50 mg/kg/day (SHR-I3C 50 mg/kg/day). The animals were submitted to daily administration orally for 28 days, and at the end of the treatment, BP and HR were measured. The protocols were approved by the Ethics Committee on the Use of Animals (CEUA) of the Federal University of Paraíba (UFPB) (nº 056/2016; 066/2017 and 4234221121). Acute administration of I3C promoted hypotension and bradycardia. Cumulative concentrations of I3C induced concentration-dependent relaxation in mesenteric rings with and without endothelium pre-contracted with PHE, this response being significantly similar when the rings were pre-contracted with 60 mM KCl. In addition, I3C inhibited the contractions induced by CaCl2 in a Ca+2-free medium in a concentration-dependent manner. This compound also induced vasodilation in arterial preparations pre-contracted with S(-)-Bay K 8644. In silico results, strong molecular interactions of I3C with the α1C subunit of the Cav1.2 channel were observed. The treatment of I3C decreased MAP and SBP in animals in a model of spontaneous hypertension. In conclusion, this study shows that I3C promotes MAP reduction acutely and after chronic treatment in SHR. In addition, it induces vasorelaxation, involving, at least in part, the participation of Cav1.2 channel blockage, resulting in reduced intracellular Ca+2 concentration [Ca+2]i, modulating vascular smooth muscle cell (VSMC) tone. These findings contribute to the understanding of the cardiovascular actions of I3C.