title: Mepivacaine-induced contraction involves increased calcium sensitization mediated via Rho kinase and protein kinase C in endothelium-denuded rat aorta.
abstract: Mepivacaine is an aminoamide local anesthetic that produces vasoconstriction in vivo and in vitro. The goals of this in vitro study were to determine whether mepivacaine-induced contraction involves calcium sensitization in isolated endothelium-denuded aortas, and to investigate the specific protein kinases involved. The effects of mepivacaine and potassium chloride on intracellular calcium concentrations ([Ca(2+)]i) and tension in the presence or absence of Y-27632 or GF 109203X were measured simultaneously using the acetoxymethyl ester of fura-2-loaded aortic strips. Cumulative mepivacaine concentration-response curves were generated in the presence or absence of the following inhibitors: Rho kinase inhibitor Y-27632, protein kinase C (PKC) inhibitor GF 109203X, extracellular signal-regulated kinase (ERK) inhibitor PD 98059, c-Jun NH2-terminal kinase (JNK) inhibitor SP600125, and p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580. Phosphorylation of PKC and MAPK, and membrane translocation of Rho kinase were detected in vascular smooth muscle cells by Western blotting. The slope of the mepivacaine-induced [Ca(2+)]i-tension curve was higher than that of the KCl-induced [Ca(2+)]i-tension curve. Pretreatment with Y-27632 or GF 109203X shifted the mepivacaine-induced [Ca(2+)]i-tension curve to the lower right. Pretreatment with Y-27632, GF 109203X, PD 98059, or SP600125 attenuated mepivacaine-induced contraction in a concentration-dependent manner. Y-27632 and GF 109203X attenuated mepivacaine-induced Rho kinase membrane translocation and PKC phosphorylation, respectively. PD 98059 and SP600125 attenuated mepivacaine-induced ERK and JNK phosphorylation, respectively. Taken together, these results indicate that mepivacaine-induced contraction involves increased calcium sensitization mediated by Rho kinase and PKC. Such contraction mainly involves activation of ERK- and JNK-mediated pathways.
authors: Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors: Seong-Ho
authors: SH
authors: Ok
authors: Department of Physiology, Kwandong University College of Medicine, Kangneung 201-701, Republic of Korea.
authors: Seong-Chun
authors: SC
authors: Kwon
authors: Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju 660-702, Republic of Korea.
authors: Jeong
authors: J
authors: Yeol Han
authors: Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju 660-702, Republic of Korea.
authors: Jongsun
authors: J
authors: Yu
authors: Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors: Il-Woo
authors: IW
authors: Shin
authors: Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors: Heon-Keun
authors: HK
authors: Lee
authors: Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors: Young-Kyun
authors: YK
authors: Chung
authors: Department of Oral and Maxillofacial Surgery, Gyeongsang National University Hospital, Jinju 660-702, Republic of Korea.
authors: Mun-Jeoung
authors: MJ
authors: Choi
authors: Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea. Electronic address: jtsohn@nongae.gsnu.ac.kr.
authors: Ju-Tae
authors: JT
authors: Sohn
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D008297:Male; D008619:Mepivacaine / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000779:Anesthetics, Local; D047428:Protein Kinase Inhibitors; D008619:Mepivacaine; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D002118:Calcium
keywords: Aorta; Calcium sensitization; Contraction; GF 109203X (PubChem CID: 2396); Mepivacaine; Mepivacaine (PubChem CID: 66070); PD 98059 (PubChem CID: 4713); Protein kinase C; Rho kinase; SB 203580 (PubChem CID: 176155); SP600125 (PubChem CID: 8515); Y-27632 (PubChem CID: 9901617)