Naringenin promotes coronary vasodilation via inhibition of L-type calcium channels (CaV1.2): Evidence from tissue bath and molecular studies.

Naringenin, a citrus-derived flavanone, was investigated for its vasorelaxant mechanisms in goat coronary arteries, focusing on endothelial signaling and direct inhibition of L-type calcium channels (CaV1.2). In silico docking against a homology-modeled CaV1.2 channel revealed that naringenin exhibited the highest binding affinity (-8.5 kcal/mol) among ten related flavanones, forming stabilizing interactions within the channel's pore region. To further validate this interaction, molecular dynamics simulations demonstrated sustained complex stability, minimal structural deviation, and consistent intermolecular contacts throughout the trajectory. RMSD, RMSF, and radius of gyration analyzes confirmed that binding did not disrupt channel architecture, while hydrogen bond analysis indicated predominantly hydrophobic and van der Waals-mediated stabilization features consistent with reversible channel blockade. Complementary to it, in silico patch clamp analysis demonstrated marked suppression of calcium ion current, reduced conductance, and altered electrostatic potential without affecting voltage dependence, confirming naringenin's functional inhibition of CaV1.2 channels. Ex vivo organ bath studies on isolated coronary artery rings showed potent, concentration-dependent relaxation to naringenin, markedly attenuated by endothelial denudation or blockade of nitric oxide synthase (L-NAME), cyclooxygenase (indomethacin), and soluble guanylate cyclase (ODQ), implicating NO and prostacyclin pathways. Under depolarized, calcium-free conditions, naringenin significantly reduced calcium-induced contractions and potentiated nifedipine's effect, confirming inhibition of voltage-gated calcium influx. RT-PCR verified CACNA1C gene expression in goat coronary tissue. Collectively, these results indicate that naringenin modulates vascular tone via dual pathways: endothelial NO/COX signaling and reversible CaV1.2 channel inhibition. This integrative mechanistic profile supports its potential as a therapeutic candidate for vascular dysfunction and coronary artery disease.