N-2 Polyphenol Targets Vascular Calcium Channels to Exert Antihypertensive Effects: In Vitro and In Vivo Evaluation
Alikhon Khasanov, Izzatullo Abdullaev, Shokhida Kadirova, Muxtorjon Mamajanov, Anvar Zaynabiddinov, Sirojiddin Omonturdiev, Л. У. Махмудов, Dolimjon Inomjonov, Ulugbek Gayibov, Rakhmat Sulton ugli Esanov, A. D. Matchanov · Trends in Sciences · 2025
This study investigated the antihypertensive potential of the natural compound N-2 polyphenol using both in vitro and in vivo approaches. In vitro assays focused on its effects on vascular smooth muscle cells, particularly voltage-dependent L-type calcium channels, receptor-operated calcium channels, and endothelium-mediated pathways. N-2 significantly inhibited Ca2+ influx through L-type channels, producing 86.2 ± 2.4% relaxation at 50 μM (IC5₀ = 30 μM), and suppressed receptor-operated channel-mediated contractions by 90.5 ± 3.5% at 45 μM. Endothelium-dependent vasorelaxation was partially mediated by nitric oxide (NO), as shown using the NOS inhibitor L-NAME (100 μM). In endothelium-denuded preparations, N-2 still reduced contractility by 38.0 ± 3.1%, suggesting partial NO-cGMP-PKG pathway involvement. In vivo, an adrenaline-induced hypertension model in rats showed that intravenous N-2 markedly lowered blood pressure. Three h after administration, systolic and diastolic pressures dropped to 74.7 ± 3.3 and 62.7 ± 4.1 mmHg, respectively. These results demonstrate that N-2 polyphenol exerts strong antihypertensive effects through both calcium channel blockade and endothelium-dependent mechanisms. Its dual mode of action highlights N-2 as a promising candidate for managing hypertension. HIGHLIGHTS N-2 polyphenol induced strong vasorelaxation in rat aortic rings. It inhibited L-type and receptor-operated Ca²⁺ channels effectively. Endothelium-dependent relaxation involved the NO–cGMP–PKG pathway. In vivo, N-2 lowered blood pressure in adrenaline-induced hypertension. N-2 is a promising natural antihypertensive candidate compound. GRAPHICAL ABSTRACT