Epidermal growth factor receptor phosphorylation contributes to levobupivacaine-induced contraction in isolated rat aorta

被引:2
作者
Lee, Soo Hee [1 ,2 ,3 ]
Ok, Seong-Ho [1 ,2 ,3 ]
Park, Kyeong-Eon [4 ]
Bae, Sung Il [4 ]
Hwang, Yeran [4 ]
Ahn, Seung Hyun [3 ,5 ]
Sim, Gyujin [3 ,5 ]
Bae, Moonju [5 ]
Sohn, Ju-Tae [3 ,4 ,6 ]
机构
[1] Gyeongsang Natl Univ, Changwon Hosp, Dept Anesthesiol & Pain Med, Changwon Si, Gyeongsangnam D, South Korea
[2] Gyeongsang Natl Univ, Coll Med, Dept Anesthesiol & Pain Med, Jinju Si, Gyeongsangnam D, South Korea
[3] Gyeongsang Natl Univ, Inst Med Sci, Jinju Si, Gyeongsangnam D, South Korea
[4] Gyeongsang Natl Univ, Coll Med, Gyeongsang Natl Univ Hosp, Dept Anesthesiol & Pain Med, 15 Jinju Daero 816 Beon Gil, Jinju Si 52727, Gyeongsangnam D, South Korea
[5] Gyeongsang Natl Univ Hosp, Dept Anesthesiol & Pain Med, 15 Jinju Daero 816 Beon Gil, Jinju Si 52727, Gyeongsangnam D, South Korea
[6] Gyeongsang Natl Univ, Gyeongsang Natl Univ Hosp, 79 Gangnam Ro, Jinju Si 52727, South Korea
基金
新加坡国家研究基金会;
关键词
Levobupivacaine; Calcium; Epidermal growth factor receptor; Vasoconstriction; c -Jun NH 2-Terminal kinase; VASCULAR SMOOTH-MUSCLE; VASOCONSTRICTION; ACTIVATION; TRANSACTIVATION; ROPIVACAINE; MECHANISMS; PATHWAYS; KINASES;
D O I
10.1016/j.ejphar.2024.176389
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Vasoconstriction induced by levobupivacaine, a local anesthetic, is mediated by increased levels of calcium, tyrosine kinase, c-Jun NH2-terminal kinase (JNK), and phospholipase D, which are associated with prolonged local anesthesia. Epidermal growth factor receptor (EGFR) phosphorylation is associated with vasoconstriction. However, its role in levobupivacaine-induced contractions remains unknown. We determined whether EGFR phosphorylation is associated with levobupivacaine-induced contractions in isolated rat thoracic aortas and identified the underlying cellular signaling pathways. The effects of various inhibitors and a calcium-free solution alone or in combination on levobupivacaine-induced contractions were then assessed. Furthermore, we examined the effects of various inhibitors on levobupivacaine-induced EGFR and JNK phosphorylation and calcium levels in vascular smooth muscle cells (VSMCs) of rat aortas. The EGFR tyrosine kinase inhibitor AG1478, matrix metalloproteinase (MMP) inhibitor GM6001, Src kinase inhibitors PP1 and PP2, and JNK inhibitor SP600125 attenuated levobupivacaine-induced contractions. Moreover, although the calcium-free solution abolished levobupivacaine-induced contractions, calcium reversed this inhibitory effect. The magnitude of the calcium-mediated reversal of abolished levobupivacaine-induced contractions was lower in the combination treatment with calcium-free solution and AG1478 than in the treatment with calcium-free solution alone. Levobupivacaine induced EGFR and JNK phosphorylation. However, AG1478, GM6001, and PP2 attenuated levobupivacaine-induced EGFR and JNK phosphorylation. Moreover, although levobupivacaine induced JNK phosphorylation in control siRNA-transfected VSMCs, EGFR siRNA inhibited levobupivacaine-induced JNK phosphorylation. Furthermore, AG1478 inhibited levobupivacaine-induced calcium increases in VSMCs. Collectively, these findings suggest that levobupivacaine-induced EGFR phosphorylation, which may occur via the Src kinase-MMP pathway, contributes to vasoconstriction via JNK phosphorylation and increased calcium levels.
引用
收藏
页数:9
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