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https://www.readbyqxmd.com/read/28603637/t-type-voltage-gated-ca-2-channels-do-not-contribute-to-the-negative-feedback-regulation-of-myogenic-tone-in-murine-superior-epigastric-arteries
#1
Brendan Mullan, Jessica Pettis, William F Jackson
T-type voltage-gated Ca(2+) channels (CaV3.2 VGCC) have been hypothesized to control spontaneous transient outward currents (STOCs) through large-conductance Ca(2+)-activated K(+) channels (BKCa), and contribute to the negative-feedback regulation of myogenic tone. We tested this hypothesis in superior epigastric arteries (SEAs) isolated from male C57BL/6 mice. SEAs were isolated and enzymatically dissociated to obtain single smooth muscle cells (SMCs) for whole-cell recording of paxilline-sensitive (PAX, 1 μmol/L) STOCs at -30 mV, or cannulated and studied by pressure myography (80 cm H2O, 37°C)...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28533239/plasmodium-falciparum-and-p-vivax-demonstrate-contrasting-chloroquine-resistance-reversal-phenotypes
#2
Grennady Wirjanata, Irene Handayuni, Pak Prayoga, Leo Leonardo, Dwi Apriyanti, Leily Trianty, Ruland Wandosa, Basbak Gobay, Enny Kenangalem, Jeanne Rini Poespoprodjo, Rintis Noviyanti, Dennis E Kyle, Qin Cheng, Ric N Price, Jutta Marfurt
High-grade chloroquine (CQ) resistance has emerged in both P. falciparum and P. vivax The aim of the present study was to investigate phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility.Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay...
May 22, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28512247/targetable-t-type-calcium-channels-drive-glioblastoma
#3
Ying Zhang, Nichola Cruickshanks, Fang Yuan, Baomin Wang, Mary Pahuski, Julia Wulfkuhle, Isela Gallagher, Alexander F Koeppel, Sarah Hatef, Christopher Papanicolas, Jeongwu Lee, Eli E Bar, David Schiff, Stephen Turner, Emanuel F Petricoin, Lloyd S Gray, Roger Abounader
Glioblastoma stem-like cells (GSC) promote tumor initiation, progression and therapeutic resistance. Here we show how GSC can be targeted by the FDA approved drug mibefradil which inhibits the T-type calcium channel Cav3.2. This calcium channel was highly expressed in human GBM specimens and enriched in GSC. Analyses of the TCGA and REMBRANDT databases confirmed upregulation of Cav3.2 in a subset of tumors and showed that overexpression associated with worse prognosis. Mibefradil treatment or RNAi-mediated attenuation of Cav3...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28438566/t-type-voltage-gated-calcium-channels-are-involved-in-endothelium-dependent-relaxation-of-mice-pulmonary-artery
#4
Guillaume Gilbert, Arnaud Courtois, Mathilde Dubois, Laure-Anne Cussac, Thomas Ducret, Philippe Lory, Roger Marthan, Jean-Pierre Savineau, Jean-François Quignard
In pulmonary arterial endothelial cells, Ca(2+) channels and intracellular Ca(2+)concentration ([Ca(2+)]i) control the release of vasorelaxant factors such as nitric oxide and are involved in the regulation of pulmonary arterial blood pressure. The present study was undertaken to investigate the implication of T-type voltage-gated Ca(2+)channels (T-VGCCs, Cav3.1 channel) in the endothelium-dependent relaxation of intrapulmonary arteries. Relaxation was quantified by means of a myograph in wild type and Cav3...
April 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28429070/properties-of-synchronous-spontaneous-ca-2-transients-in-the-mural-cells-of-rat-rectal-arterioles
#5
Retsu Mitsui, Hikaru Hashitani
Synchrony of spontaneous Ca(2+) transients among venular mural cells (smooth muscle cells and pericytes) in visceral organs relies on the intercellular spread of L-type voltage-dependent Ca(2+) channel (LVDCC)-dependent depolarisations. However, the mechanisms underlying the synchrony of spontaneous Ca(2+) transients between arteriolar mural cells are less understood. The spontaneous intracellular Ca(2+) dynamics of arteriolar mural cells in the rat rectal submucosa were visualised by Cal-520 Ca(2+) imaging to analyse their synchrony...
