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Nifedipine cav1

David Schaller, Miyase Gözde Gündüz, Fang Xiong Zhang, Gerald W Zamponi, Gerhard Wolber
Nifedipine and isradipine are prominent examples of calcium channel blockers with a 1,4-dihydropyridine (DHP) scaffold. Although successfully used in clinics since decades for the treatment of hypertension, the binding mechanism to their target, the L-type voltage-gated calcium channel Cav1.2, is still incompletely understood. Recently, novel DHP derivatives with a condensed ring system have been discovered that show distinct selectivity profiles to different calcium channel subtypes. This property renders this DHP class as a promising tool to achieve selectivity towards distinct calcium channel subtypes...
May 23, 2018: European Journal of Medicinal Chemistry
Jiaqi Tang, Na Li, Xueyi Chen, Qinqin Gao, Xiuwen Zhou, Yingying Zhang, Bailin Liu, Miao Sun, Zhice Xu
BACKGROUND: Hypoxia during pregnancy could cause abnormal development and lead to increased risks of vascular diseases in adults. This study determined angiotensin II (AII)-mediated vascular dysfunction in offspring middle cerebral arteries (MCA). METHODS AND RESULTS: Pregnant rats were subjected to hypoxia. Vascular tension in offspring MCA by AII with or without inhibitors, calcium channel activities, and endoplasmic reticulum calcium stores were tested. Whole-cell patch clamping was used to investigate voltage-dependent calcium channel currents...
October 3, 2017: Journal of the American Heart Association
Futoshi Toyoda, Pietro Mesirca, Stefan Dubel, Wei-Guang Ding, Joerg Striessnig, Matteo E Mangoni, Hiroshi Matsuura
The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca(2+) dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na(+) current (I st), a key player in SAN automaticity, is still unknown. Here we show that I st and the L-type Ca(2+) current (I Ca,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that I st is activated in the diastolic depolarization range, and displays Na(+) permeability and minimal inactivation and sensitivity to I Ca,L activators and blockers...
August 11, 2017: Scientific Reports
Qiuxia Liao, Rui Zhang, Xiaoyu Wang, Weiwei Nian, Lulu Ke, Wei Ouyang, Zigui Zhang
This study investigated the effects of fluoride exposure on the mRNA expression of Cav1.2 calcium signaling pathway and apoptosis regulatory molecules in PC12 cells. The viability of PC12 cell receiving high fluoride (5.0mM) and low fluoride (0.5mM) alone or fluoride combined with L-type calcium channel (LTCC) agonist/inhibitor (5umol/L FPL6417/2umol/L nifedipine) was detected using cell counting kit-8 at different time points (2, 4, 6, 8, 12, 10, and 24h). Changes in the cell configuration were observed after exposing the cells to fluoride for 24h...
September 2017: Environmental Toxicology and Pharmacology
Kristoffer Bernhem, Kalaiselvan Krishnan, Alexander Bondar, Hjalmar Brismar, Anita Aperia, Lena Scott
BACKGROUND: Blockers of angiotensin II type 1 receptor (AT1 R) and the voltage gated calcium channel 1.2 (CaV 1.2) are commonly used for treatment of hypertension. Yet there is little information about the effect of physiological concentrations of angiotensin II (AngII) on AT1 R signaling and whether there is a reciprocal regulation of AT1 R signaling by CaV 1.2. METHODS: To elucidate these questions, we have studied the Ca2+ signaling response to physiological and pharmacological AngII doses in HEK293a cells, vascular smooth muscle cells and cardiomyocytes using a Ca2+ sensitive dye as the principal sensor...
May 17, 2017: BMC Cardiovascular Disorders
Fei Wang, Masayo Koide, George C Wellman
Voltage-dependent calcium channels (VDCCs) play an essential role in regulating cerebral artery diameter and it is widely appreciated that the L-type VDCC, CaV1.2, encoded by the CACNA1C gene, is a principal Ca(2+) entry pathway in vascular myocytes. However, electrophysiological studies using 10 mM extracellular barium ([Ba(2+)]o) as a charge carrier have shown that ~20% of VDCC currents in cerebral artery myocytes are insensitive to 1,4-dihydropyridine (1,4-DHP) L-type VDDC inhibitors such as nifedipine. Here, we investigated the hypothesis that the concentration of extracellular divalent cations can influence nifedipine inhibition of VDCC currents...
