Ethanol extract of Piper nigrum L. fruit induces endothelium-independent vasorelaxation via calcium channel blockade and suppresses vascular smooth muscle cell proliferation and migration

The vascular system maintains physiological homeostasis, and its dysfunction contributes to the development of cardiovascular diseases. This study investigated the vasoprotective effects of Piper nigrum ethanol extract (PNE) and its major constituent, piperine, focusing on vascular contractility and angiotensin II (Ang II)-stimulated vascular smooth muscle cell (VSMC) responses. In isolated rat aortic rings, PNE induced potent endothelium-independent vasorelaxation and markedly suppressed extracellular Ca 2+ -dependent contractions elicited by phenylephrine and KCl, supporting an inhibitory effect on Ca 2+ -dependent contractile responses. PNE also attenuated Ang II-induced vascular contraction. At concentrations that were non-cytotoxic under basal conditions, PNE and piperine attenuated Ang II-induced proliferative and migratory responses. Furthermore, both PNE and piperine significantly attenuated Ang II-induced CaMKII phosphorylation, providing molecular evidence for modulation of Ca 2+ -dependent signaling. PNE exhibited greater vasorelaxant activity than the water extract, consistent with its substantially higher piperine content. Collectively, these findings indicate that PNE exerts vascular protective effects by modulating Ca 2+ -dependent contractile signaling and VSMC activation, supporting the potential of P. nigrum as a functional food resource for vascular health.