April 21, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28371832/timed-sequential-therapy-of-the-selective-t-type-calcium-channel-blocker-mibefradil-and-temozolomide-in-patients-with-recurrent-high-grade-gliomas
#6
Matthias Holdhoff, Xiaobu Ye, Jeffrey G Supko, Louis B Nabors, Arati S Desai, Tobias Walbert, Glenn J Lesser, William L Read, Frank S Lieberman, Martin A Lodge, Jeffrey Leal, Joy D Fisher, Serena Desideri, Stuart A Grossman, Richard L Wahl, David Schiff
Background: Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG. Methods: Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q...
June 1, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28364016/reduced-membrane-cholesterol-limits-pulmonary-endothelial-ca-2-entry-following-chronic-hypoxia
#7
Bojun Zhang, Jay S Naik, Nikki L Jernigan, Benjimen R Walker, Thomas C Resta
Chronic hypoxia (CH)-induced pulmonary hypertension is associated with diminished production of endothelium-derived Ca(2+)-dependent vasodilators such as nitric oxide. Interestingly, ATP-induced endothelial Ca(2+) entry as well as membrane cholesterol (Chol) are decreased in pulmonary arteries from CH rats (4 wk, PB = 380 Torr) compared to normoxic controls. Store-operated Ca(2+) entry (SOCE) and depolarization-induced Ca(2+) entry are major components of the response to ATP and are similarly decreased after CH...
March 31, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28163191/csahi-study-detection-of-drug-induced-ion-channel-receptor-responses-qt-prolongation-and-arrhythmia-using-multi-electrode-arrays-in-combination-with-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#8
Takashi Kitaguchi, Yuta Moriyama, Tomohiko Taniguchi, Sanae Maeda, Hiroyuki Ando, Takaaki Uda, Koji Otabe, Masao Oguchi, Shigekazu Shimizu, Hiroyuki Saito, Atsushi Toratani, Mahoko Asayama, Wataru Yamamoto, Emi Matsumoto, Daisuke Saji, Hiroki Ohnaka, Norimasa Miyamoto
INTRODUCTION: The use of multi-electrode arrays (MEA) in combination with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides a promising method to predict comprehensive cardiotoxicity, including drug-induced QT prolongation and arrhythmia. We previously demonstrated that MEA in combination with hiPSC-CMs could provide a generalizable platform by using 7 reference drugs at 10 testing facilities. Using this approach, we evaluated responses to reference drugs that modulate a range of cardiac ion currents and have a range of arrhythmogenic effects...
February 2, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28077244/the-catsper-channel-modulates-boar-sperm-motility-during-capacitation
#9
Alejandro Vicente-Carrillo, Manuel Álvarez-Rodríguez, Heriberto Rodríguez-Martínez
The cation channel of sperm (CatSper) comprises four transmembrane subunits specifically expressed in human, equine, murine and ovine spermatozoa, apparently implicated in capacitation, hyperactivation and acrosome exocytosis. Western blotting and immunocytochemistry showed hereby that CatSper subunits are also present in boar spermatozoa, primarily over the sperm neck, tail and cytoplasmic droplets; albeit CatSper -1 presented in addition some distribution over the membrane of the acrosome and CatSper -2 and -4 over the membrane of the post-acrosome...
January 8, 2017: Reproductive Biology
https://www.readbyqxmd.com/read/28069437/indispensable-role-of-the-voltage-gated-calcium-channels-in-the-procognitive-effects-of-angiotensin-iv
#10
Jan Józef Braszko
BACKGROUND: Voltage-gated calcium channels (VGCCs) play a major role in brain functioning, including that of cognition-related structures such as cerebral cortex and hippocampus. Cellular mechanisms underlying learning and memory enhancing effect of the neuropeptide angiotensin IV (Ang IV) have been linked to VGCCs but only in respect of its long-term potentiation (LTP)-inducing effect. OBJECTIVE: To assess behaviorally effects of L- and T-type VGCCs blocking drugs in low, behaviorally inactive, doses on Ang IV facilitation of recall of aversively (foot-shock) and appetitively (curiosity for novelty) motivated behaviors...