2017: Frontiers in Physiology
Philippe F Y Vincent, Yohan Bouleau, Gilles Charpentier, Alice Emptoz, Saaid Safieddine, Christine Petit, Didier Dulon
The mechanisms orchestrating transient and sustained exocytosis in auditory inner hair cells (IHCs) remain largely unknown. These exocytotic responses are believed to mobilize sequentially a readily releasable pool of vesicles (RRP) underneath the synaptic ribbons and a slowly releasable pool of vesicles (SRP) at farther distance from them. They are both governed by Cav1.3 channels and require otoferlin as Ca(2+) sensor, but whether they use the same Cav1.3 isoforms is still unknown. Using whole-cell patch-clamp recordings in posthearing mice, we show that only a proportion (∼25%) of the total Ca(2+) current in IHCs displaying fast inactivation and resistance to 20 μm nifedipine, a l-type Ca(2+) channel blocker, is sufficient to trigger RRP but not SRP exocytosis...
March 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yudan Liu, Meghan Harding, Jules Dore, Xihua Chen
Nicotine use is one of the most common forms of drug addiction. Although L-type calcium channels (LTCCs) are involved in nicotine addiction, the contribution of the two primary LTCC subtypes (Cav1.2 and 1.3) is unknown. This study aims to determine the contribution of these two LTCC subtypes to nicotine-induced conditioned place preference (CPP) responses by using transgenic mouse models that do not express Cav1.3 (Cav1.3(-/-)) or contain a mutation in the dihydropyridine (DHP) site of the Cav1.2 (Cav1.2DHP(-/-))...
April 3, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
Laura Guarina, David H F Vandael, Valentina Carabelli, Emilio Carbone
KEY POINTS: Mouse chromaffin cells (MCCs) generate spontaneous burst-firing that causes large increases of Ca2+ -dependent catecholamine release, and is thus a key mechanism for regulating the functions of MCCs. With the aim to uncover a physiological role for burst-firing we investigated the effects of acidosis on MCC activity. Lowering the extracellular pH (pHo ) from 7.4 to 6.6 induces cell depolarizations of 10-15 mV that generate bursts of ∼330 ms at 1-2 Hz and a 7.4-fold increase of cumulative catecholamine-release...
April 15, 2017: Journal of Physiology
Alicia Hernández-Vivanco, Sara Sanz-Lázaro, Amanda Jiménez-Pompa, Nuria García-Magro, Beatriz Carmona-Hidalgo, Alberto Pérez-Alvarez, Jose Carlos Caba-González, Angel Tabernero, Sergio Alonso Y Gregorio, Juan Passas, Jesús Blázquez, Carmen González-Enguita, Cristina de Castro-Guerín, Almudena Albillos
The present study was performed to evaluate the Cav1 channel subtypes expressed in human chromaffin cells and the role that these channels play in exocytosis and cell excitability. Here we show that human chromaffin cells obtained from organ donors express Cav1.2 and Cav1.3 subtypes using molecular and pharmacological techniques. Immunocytochemical data demonstrated the presence of Cav1.2 and Cav1.3 subtypes, but not Cav1.1 or Cav1.4. Electrophysiological experiments were conducted to investigate the contribution of Cav1 channels to the exocytotic process and cell excitability...
February 5, 2017: European Journal of Pharmacology
Armando Lagrutta, Haoyu Zeng, John Imredy, Bharathi Balasubramanian, Spencer Dech, Edward Lis, Jixin Wang, Jin Zhai, Joseph DeGeorge, Frederick Sannajust
Several clinical cases of severe bradyarrhythmias have been reported upon co-administration of the Hepatitis-C NS5B Nucleotide Polymerase Inhibitor (HCV-NI) direct-acting antiviral agent, sofosbuvir (SOF), and the Class-III anti-arrhythmic amiodarone (AMIO). We model the cardiac drug-drug interaction (DDI) between AMIO and SOF, and between AMIO and a closely-related SOF analog, MNI-1 (Merck Nucleotide Inhibitor #1), in functional assays of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), to provide mechanistic insights into recently reported clinical cases...
