Screening Five Qi-Tonifying Herbs on M2 Phenotype Macrophages

Tumor-associated macrophages (TAMs) with M2 phenotype play an essential role in tumor microenvironment (TME) during the progression and development of numerous cancers and associated with poor prognosis. Thus, regulation of TAMs polarization emerged as a new strategy for tumor immune therapy. According to Traditional Chinese Medicine (TCM) theory, herbs with Qi-tonifying character are involved in improving the defense capacity of immune system. In this study, we screened extracts and ingredients from five Qi-tonifying herbs exhibiting an inhibitory effect on M2 polarization of murine macrophages RAW264.7 induced by IL-4 and IL-13. Among these candidates, total flavonoids from Glycyrrhiza Radix et Rhizoma (TFRG) and ethanol extract of Ginseng Radix et Rhizoma significantly inhibited the expression of Arginase-1 (Arg-1) (above 90% at 100μg/mL), one of the phenotype markers of M2 macrophages. The inhibition of total saponins of Ginseng Radix et Rhizoma, ethanol extract of Cordyceps, ethanol extract of Acanthopanacis senticosi Radix et Rhizoma Seu caulis, and ethanol extract of Astragali Radix reached above 50% at 100μg/mL. The inhibition of ingredients including glabridin, isoliquiritin apioside, lysionotin, cordycepin, astragaloside IV, and calycosin reached above 50% at 50μM. Then, we investigated the molecular mechanisms of TFRG. TFRG abolished the migration of murine breast cancer 4T1 stimulated by the conditioned medium from M2 macrophages (M2-CM). In addition to Arg-1, TFRG also antagonized the IL-4/13-mediated mRNA upregulation of the M2 markers including found in inflammatory zone 1 (FIZZ1), chitinase-3-like protein 3 (YM1), and mannose receptor (CD206) and upregulated the expression of inducible nitric oxide synthase (iNOS), one of the M1 markers. The further exploration showed that TFRG decreased the phosphorylation of STAT6 and increased the expression of miR-155. Our study provides a series of potential immune regulating natural products from five Qi-tonifying herbs on M2 phenotype. For instance, TFRG suppressed M2 polarization of macrophages partly by inactivating STAT6 pathway and enhanced the level of miR-155 to regulate the expressions of M1 and M2 markers.

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Tetracycline Analogs Inhibit Osteoclast Differentiation by Suppressing MMP-9-Mediated Histone H3 Cleavage

International Journal of Molecular Sciences ◽

10.3390/ijms20164038 ◽

2019 ◽

Vol 20 (16) ◽

pp. 4038 ◽

Cited By ~ 5

Author(s):

Yeojin Kim ◽

Jinman Kim ◽

Hyerim Lee ◽

Woo-Ri Shin ◽

Sheunghun Lee ◽

...

Keyword(s):

Molecular Mechanisms ◽

Osteoclast Differentiation ◽

Histone H3 ◽

Inhibitory Effect ◽

Osteoclast Formation ◽

Receptor Activator ◽

New Strategy ◽

Docking Approach ◽

Metalloproteinase 9

Osteoporosis is a common disorder of bone remodeling, caused by the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Recently, we reported that matrix metalloproteinase-9 (MMP-9)-dependent histone H3 proteolysis is a key event for proficient osteoclast formation. Although it has been reported that several MMP-9 inhibitors, such as tetracycline and its derivatives, show an inhibitory effect on osteoclastogenesis, the molecular mechanisms for this are not fully understood. Here we show that tetracycline analogs, especially tigecycline and minocycline, inhibit osteoclast formation by blocking MMP-9-mediated histone H3 tail cleavage. Our molecular docking approach found that tigecycline and minocycline are the most potent inhibitors of MMP-9. We also observed that both inhibitors significantly inhibited H3 tail cleavage by MMP-9 in vitro. These compounds inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast formation by blocking the NFATc1 signaling pathway. Furthermore, MMP-9-mediated H3 tail cleavage during osteoclast differentiation was selectively blocked by these compounds. Treatment with both tigecycline and minocycline rescued the osteoporotic phenotype induced by prednisolone in a zebrafish osteoporosis model. Our findings demonstrate that the tetracycline analogs suppress osteoclastogenesis via MMP-9-mediated H3 tail cleavage, and suggest that MMP-9 inhibition could offer a new strategy for the treatment of glucocorticoid-induced osteoporosis.

