Applied Science and Environmental Studies, Department of Science, School of Science and Technology, The Open University of Hong Kong, Hong Kong.
Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong.
Eur J Pharmacol. 2021 Aug 15;905:174190. doi: 10.1016/j.ejphar.2021.174190. Epub 2021 May 18.
Narirutin is one of the most common flavanones found in citrus fruits. The vascular effects of its analogues naringenin and naringin have been reported but its effects on the cardiovascular system are largely unknown. In this study, relaxation effect of narirutin and its mechanisms of action were investigated by measuring isometric tension in rat mesenteric arteries. Patch-clamping was also used to study the effect of narirutin on potassium channels in vascular smooth muscle cells. Moreover, its effects on phosphorylation of endothelial nitric oxide synthase, cAMP level and phosphodiesterase activity in rat mesenteric arteries were studied by Western blot and biochemical assays. The results showed that pre-incubation of rat mesenteric arteries with narirutin had no influence on acetylcholine-induced endothelial-dependent relaxation. However, narirutin caused a direct concentration-dependent relaxation in rat mesenteric arteries. This relaxation effect was comparable to that of narirutin's structural analogue naringenin. Narirutin-induced relaxation was reduced by the removal of endothelium, N-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), and 4-aminopyridine (a voltage-gated potassium channel blocker). In addition, narirutin increased the phosphorylation of endothelial nitric oxide synthase and increased the voltage-dependent potassium current in mesenteric arterial smooth muscle cells. These effects were abolished by protein kinase A inhibitor. Furthermore, narirutin could increase cAMP level and inhibit phosphodiesterase activity in rat mesenteric arteries. In conclusion, narirutin has vasorelaxing effect and the mechanism involves the inhibition of phosphodiesterase, which increases intracellular cAMP, thereby stimulating the endothelial nitric oxide synthase and activating the voltage-gated potassium channels in vascular smooth muscle cells.
柚皮苷是柑橘类水果中最常见的类黄酮之一。已报道其类似物柚皮素和柚皮苷的血管作用，但柚皮苷对心血管系统的影响在很大程度上尚不清楚。在这项研究中，通过测量大鼠肠系膜动脉的等长张力来研究柚皮苷的舒张作用及其作用机制。还使用膜片钳技术研究柚皮苷对血管平滑肌细胞钾通道的影响。此外，通过Western blot 和生化测定研究柚皮苷对大鼠肠系膜动脉内皮型一氧化氮合酶磷酸化、cAMP 水平和磷酸二酯酶活性的影响。结果表明，柚皮苷预孵育对乙酰胆碱诱导的内皮依赖性舒张没有影响。然而，柚皮苷可直接引起大鼠肠系膜动脉浓度依赖性舒张。这种舒张作用与柚皮苷的结构类似物柚皮素相当。柚皮苷诱导的舒张作用被去除内皮、N-硝基-L-精氨酸甲酯（一氧化氮合酶抑制剂）和 4-氨基吡啶（电压门控钾通道阻滞剂）所减弱。此外，柚皮苷增加了内皮型一氧化氮合酶的磷酸化，并增加了肠系膜动脉平滑肌细胞中的电压依赖性钾电流。这些作用被蛋白激酶 A 抑制剂所阻断。此外，柚皮苷可增加大鼠肠系膜动脉中的 cAMP 水平并抑制磷酸二酯酶活性。总之，柚皮苷具有血管舒张作用，其机制涉及抑制磷酸二酯酶，从而增加细胞内 cAMP，从而刺激内皮型一氧化氮合酶并激活血管平滑肌细胞中的电压门控钾通道。
