Endothelium-Independent Vasorelaxant Effects of Sudachitin and Demethoxysudachitin, Polymethoxyflavone from the Peel of Citrus sudachi on Isolated Rat Aorta

• Published in: Biological & pharmaceutical bulletin 2023/11/01, Vol.46(11), pp.1583-1591
• Main Authors: Noguchi, Kazuo, Ueda, Chinami, Watanabe, Mako, Goma, Misaki, Umeda, Saki, Tabira, Sawako, Furuyama, Koto, Kanae, Haruna
• Format: Article
• Language: English
• Subjects: Adenylate cyclase; Aorta; Arginine; cAMP; Cardiovascular system; Citrus sudachi; Coronary vessels; Endothelium; Forskolin; guanosine 3′,5′-cyclic monophosphate (cGMP); Guanylate cyclase; Indomethacin; NG-Nitroarginine methyl ester; Nitric oxide; Nitric-oxide synthase; Phenylephrine; Phosphodiesterase; Phosphodiesterase inhibitors; polymethoxyflavone; Potassium chloride; Propranolol; Prostaglandin endoperoxide synthase; Quinoxaline; rat aorta; Sodium nitroprusside; sudachitin; Vasodilation; vasorelaxation
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b23-00386

Although polymethoxyflavones have been reported to exhibit various pharmacological actions, the effects of polymethoxyflavones sudachitin and demethoxysudachitin from the peel of Citrus sudachi on the cardiovascular system have not been clarified. This study investigated the mechanisms of vasorelaxation induced by sudachitin and demethoxysudachitin in rat aorta. Both compounds inhibited phenylephrine-induced contractions in a concentration-dependent manner. This was also observed in the case of potassium chloride (KCl)-induced contractions although the inhibitory effect was weak. In both contraction types, no differences were found in the inhibitory effects of sudachitin and demethoxysudachitin between endothelium-intact and -denuded aorta. The relaxant effects of sudachitin in endothelium-intact aortas were not affected by the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester hydrochloride (L-NAME) or the cyclooxygenase inhibitor indomethacin. In endothelium-denuded aorta, propranolol did not affect the relaxant effect of sudachitin. Both the adenylate cyclase activator forskolin- and soluble guanylate cyclase activator sodium nitroprusside-induced relaxant effects were potentiated by preincubation of sudachitin. Furthermore, the relaxant effect of sudachitin was not affected by the adenylate and guanylate cyclase inhibitors SQ22536 and or 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), respectively. Finally, we examined the effect of phosphodiesterase inhibition. Phosphodiesterase inhibitors (3-isobutyl-1-methylxanthine, cilostamide or sildenafil) alone, sudachitin alone, and a combination of phosphodiesterase inhibitors with sudachitin exhibited relaxant effects, while the lack of any interaction between each phosphodiesterase inhibitor and sudachitin indicated an additive effect between the two substance categories. These results suggest that sudachitin and demethoxysudachitin cause endothelial-independent relaxation, and that the mechanism of vasorelaxation by sudachitin is associated with the enhancement of cAMP- and guanosine 3′,5′-cyclic monophosphate (cGMP)-dependent pathways.