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Asaronic Acid Inhibited Glucose-Triggered M2-Phenotype Shift Through Disrupting the Formation of Coordinated Signaling of IL-4Rα-Tyk2-STAT6 and GLUT1-Akt-mTOR-AMPK

Nutrients ◽

10.3390/nu12072006 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2006

Author(s):

Hyeongjoo Oh ◽

Sin-Hye Park ◽

Min-Kyung Kang ◽

Yun-Ho Kim ◽

Eun-Jung Lee ◽

...

Keyword(s):

High Glucose ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Macrophage Polarization ◽

Arginase 1 ◽

M2 Polarization ◽

Functional Transition ◽

Functional Induction ◽

M2 Phenotype ◽

Functional Phenotype

Macrophage polarization has been implicated in the pathogenesis of metabolic diseases such as obesity, diabetes, and atherosclerosis. Macrophages responsiveness to polarizing signals can result in their functional phenotype shifts. This study examined whether high glucose induced the functional transition of M2 macrophages, which was inhibited by asaronic acid, one of purple perilla constituents. J774A.1 murine macrophages were incubated with 40 ng/mL interleukin (IL)-4 or exposed to 33 mM glucose in the presence of 1-20 μΜ asaronic acid. In macrophages treated with IL-4 for 48 h, asaronic acid further accelerated cellular induction of the M2 markers of IL-10, arginase-1, CD163, and PPARγ via increased IL-4-IL-4Rα interaction and activated Tyk2-STAT6 pathway. Asaronic acid promoted angiogenic and proliferative capacity of M2-polarized macrophages, through increasing expression of VEGF, PDGF, and TGF-β. In glucose-loaded macrophages, there was cellular induction of IL-4, IL-4 Rα, arginase-1, and CD163, indicating that high glucose skewed naïve macrophages toward M2 phenotypes via an IL-4-IL-4Rα interaction. However, asaronic acid inhibited M2 polarization in diabetic macrophages in parallel with inactivation of Tyk2-STAT6 pathway and blockade of GLUT1-mediated metabolic pathway of Akt-mTOR-AMPKα. Consequently, asaronic acid deterred functional induction of COX-2, CTGF, α-SMA, SR-A, SR-B1, and ABCG1 in diabetic macrophages with M2 phenotype polarity. These results demonstrated that asaronic acid allayed glucose-activated M2-phenotype shift through disrupting coordinated signaling of IL-4Rα-Tyk2-STAT6 in parallel with GLUT1-Akt-mTOR-AMPK pathway. Thus, asaronic acid has therapeutic potential in combating diabetes-associated inflammation, fibrosis, and atherogenesis through inhibiting glucose-evoked M2 polarization.

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Abstract 07: Collecting Duct (Pro) Renin Receptor(PRR) Promotes Kidney Fibrosis Via Macrophage Alternative Activation Mediated By Soluble PRR (sPRR)-Dependent Activation Of Yap/Taz Axis

Hypertension ◽

10.1161/hyp.78.suppl_1.07 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Ye Feng ◽

Shiying Xie ◽

Renfei Luo ◽

Fei Wang ◽

Tianxin Yang

Keyword(s):

