Pharmacological characterization of the cardiovascular effect of Nibethione: ex vivo, in vivo and in silico studies

Abstract

Objective: This work describes the vasorelaxant and antihypertensive effects and the mechanism of action on vascular smooth muscle cells of Nibethione, a synthetic thiazolidinedione derivative. Additionally, evidence of its cytotoxicity is assessed.

Methods: Nibethione (NB) was synthesized, and its vasorelaxant effect and mechanism of action were assessed through ex vivo experiments. Molecular docking studies were used to predict the mode of interaction with L-type Ca²⁺ channel, and in vivo antihypertensive activity was assayed on spontaneously hypertensive rats (SHR). The cytotoxicity potential was evaluated in porcine aortic endothelial cells (PAECs) from primary explants.

Key findings: Nibethione vasorelaxant effect was efficient on KCl (80 mm) and NE-contraction. This effect was deleteriously modified in the presence of potassium channel block drugs, while the maximal contraction induced with NE was significantly decreased by NB; the CaCl₂ -induced contraction was abolished entirely. In vivo experiments showed that NB decreased diastolic blood pressure in 20.3 % after its administration on SHR. The molecular docking showed that NB blocks L-type Ca²⁺ channel, and in vitro tests showed that NB did not produce cytotoxic activity on PAECs (IC₅₀ >1000 µm).

Conclusions: Nibethione showed in vivo antihypertensive and ex vivo vasorelaxant effects with implication of voltage-dependent L-type Ca²⁺ channel blocking, and this may contribute to the research of novel antihypertensive drugs.

Keywords: Nibethione; antihypertensive effect; calcium channel; mechanism of action; molecular docking; vasorelaxant activity.