Novel Oxime Synthesized from a Natural Product of Senecio nutans SCh. Bip. (Asteraceae) Enhances Vascular Relaxation in Rats by an Endothelium-Independent Mechanism.

Senecio nutans Sch. Bip. and its constituents are reported to have antihypertensive effects. We isolated metabolite-1, a natural compound from S. nutans (4-hydroxy-3-(isopenten-2-yl)-acetophenone), and synthesized novel oxime - 1 (4-hydroxy-3-(isopenten-2-yl)-acetophenoxime) to evaluate their effect on vascular reactivity. Compounds were purified (metabolite-1) or synthetized (oxime-1) and characterized using IR and NMR spectroscopy and Heteronuclear Multiple Quantum Coherence (HMQC). Using pharmacological agents such as phenylephrine (PE) and KCl (enhancing contraction), acetylcholine (ACh), L-NAME (nitric oxide (NO) and endothelial function), Bay K8644-induced Ca V1.2 channel (calcium channel modulator), and isolated aortic rings in an organ bath setup, the possible mechanisms of vascular action were determined. Pre-incubation of aortic rings with 10 -5 M oxime-1 significantly ( p < 0.001) decreased the contractile response to 30 mM KCl. EC 50 to KCl significantly ( p < 0.01) increased in the presence of oxime-1 (37.72 ± 2.10 mM) compared to that obtained under control conditions (22.37 ± 1.40 mM). Oxime-1 significantly reduced ( p < 0.001) the contractile response to different concentrations of PE (10 -7 to 10 -5 M) by a mechanism that decreases Cav1.2-mediated Ca 2+ influx from the extracellular space and reduces Ca 2+ release from intracellular stores. At a submaximal concentration (10 -5 M), oxime-1 caused a significant relaxation in rat aorta even without vascular endothelium or after pre-incubate the tissue with L-NAME. Oxime-1 decreases the contractile response to PE by blunting the release of Ca 2+ from intracellular stores and blocking of Ca 2+ influx by channels. Metabolite-1 reduces the contractile response to KCl, apparently by reducing the plasma membrane depolarization and Ca 2+ influx from the extracellular space. These acetophenone derivates from S. nutans (metabolite-1 and oxime-1) cause vasorelaxation through pathways involving an increase of the endothelial NO generation or a higher bioavailability, further highlighting that structural modification of naturally occurring metabolites can enhance their intended pharmacological functions.