January 6, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28039042/role-of-low-voltage-activated-calcium-current-and-extracellular-calcium-in-controlling-the-firing-pattern-of-developing-ca1-pyramidal-neurons
#11
Alberto Sánchez-Aguilera, José Luis Sánchez-Alonso, María Ángeles Vicente-Torres, Asunción Colino
The firing pattern of individual neurons is an important element for information processing and storing. During the first weeks of development, there is a transitional period during which CA1 pyramidal neurons display burst-spiking behavior in contrast to the adult regular-firing pattern. Spike after-depolarizations (ADPs) constitute a major factor underlying burst-spiking behavior. Using current-clamp recordings, we studied ADP waveforms and firing patterns in CA1 pyramidal neurons of Wistar rats from 9 to 19 postnatal days (P9-19)...
March 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/27986742/assessment-of-the-effectiveness-and-safety-of-ethosuximide-in-the-treatment-of-non-diabetic-peripheral-neuropathic-pain-edonot-protocol-of-a-randomised-parallel-controlled-double-blinded-and-multicentre-clinical-trial
#12
Nicolas Kerckhove, Christophe Mallet, Bruno Pereira, Chouki Chenaf, Christian Duale, Claude Dubray, Alain Eschalier
INTRODUCTION: Currently available analgesics are ineffective in 30-50% of patients suffering from neuropathic pain and often induce deleterious side effects. T-type calcium channel blockers (mibefradil, ethosuximide, NNC 55-0396) are of great interest for the development of new symptomatic treatments of neuropathic pain, due to their various effects on pain perception. Interestingly, ethosuximide, which has already been approved for treating epilepsy, is available on the European market for clinical use...
December 16, 2016: BMJ Open
https://www.readbyqxmd.com/read/27793923/enhancing-the-therapeutic-efficacy-of-2-deoxyglucose-in-breast-cancer-cells-using-cell-cycle-synchronization
#13
Su Jin Lee, Bok-Nam Park, Jung Hyun Roh, Young-Sil An, Hoon Hur, Joon-Kee Yoon
AIM: We assessed the effect of cell-cycle synchronization using the T-type calcium channel inhibitor mibefradil on the anticancer effects of 2-deoxy-D-glucose (2-DG) and glucose metabolism in breast cancer cells. MATERIALS AND METHODS: MDA-MB-231 cells were treated with mibefradil, followed by 2-DG with/without paclitaxel, then cells were assessed for viability. Glucose metabolism was evaluated by (3)H-2-DG uptake, lactate concentration, and membrane glucose transporter 1 expression after mibefradil treatment...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27765616/chronic-intrathecal-infusion-of-t-type-calcium-channel-blockers-attenuates-cav3-2-upregulation-in-nerve-ligated-rats
#14
Sheng-Jie Shiue, Chi-Hsu Wang, Tao-Yeuan Wang, Yi-Chun Chen, Jen-Kun Cheng
OBJECTIVE: T-type channel (TCC) CaV3.2 plays a pivotal role in pain transmission. In this study, we examined the effects of intrathecal TCC blockers on CaV3.2 expression in a L5/6 spinal nerve ligation (SNL) pain model. The neurotoxicity of TCC blockers were also evaluated. METHODS: Male Sprague-Dawley rats (200-250 g) were used for right L5/6 SNL to induce neuropathic pain. Intrathecal infusion of saline or TCC blockers [mibefradil (0.7 μg/h) or ethosuximide (60 μg/h)] was started after surgery for 7 days...
September 2016: Acta Anaesthesiologica Taiwanica: Official Journal of the Taiwan Society of Anesthesiologists
https://www.readbyqxmd.com/read/27676055/mibefradil-dihydrochloride-with-hypofractionated-radiation-for-recurrent-glioblastoma-preliminary-results-of-a-phase-1-dose-expansion-trial
#15
N H Lester-Coll, J Kluytenaar, K F Pavlik, J B Yu, J N Contessa, J Moliterno, J Piepmeier, K P Becker, J Baehring, A J Huttner, A O Vortmeyer, R Ramani, R J Lampert, X Yao, R S Bindra
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/27517811/synthesis-and-t-type-calcium-channel-blocking-effects-of-aryl-1-5-disubstituted-pyrazol-3-yl-methyl-sulfonamides-for-neuropathic-pain-treatment
#16
Jung Hyun Kim, Gyochang Keum, Hesson Chung, Ghilsoo Nam
A novel series of aryl(1,5-disubstituted pyrazol-3-yl)methyl sulfonamide derivatives was designed, synthesized, and evaluated for T-type calcium channel (α1G and α1H) inhibitory activity. We identified several compounds, 9a, 9b, 9g, and 9h that displayed good T-type channel inhibitory potency with low hERG channel and CYP450 inhibition. Among them, 9a and 9b exhibited neuropathic pain alleviation effects in mechanical and cold allodynia induced in the SNL rat model. Compounds 9a and 9b displayed better efficacy than mibefradil and gabapentin against cold allodynia...
