Antihypertensive Effects of Compound A-42 via Regulation of Calcium-Dependent Ion Transport Systems

Abstract

Hypertension is a complex cardiovascular disorder associated with impaired calcium (Ca²⁺) regulation in vascular smooth muscle and cardiac tissues. The present study investigated the antihypertensive potential of a new bioactive compound, A-42, through a combined in silico and in vivo approach. Molecular docking analysis demonstrated that A-42 interacts with several calcium-regulating proteins, including L-type and R-type Ca²⁺ channels, SERCA, RyR2, Ca²⁺-ATPase, Na⁺/Ca²⁺ exchanger (NCX), and renin. The compound exhibited notable binding affinities, with binding energies ranging from –5.3 to –6.2 kcal/mol. The strongest affinities were observed for the L-type Ca²⁺ channel (–6.2 kcal/mol), SERCA (–6.0 kcal/mol), and NCX (–6.0 kcal/mol). Key amino acid interactions included hydrogen bonds and π–alkyl or π–anion interactions with residues such as ARG A:593, PHE A:587, LEU F:269, LYS A:158, THR A:230, and ASP A:829, indicating a stable ligand–protein complex formation and potential calcium-channel-modulating activity. The in vivo studies, performed using the tail-cuff method, confirmed the hypotensive effects of A-42 in rats. Intravenous administration at doses of 10, 20, and 30 mg/kg led to a dose-dependent reduction in systolic and diastolic blood pressure. The 20 mg/kg dose produced the most pronounced and stable antihypertensive effect, significantly lowering blood pressure (p-value < 0.05) and preventing the sharp rise in pressure induced by adrenaline in the hypertensive model. In the adrenaline-induced hypertension model, the systolic and diastolic pressures in A-42–treated rats decreased from 138.3 ± 13.6 / 102.8 ± 10.1 mmHg to 103.8 ± 11.2 / 73.5 ± 8.7 mmHg, respectively, within the first hour of administration. The combined in silico and in vivo results indicate that compound A-42 acts as a multi-target modulator of calcium homeostasis, affecting both membrane and intracellular Ca²⁺ transport systems. These interactions likely contribute to its antihypertensive mechanism by reducing intracellular Ca²⁺ influx, enhancing Ca²⁺ sequestration, and restoring vascular tone.

HIGHLIGHTS

• A-42 exhibits potent antihypertensive activity through multi-target calcium regulation.
• Molecular docking revealed strong binding of A-42 to L-type Ca²⁺ channels, SERCA, and NCX (–6.0 to –6.2 kcal/mol).
• Key hydrogen bonding and π-interactions indicate stable A-42–protein complex formation.
• In vivo studies confirmed dose-dependent blood pressure reduction in hypertensive rats.
• A-42 restores vascular tone by modulating both membrane and intracellular Ca²⁺ transport systems.

GRAPHICAL ABSTRACT