Molecular Mechanisms and Experimental Protocols in the Study of Vasorelaxant Activity in Aortic Smooth Muscle Cells

Vasorelaxation is a key process in cardiovascular regulation and a promising target for treating hypertension and vascular dysfunctions. This study outlines a comprehensive experimental framework for evaluating vasorelaxant mechanisms in isolated rat aortic rings using isometric tension recording. A combination of pharmacological tools and ionic modulation was used to explore the roles of voltage-dependent calcium channels, GPCR signaling, intracellular calcium stores (SERCA and ryanodine receptors), ion exchangers (NCX, Na⁺/K⁺-ATPase) and endothelium-derived factors. Computational docking complemented experimental data by identifying ligand-binding sites on key ion channels. Findings revealed that vasorelaxation involves multifaceted modulation of calcium influx, receptor-mediated signaling, and intracellular calcium cycling, with both endothelium-dependent and -independent pathways contributing. This integrative approach provides novel insights into vascular smooth muscle regulation and supports the development of targeted cardiovascular therapies. HIGHLIGHTS Isolated rat aortic rings were used to evaluate vasorelaxation via isometric tension recording. Pharmacological modulators revealed roles of VGCCs, GPCR pathways, SERCA, RyR, NCX, and Na⁺/K⁺-ATPase in vascular relaxation. Endothelium-dependent and -independent mechanisms both contributed to the vasorelaxant responses. Intracellular Ca²⁺ cycling and reduced Ca²⁺ influx were identified as key determinants of smooth muscle relaxation. Computational docking supported experimental findings by identifying ligand-binding sites on major ion channels. The integrated experimental–computational approach provides insights for developing targeted cardiovascular therapeutics. GRAPHICAL ABSTRACT

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