Mrna Expression ◽

Collecting Duct ◽

Mannose Receptor ◽

Fine Tuning ◽

Alternative Activation ◽

Binding Motif ◽

M2 Macrophage ◽

Water Excretion ◽

Arginase 1 ◽

M2 Polarization

Renal collecting duct (CD), an important site for fine-tuning urinary Na + and water excretion, is not traditionally thought to play a role in pathogenesis of chronic kidney disease. In the present study, we examined a profibrotic role of CD PRR in a mouse model of unilateral ureteral obstruction (UUO) and further defined the underlying mechanism involving soluble PRR (sPRR)-dependent activation of alternative macrophages activation. We subjected mice with CD-specific deletion of PRR (CD PRR KO) and their floxed controls to UUO or sham surgery. After 7 days of UUO, CD PRR KO decreased the fibronectin (28.6±6.8%) and α-SMA (39.2±7.8%) protein expression in obstructed kidneys. The Masson’s trichrome staining data also showed that CD PRR KO significantly attenuated UUO-induced collagen deposition and histological damage in the kidney. In parallel, CD PRR KO reduced TGF-β1 (56.7±3.2%) and TGF-β2 (53±1.2%) mRNA expression in obstructed kidneys. Moreover, in macrophages sorted from obstructed kidneys of CD PRR KO mice showed a significantly reduced of M2 macrophage markers such as mannose receptor ( MR ) (58.7±2.1%), arginase-1 ( Arg-1 ) (50±1.5%), chitinase-like lectins ( YM-1 ) (59.3±1.9%), inflammatory zone-1 ( Fizz1 ) (39.1±4.1%) mRNA expression and Yes-associated protein ( Yap ) (77±6.8%)/ transcriptional coactivator with PDZ-binding motif ( Taz ) (54.5±1.8%) mRNA expression compared with macrophages sorted from obstructed kidneys of floxed mice. Meanwhile, plasma sPRR was elevated in floxed mice by UUO and this elevation was blunted by CD PRR KO (23.7±0.4%). Administration of site-1 protease (S1P) inhibitor PF-429242 to C57BL/6 mice with UUO almost completely recapitulated the antifibrotic action as well as the inhibitory effect on M2 activation of CD PRR KO. In bone marrow-derived macrophages, sPRR-His treatment promoted macrophage M2 polarization, fibrosis and Yap/Taz expression. Overall, these results suggest that activation of CD PRR releases sPRR that activates M2 polarization via Yap/Taz axis, leading to renal fibrosis during UUO.

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Ethanol Extract of Mylabris phalerata Inhibits M2 Polarization Induced by Recombinant IL-4 and IL-13 in Murine Macrophages

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/4218468 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Hwan-Suck Chung ◽

Bong-Seon Lee ◽

Jin Yeul Ma

Keyword(s):

Tumor Progression ◽

Ethanol Extract ◽

Mechanism Study ◽

M1 Macrophages ◽

Transwell Migration Assay ◽

Migration Assay ◽

Arginase 1 ◽

Anticancer Effects ◽

M2 Polarization ◽

Stat3 Phosphorylation

Mylabris phalerata (MP) is an insect used in oriental herbal treatments for tumor, tinea infections, and stroke. Recent studies have shown that tumor-associated macrophages (TAM) have detrimental roles such as tumor progression, angiogenesis, and metastasis. Although TAM has phenotypes and characteristics in common with M2-polarized macrophages, M1 macrophages have tumor suppression and immune stimulation effects. Medicines polarizing macrophages to M1 have been suggested to have anticancer effects via the modulation of the tumor microenvironment. In this line, we screened oriental medicines to find M1 polarizing medicines in M2-polarized macrophages. Among approximately 400 types of oriental medicine, the ethanol extract of M. phalerata (EMP) was the most proficient in increasing TNF-α secretion in M2-polarized macrophages and TAM. Although EMP enhanced the levels of an M1 cytokine (TNF-α) and a marker (CD86), it significantly reduced the levels of an M2 marker (arginase-1) in M2-polarized macrophages. In addition, EMP-treated macrophages increased the levels of M1 markers (Inos and Tnf-α) and reduced those of the enhanced M2 markers (Fizz-1, Ym-1, and arginase-1). EMP-treated macrophages significantly reduced Lewis lung carcinoma cell migration in a transwell migration assay and inhibited EL4-luc2 lymphoma proliferation. In our mechanism study, EMP was found to inhibit STAT3 phosphorylation in M2-polarized macrophages. These results suggest that EMP is effective in treating TAM-mediated tumor progression and metastasis.

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Anti-Inflammatory Effect of Rhapontici Radix Ethanol Extract via Inhibition of NF-κB and MAPK and Induction of HO-1 in Macrophages

Mediators of Inflammation ◽

10.1155/2016/7216912 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 11

Author(s):

Yun Hee Jeong ◽

You-Chang Oh ◽

Won-Kyung Cho ◽

Nam-Hui Yim ◽

Jin Yeul Ma

Keyword(s):

Molecular Mechanisms ◽

Nuclear Translocation ◽

Ethanol Extract ◽

Inhibitory Effect ◽

Peritoneal Macrophages ◽

Biological Properties ◽

Mapk Signaling ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Anti Inflammatory

