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      Midazolam’s Effects on Delayed-Rectifier K + Current and Intermediate-Conductance Ca 2+-Activated K + Channel in Jurkat T-lymphocytes

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          Abstract

          Midazolam (MDZ) could affect lymphocyte immune functions. However, the influence of MDZ on cell’s K + currents has never been investigated. Thus, in the present study, the effects of MDZ on Jurkat T lymphocytes were studied using the patch-clamp technique. Results showed that MDZ suppressed the amplitude of delayed-rectifier K + current ( I K(DR)) in concentration-, time-, and state-dependent manners. The IC 50 for MDZ-mediated reduction of I K(DR) density was 5.87 μM. Increasing MDZ concentration raised the rate of current-density inactivation and its inhibitory action on I K(DR) density was estimated with a dissociation constant of 5.14 μM. In addition, the inactivation curve of I K(DR) associated with MDZ was shifted to a hyperpolarized potential with no change on the slope factor. MDZ-induced inhibition of I K(DR) was not reversed by flumazenil. In addition, the activity of intermediate-conductance Ca 2+-activated K + (IK Ca) channels was suppressed by MDZ. Furthermore, inhibition by MDZ on both I K(DR) and IK Ca-channel activity appeared to be independent from GABAA receptors and affected immune-regulating cytokine expression in LPS/PMA-treated human T lymphocytes. In conclusion, MDZ suppressed current density of I K(DR) in concentration-, time-, and state-dependent manners in Jurkat T-lymphocytes and affected immune-regulating cytokine expression in LPS/PMA-treated human T lymphocytes.

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          Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation.

          Manreetpal S. Brar, Wansu Chen, Claus Jørgensen … (2007)
          This study was designed to study racial/ethnic differences in the risk for intracranial hemorrhage (ICH) and the effect of warfarin on ICH risk among patients with atrial fibrillation (AF). Nonwhites are at greater risk for ICH than whites in the general population. Whether this applies to patients with AF and whether warfarin therapy is associated with comparable risk of ICH in nonwhites are unknown. We retrospectively identified a multiethnic stroke-free cohort hospitalized with nonrheumatic AF. Warfarin use and anticoagulation intensity were assessed by searching pharmacy and laboratory records. Crude ICH event rates were calculated by Poisson regression. Cox proportional hazard models were constructed to assess the independent effect of race/ethnicity on ICH after adjusting for age, gender, hypertension, diabetes, heart failure, and warfarin exposure. Between 1995 and 2000, we identified 18,867 qualifying AF hospitalizations (78.5% white, 8% black, 9.5% Hispanic, and 3.9% Asian) and 173 qualifying ICH events over 3.3 years follow-up. Achieved anticoagulation intensity was lower among blacks but not different between the other groups. Warfarin was associated with increased ICH risk in all races, but the magnitude of risk was greater among nonwhites. There were no gender differences. The hazard ratio for ICH with whites as referent was 4.06 for Asians (95% confidence interval [CI] 2.47 to 6.65), 2.06 for Hispanics (95% CI 1.31 to 3.24), and 2.04 (95% CI 1.25 to 3.35) for blacks. Nonwhites with AF were at greater risk for warfarin-related ICH. Blacks, Hispanics, and Asians were at successively greater ICH risk than whites.
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            Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes.

            Mario Zoratti, Florian J. Bock, Barbara Wilker … (2008)
            The potassium channel Kv1.3 has recently been located to the inner mitochondrial membrane of lymphocytes. Here, we show that mouse and human cells either genetically deficient in Kv1.3 or transfected with siRNA to suppress Kv1.3-expression resisted apoptosis induced by several stimuli, including Bax over-expression [corrected]. Retransfection of either Kv1.3 or a mitochondrial-targeted Kv1.3 restored cell death . Bax interacted with and functionally inhibited mitochondrial Kv1.3. Incubation of isolated Kv1.3-positive mitochondria with recombinant Bax, t-Bid, or toxins that bind to and inhibit Kv1.3 successively triggered hyperpolarization, formation of reactive oxygen species, release of cytochrome c, and marked depolarization. Kv1.3-deficient mitochondria were resistant to Bax, t-Bid, and the toxins. Mutation of Bax at K128, which corresponds to a conserved lysine in Kv1.3-inhibiting toxins, abrogated its effects on both Kv1.3 and mitochondria. These findings suggest that Bax mediates cytochrome c release and mitochondrial depolarization in lymphocytes, at least in part, via its interaction with mitochondrial Kv1.3.
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              Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells

