Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, 15 Jinju-daero 816 Beon-gil, Jinju-si 52727, Gyeongsangnam-do, Republic of Korea.
Department of Anesthesiology and Pain Medicine, Gyeongsang National University Changwon Hospital, Changwon-si 51472, Gyeongsangnam-do, Republic of Korea.
Int J Mol Sci. 2023 May 14;24(10):8741. doi: 10.3390/ijms24108741.
This study aimed to examine the effect of lipid emulsion on the vasodilation induced by a toxic dose of amlodipine in isolated rat aorta and elucidate its mechanism, with a particular focus on nitric oxide. The effects of endothelial denudation, N-nitro-L-arginvine methyl ester (L-NAME), methylene blue, lipid emulsion, and linolenic acid on the amlodipine-induced vasodilation and amlodipine-induced cyclic guanosine monophosphate (cGMP) production were examined. Furthermore, the effects of lipid emulsion, amlodipine, and PP2, either alone or combined, on endothelial nitric oxide synthase (eNOS), caveolin-1, and Src-kinase phosphorylation were examined. Amlodipine-induced vasodilation was higher in endothelium-intact aorta than in endothelium-denuded aorta. L-NAME, methylene blue, lipid emulsion, and linolenic acid inhibited amlodipine-induced vasodilation and amlodipine-induced cGMP production in the endothelium-intact aorta. Lipid emulsion reversed the increased stimulatory eNOS (Ser1177) phosphorylation and decreased inhibitory eNOS (Thr495) phosphorylation induced via amlodipine. PP2 inhibited stimulatory eNOS, caveolin-1, and Src-kinase phosphorylation induced via amlodipine. Lipid emulsion inhibited amlodipine-induced endothelial intracellular calcium increase. These results suggest that lipid emulsion attenuated the vasodilation induced via amlodipine through inhibiting nitric oxide release in isolated rat aorta, which seems to be mediated via reversal of stimulatory eNOS (Ser1177) phosphorylation and inhibitory eNOS (Thr495) dephosphorylation, which are also induced via amlodipine.
本研究旨在探讨脂肪乳剂对分离大鼠主动脉中毒剂量氨氯地平诱导的血管舒张的影响，并阐明其机制，特别是一氧化氮。观察了内皮剥脱、N-硝基-L-精氨酸甲酯（L-NAME）、亚甲蓝、脂肪乳剂和亚麻酸对氨氯地平诱导的血管舒张和氨氯地平诱导的环鸟苷单磷酸（cGMP）产生的影响。此外，还观察了脂肪乳剂、氨氯地平和 PP2 单独或联合对内皮型一氧化氮合酶（eNOS）、窖蛋白-1 和Src-激酶磷酸化的影响。与内皮剥脱的主动脉相比，完整内皮的主动脉中氨氯地平诱导的血管舒张作用更高。L-NAME、亚甲蓝、脂肪乳剂和亚麻酸抑制完整内皮的主动脉中氨氯地平诱导的血管舒张和氨氯地平诱导的 cGMP 产生。脂肪乳剂逆转了氨氯地平诱导的 eNOS（Ser1177）磷酸化增加和 eNOS（Thr495）磷酸化抑制。PP2 抑制了氨氯地平诱导的 eNOS、窖蛋白-1 和 Src-激酶磷酸化。脂肪乳剂抑制了氨氯地平诱导的内皮细胞内钙增加。这些结果表明，脂肪乳剂通过抑制分离大鼠主动脉中一氧化氮的释放来减轻氨氯地平诱导的血管舒张，这似乎是通过逆转氨氯地平诱导的刺激型 eNOS（Ser1177）磷酸化和抑制型 eNOS（Thr495）去磷酸化来介导的。
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