Rhapontici Radix (RR) has been used in traditional medicine in East Asia and has been shown to have various beneficial effects. However, its biological properties or mechanism on inflammation-related diseases is unknown. The goal of this study was to determine the anti-inflammatory activity and underlying molecular mechanisms of Rhapontici Radix ethanol extract (RRE). The inhibitory effect of RRE on the production of NO, cytokines, inflammatory-related proteins, and mRNAs in LPS-stimulated macrophages was determined by the Griess assay, ELISA, Western blot analysis, and real-time RT-PCR, respectively. Our results indicate that treatment with RRE significantly inhibited the secretion of NO and inflammatory cytokines in RAW 264.7 cells and mouse peritoneal macrophages without cytotoxicity. We also found that RRE strongly suppressed the expression of iNOS and COX-2 and induced HO-1 expression. It also prevented nuclear translocation of NF-κB by inhibiting the phosphorylation and degradation of IκBα. Furthermore, the phosphorylation of MAPKs in LPS-stimulated RAW 264.7 cells was significantly inhibited by RRE. These findings suggest that RRE may operate as an effective anti-inflammatory agent by inhibiting the activation of NF-κB and MAPK signaling pathways and inducing HO-1 expression in macrophages. Our results suggest that RRE has potential value as candidate to inflammatory therapeutic phytomedicine.

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M2 Macrophages as a Potential Target for Antiatherosclerosis Treatment

Neural Plasticity ◽

10.1155/2019/6724903 ◽

2019 ◽

Vol 2019 ◽

pp. 1-21 ◽

Cited By ~ 20

Author(s):

Ying Bi ◽

Jixiang Chen ◽

Feng Hu ◽

Jing Liu ◽

Man Li ◽

...

Keyword(s):

Current Treatment ◽

Membrane Receptors ◽

Pomegranate Juice ◽

Lipid Lowering ◽

Inflammatory Factors ◽

Atherosclerotic Cardiovascular Disease ◽

M2 Macrophages ◽

Collagen Formation ◽

M2 Polarization ◽

M2 Phenotype

Atherosclerosis is a chronic progressive inflammation course, which could induce life-threatening diseases such as stroke and myocardial infarction. Optimal medical treatments for atherosclerotic risk factors with current antihypertensive and lipid-lowering drugs (for example, statins) are widely used in clinical practice. However, many patients with established disease still continue to have recurrent cardiovascular events in spite of treatment with a state-of-the-art therapy. Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Hence, current treatment of atherosclerosis is still far from being satisfactory. Recently, M2 macrophages have been found associated with atherosclerosis regression. The M2 phenotype can secrete anti-inflammatory factors such as IL-10 and TGF-β, promote tissue remodeling and repairing through collagen formation, and clear dying cells and debris by efferocytosis. Therefore, modulators targeting macrophages’ polarization to the M2 phenotype could be another promising treatment strategy for atherosclerosis. Two main signaling pathways, the Akt/mTORC/LXR pathway and the JAK/STAT6 pathway, are found playing important roles in M2 polarization. In addition, researchers have reported several potential approaches to modulate M2 polarization. Inhibiting or activating some kinds of enzymes, affecting transcription factors, or acting on several membrane receptors could regulate the polarization of the M2 phenotype. Besides, biomolecules, for example vitamin D, were found to affect the process of M2 polarization. Pomegranate juice could promote M2 polarization via unclear mechanism. In this review, we will discuss how M2 macrophages affect atherosclerosis regression, signal transduction in M2 polarization, and outline potential targets and compounds that affect M2 polarization, thus controlling the progress of atherosclerosis.

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Asaronic Acid Inhibited Glucose-Triggered M2-Phenotype Shift Through Disrupting the Formation of Coordinated Signaling of IL-4Rα-Tyk2-STAT6 and GLUT1-Akt-mTOR-AMPK

Current Developments in Nutrition ◽

10.1093/cdn/nzaa052_035 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 766-766

Author(s):

Hyeongjoo Oh ◽

Young-Hee Kang

Keyword(s):

High Glucose ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Macrophage Polarization ◽

