British journal of pharmacology · 2026
Pharmacological and molecular characterization of a chalcone analogue derived from a Senecio nutans metabolite: Modulation of CaV1.2 and KCa1.1 channels in hypertensive rats.
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Asunción-Alvarez Daniel, Palacios Javier, Cifuentes Fredi, Ruiz Karina B, Paredes Adrián, Brito Iván, Delgado Gerzon E, Nwokocha Chukwuemeka R, Parra Claudio
Аннотация
BACKGROUND AND PURPOSE: In this study, we evaluated the beneficial vascular effects of a newly semi-synthesized chalcone derived from the Senecio nutans metabolite-1 [4-hydroxy-3-(3-methyl-2-butenyl) acetophenone] in hypertensive rats. We investigated chalcone (CHAL13) through functional assays in spontaneously hypertensive rat (SHR) aorta. 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 signalling 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). 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 with its precursor 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 favourable chemical, pharmacokinetic and toxicological profiles support its potential as a novel antihypertensive scaffold.
KEY RESULTS: CHAL13-induced vasorelaxation was unaffected by endothelial removal or inhibition of the eNOS-NO-sGC-cGMP signalling 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). 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 with its precursor 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 favourable chemical, pharmacokinetic and toxicological profiles support its potential as a novel antihypertensive scaffold.