November 10, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27498589/comprehensive-evaluation-of-liver-microsomal-cytochrome-p450-3a-cyp3a-inhibition-comparison-of-cynomolgus-monkey-and-human
#17
Zuzana E Haarhoff, Melissa A Kramer, Tatyana A Zvyaga, Jun Zhang, Priyadeep Bhutani, Murali Subramanian, A David Rodrigues
1. Members of the cytochrome P450 3A (CYP3A) subfamily metabolize numerous compounds and serve as the loci of drug-drug interactions (DDIs). Because of high amino acid sequence identity with human CYP3A, the cynomolgus monkey has been proposed as a model species to support DDI risk assessment. 2. Therefore, the objective of this study was to evaluate 35 known inhibitors of human CYP3A using human (HLM) and cynomolgus monkey (CLM) liver microsomes. Midazolam was employed as substrate to generate IC50 values (concentration of inhibitor rendering 50% inhibition) in the absence and presence of a preincubation (30 mins) with NADPH...
June 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27273014/p-q-type-and-t-type-voltage-gated-calcium-channels-are-involved-in-the-contraction-of-mammary-and-brain-blood-vessels-from-hypertensive-patients
#18
A D Thuesen, K S Lyngsø, L Rasmussen, J Stubbe, O Skøtt, F R Poulsen, C B Pedersen, L M Rasmussen, P B L Hansen
AIM: Calcium channel blockers are widely used in cardiovascular diseases. Besides L-type channels, T- and P/Q-type calcium channels are involved in the contraction of human renal blood vessels. It was hypothesized that T- and P/Q-type channels are involved in the contraction of human brain and mammary blood vessels. METHODS: Internal mammary arteries from bypass surgery patients and cerebral arterioles from patients with brain tumours with and without hypertension were tested in a myograph and perfusion set-up...
March 2017: Acta Physiologica
https://www.readbyqxmd.com/read/27258646/cacna1h-m1549v-mutant-calcium-channel-causes-autonomous-aldosterone-production-in-hac15-cells-and-is-inhibited-by-mibefradil
#19
Esther N Reimer, Gudrun Walenda, Eric Seidel, Ute I Scholl
We recently demonstrated that a recurrent gain-of-function mutation in a T-type calcium channel, CACNA1H(M1549V), causes a novel Mendelian disorder featuring early-onset primary aldosteronism and hypertension. This variant was found independently in five families. CACNA1H(M1549V) leads to impaired channel inactivation and activation at more hyperpolarized potentials, inferred to cause increased calcium entry. We here aimed to study the effect of this variant on aldosterone production. We heterologously expressed empty vector, CACNA1H(WT) and CACNA1H(M1549V) in the aldosterone-producing adrenocortical cancer cell line H295R and its subclone HAC15...
August 2016: Endocrinology
https://www.readbyqxmd.com/read/27255432/gating-modulation-of-the-tumor-related-kv10-1-channel-by-mibefradil
#20
Froylán Gómez-Lagunas, Elisa Carrillo, Luis A Pardo, Walter Stühmer
Several reports credit mibefradil with tumor suppressing properties arising from its known inhibition of Ca(2+) currents. Given that mibefradil (Mb) is also known to inhibit K(+) channels, we decided to study the interaction between this organic compound and the tumor-related Kv10.1 channel. Here we report that Mb modulates the gating of Kv10.1. Mb induces an apparent inactivation from both open and early closed states where the channels dwell at hyperpolarized potentials. Additionally, Mb accelerates the kinetics of current activation, in a manner that depends on initial conditions...
August 2017: Journal of Cellular Physiology
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