Funding Sources ◽

Arginase 1 ◽

M2 Polarization ◽

Inflammatory State ◽

Functional Induction ◽

M2 Phenotype

Abstract Objectives Macrophage polarization has been implicated in the pathogenesis of metabolic diseases such as obesity, diabetes and atherosclerosis. Macrophages responsive to polarizing signals can result in their functional phenotype shifts. This study examined whether high glucose induced the functional transition of M2 macrophages, which was inhibited by asaronic acid, one of purple perilla constituents. Methods J774A.1 murine macrophages were incubated with 40 ng/ml interleukin(IL)-4 or 33 mM glucose in the absence and presence of 1–20 μΜ asaronic acid, which led to M2 or diabetic inflammatory state at 48 h. TheM2 macrophage biomarkers were estimated by conducting Western blot analysis, IHC and ELISA with specific antibodies. Results In macrophages treated with IL-4 for 48 h, asaronic acid further accelerated cellular induction of the M2 markers of IL-10, arginase-1, CD163 and PPARγ via increased IL-4-IL-4Rα interaction and activated Tyk2-STAT6 pathway. Asaronic acid promoted angiogenic and proliferative capacity of M2-polarized macrophages, through increasing expression of VEGF, PDGF and TGF-β. In glucose-loaded macrophages there was cellular induction of IL-4, IL-4 Rα, arginase-1 and CD163, indicating that high glucose skewed naïve macrophages toward M2 phenotypes. However, asaronic acid inhibited M2 polarization in diabetic macrophages in parallel with inactivation of Tyk2-STAT6pathway and blockade of GLUT1-mediated metabolic pathway of Akt-mTOR-AMPKα. Consequently, asaronic acid deterred functional induction of COX-2, CTGF, α-SMA, SR-A and SR-B1in diabetic macrophages with M2 phenotype. Conclusions These results demonstrated that asaronic acid allayed glucose-activated M2-phenotype shift through disrupting coordinated signaling of IL-4Rα-Tyk2-STAT6 in parallel with GLUT1-Akt-mTOR-AMPK pathway. Thus, asaronic acid has therapeutic potential in combating diabetes-associated inflammation, fibrosis, and atherogenesis through inhibiting glucose-evoked M2 polarization. Funding Sources This work was supported by the Hallym University Research Fund, 2019 (HRF-201,910–007) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2019R1A2C1003218).

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E6 and E7 oncoproteins: Potential targets of cervical cancer

Current Medicinal Chemistry ◽

10.2174/0929867327666201111145546 ◽

2020 ◽

Vol 27 ◽

Author(s):

Ramarao Malla ◽

Mohammad Amjad Kamal

Keyword(s):

Cervical Cancer ◽

Drug Resistance ◽

Host Cell ◽

Molecular Mechanisms ◽

Immune Therapy ◽

Cervical Lesions ◽

Diagnostic Strategies ◽

E6 And E7 Oncoproteins ◽

E6 And E7

: Cervical cancer (CC) is the fourth leading cancer in women in the age group 15-44 globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers the recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies could be useful for the prevention and treatment of cervical cancer.

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Natural Products for Regulating Macrophages M2 Polarization

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190523093535 ◽

2020 ◽

Vol 15 (7) ◽

pp. 559-569 ◽

Cited By ~ 1

Author(s):

Zhen Chang ◽

Youhan Wang ◽

Chang Liu ◽

Wanli Smith ◽

Lingbo Kong

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Therapeutic Strategies ◽

Research Progress ◽

Cellular Mechanisms ◽

Pharmacological Activities ◽

Current Review ◽

M2 Polarization ◽

Macrophages Polarization ◽

Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

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Molecular Mechanisms of the Inhibitory Effects of Bupivacaine, Levobupivacaine, and Ropivacaine on Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channels in the Cardiovascular System

Anesthesiology ◽

10.1097/00000542-200408000-00020 ◽

2004 ◽

Vol 101 (2) ◽

pp. 390-398 ◽

Cited By ~ 24

Author(s):

Takashi Kawano ◽

Shuzo Oshita ◽

Akira Takahashi ◽

Yasuo Tsutsumi ◽

Yoshinobu Tomiyama ◽

...

Keyword(s):

Cardiovascular System ◽

Adenosine Triphosphate ◽

Local Anesthetics ◽

Molecular Mechanisms ◽

Transmembrane Domain ◽

Katp Channels ◽

Inhibitory Effect ◽

Amino Acid Residues ◽

Sulfonylurea Receptor ◽

Inhibitory Effects

Background Sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted KATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits. Methods The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted KATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs. Results Bupivacaine inhibited the activities of cardiac KATP channels (IC50 = 52 microm) stereoselectively (levobupivacaine, IC50 = 168 microm; ropivacaine, IC50 = 249 microm). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2 delta C36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac KATP channels with approximately eightfold higher potency than vascular KATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit. Conclusions Inhibitory effects of local anesthetics on KATP channels in the cardiovascular system are (1) stereoselective: bupivacaine was more potent than levobupivacaine and ropivacaine; and (2) tissue specific: local anesthetics blocked cardiac KATP channels more potently than vascular KATP channels, via the intracellular pore mouth of the Kir6.0 subunit and the 42 amino acids at the C-terminal tail of the SUR2A subunit, respectively.

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