Abstract

Background and Purpose: Medicinal chemistry often utilizes natural products as a foundation for designing new drugs, including treatments for hypertension. In this study, we aimed to evaluate the beneficial vascular effects of a newly semi-synthesized chalcone derived from Senecio nutans metabolite-1 [4-hydroxy-3-(3-methyl-2-butenyl) acetophenone] in hypertensive rats. Experimental Approach: We investigated the vascular properties of a chalcone (CHAL13) through functional assays in the aorta of spontaneously hypertensive rats (SHR). We also used fluorescence microscopy, RT-qPCR, molecular docking, and X-ray crystallography. Key Results: CHAL13-induced vasorelaxation was unaffected by endothelial removal or inhibition of the eNOS-NO-sGC-cGMP signaling pathway in SHR. CHAL13 reduced extracellular Ca²⁺ influx in Ca²⁺-free medium and decreased KCl-induced intracellular Ca²⁺ increases in primary vascular smooth muscle cells (pVSMCs) loaded with Fluo-4 AM. CHAL13 also suppressed the contraction induced by the CaV1.2 agonist Bay-K8644 in SHR aortic rings, supporting a direct inhibitory effect on vascular CaV1.2 channels. Notably, activation of KCa, KV, and KATP channels contributed significantly to CHAL13’s vasorelaxant effect. Compared to its metabolite, CHAL13 exhibited stronger interactions with the pore-forming α1C subunit of the CaV1.2 channel, near the binding site of voltage-gated calcium channel blockers, and with the α1 subunit of the KCa1.1 channel, near the binding site of known channel activators. CHAL13 also showed predicted interactions with KV1.2 and vascular KATP channels. Aortic tissues treated with CHAL13 showed upregulated expression of Kcnmb1 and Kcna5 transcripts, which are associated with vascular relaxation. Conclusions and Implications: CHAL13 exerts a vasorelaxant effect primarily through CaV1.2 channel blockade and coordinated activation of multiple K⁺ channel subtypes, suggesting membrane hyperpolarization in vascular smooth muscle. Its favorable chemical, pharmacokinetic, and toxicological profiles support its potential as a novel antihypertensive scaffold.