              Luigi Leanza, Brian Henry, Nicola Sassi … (2012)
              Overcoming the resistance of tumours to chemotherapy, often due to downregulation of Bax and Bak, represents a significant clinical challenge. It is therefore important to identify novel apoptosis inducers that bypass Bax and Bak. Potassium channels are emerging as oncological targets and a crucial role of mitochondrial Kv1.3 in apoptosis has been demonstrated. Here we report for the first time that Psora-4, PAP-1 and clofazimine, three distinct membrane-permeant inhibitors of Kv1.3, induce death by directly targeting the mitochondrial channel in multiple human and mouse cancer cell lines. Importantly, these drugs activated the intrinsic apoptotic pathway also in the absence of Bax and Bak, a result in agreement with the current mechanistic model for mitochondrial Kv1.3 action. Genetic deficiency or short interfering RNA (siRNA)-mediated downregulation of Kv1.3 abrogated the effects of the drugs. Intraperitoneal injection of clofazimine reduced tumour size by 90% in an orthotopic melanoma B16F10 mouse model in vivo, while no adverse effects were observed in several healthy tissues. The study indicates that inhibition of mitochondrial Kv1.3 might be a novel therapeutic option for the induction of cancer cell death independent of Bax and Bak.
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                Author and article information

                Contributors
                Victor V. Nikonenko: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 04 July 2021
                Publication date Collection: July 2021
                Volume: 22
                Issue: 13
                Electronic Location Identifier: 7198
                Affiliations
                [1 ]Department of Emergency Medicine, An Nan Hospital, China Medical University, Tainan City 709204, Taiwan; ningping.tw@ 123456gmail.com
                [2 ]Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan City 711301, Taiwan
                [3 ]Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City 100233, Taiwan; uys1222@ 123456gmail.com
                [4 ]Department of Biomedical Engineering, National Cheng Kung University, Tainan City 70101, Taiwan; wbcxyz@ 123456gmail.com
                [5 ]Institute of Oral Medicine and Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City 704302, Taiwan
                [6 ]Center of Applied Nanomedicine, National Cheng Kung University, Tainan City 70101, Taiwan
                [7 ]Medical Device Innovation Center, Taiwan Innovation Center of Medical Devices and Technology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan City 704302, Taiwan
                [8 ]Department of Anesthesia, Chi Mei Medical Center, Tainan City 710402, Taiwan; biohsing@ 123456gmail.com
                [9 ]Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan City 70101, Taiwan
                [10 ]Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404332, Taiwan
                [11 ]Department of Anesthesia & Medical Research, An Nan Hospital, China Medical University, Tainan City 709204, Taiwan
                Author notes
                [* ]Correspondence: bumiin@ 123456mail.ncku.edu.tw (B.-M.H.); edmundsotw@ 123456gmail.com (E.-C.S.); Tel.: +886-6-2353535-5337 (B.-M.H.); +886-6-3553111-1517 (E.-C.S.)
                Author information
                https://orcid.org/0000-0002-2480-8843
                Article
                Publisher ID: ijms-22-07198
                DOI: 10.3390/ijms22137198
                PMC ID: 8267671
                SO-VID: 33ff8197-9d3f-4eea-98fe-25c7515a8f75
                Copyright © © 2021 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 24 June 2021
                Date accepted : 01 July 2021
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: midazolam,lymphocyte,delayed-rectifier k+ current,inactivation kinetics,intermediate-conductance ca2+-activated k+ channel,interleukin
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: midazolam, lymphocyte, delayed-rectifier k+ current, inactivation kinetics, intermediate-conductance ca2+-activated k+ channel, interleukin

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