October 1, 2016: Toxicology and Applied Pharmacology
Sulayma A Albarwani, Fathi Mansour, Abdul Aleem Khan, Intisar Al-Lawati, Abdulla Al-Kaabi, Al-Manar Al-Busaidi, Safa Al-Hadhrami, Isehaq Al-Husseini, Sultan Al-Siyabi, Musbah O Tanira
Calcium channel blockers (CCBs) are widely used to treat cardiovascular disease (CVD) including hypertension. As aging is an independent risk factor for CVD, the use of CCBs increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC) blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2...
2016: Frontiers in Physiology
Jun-Mei Lu, Chang-Ying Wang, Changlong Hu, Yan-Jia Fang, Yan-Ai Mei
GDF-15 (growth/differentiation factor 15) is a novel member of the TGF (transforming growth factor)-β superfamily that has critical roles in the central and peripheral nervous systems. We reported previously that GDF-15 increased delayed rectifier outward K(+) currents and Kv2.1 α subunit expression through TβRII (TGF-β receptor II) to activate Src kinase and Akt/mTOR (mammalian target of rapamycin) signalling in rat CGNs (cerebellar granule neurons). In the present study, we found that treatment of CGNs with GDF-15 for 24 h increased the intracellular Ca(2+) concentration ([Ca(2+)]i) in response to membrane depolarization, as determined by Ca(2+) imaging...
July 1, 2016: Biochemical Journal
Bettina Sommer, Edgar Flores-Soto, Jorge Reyes-García, Verónica Díaz-Hernández, Verónica Carbajal, Luis M Montaño
UNLABELLED: Membrane depolarization of airway smooth muscle (ASM) opens L-type voltage dependent Ca(2+) channels (L-VDCC) allowing Ca(2+) entrance to produce contraction. In Ca(2+) free conditions Na(+) permeates through L-VDCC in excitable and non-excitable cells and this phenomenon is annulled at µM Ca(2+) concentrations. Membrane depolarization also induces activation of Gq proteins and sarcoplasmic reticulum Ca(2+) release. In bovine ASM, KCl induced a transient contraction sensitive to nifedipine in Ca(2+)free medium, indicating an additional mechanism to the SR-Ca(2+) release...
July 5, 2016: European Journal of Pharmacology
Catherine B Xie, Lalarukh Haris Shaikh, Sumedha Garg, Gizem Tanriver, Ada E D Teo, Junhua Zhou, Carmela Maniero, Wanfeng Zhao, Soosung Kang, Richard B Silverman, Elena A B Azizan, Morris J Brown
Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) CaV1.3. Using a novel antagonist of CaV1.3, compound 8, we investigated the role of CaV1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, CaV1.2, over CaV1...
April 21, 2016: Scientific Reports
Bruno Bragança, Nádia Oliveira-Monteiro, Fátima Ferreirinha, Pedro A Lima, Miguel Faria, Ana P Fontes-Sousa, Paulo Correia-de-Sá
Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A1 and M2 receptors coupled to inwardly rectifying GIRK/KIR3.1/3.4 channels, respectively. Unlike M2 receptors, bradycardia produced by A1 receptors activation predominates over negative inotropy. Such difference suggests that other ion currents may contribute to adenosine chronoselectivity. In isolated spontaneously beating rat atria, blockade of KCa2/SK channels with apamin and Cav1 (L-type) channels with nifedipine or verapamil, sensitized atria to the negative inotropic action of the A1 agonist, R-PIA, without affecting the nucleoside negative chronotropy...
2016: Frontiers in Pharmacology
Yun He, Qinqin Gao, Bing Han, Xiaolin Zhu, Di Zhu, Jianying Tao, Jie Chen, Zhice Xu
The aim of this study was to evaluate the actions of progesterone on human umbilical vein (HUV) from normal pregnancies and the possible underlying mechanisms involved. HUV rings were suspended in organ baths and exposed to progesterone followed by phenylephrine (PE) or serotonin (5-HT). Progesterone suppressed PE- or 5-HT-induced vasoconstriction in HUV rings. The inhibitory effect induced by progesterone was not influenced by nitric oxide syntheses inhibitor, prostaglandins syntheses blocker, the integrity of endothelium, selective progesterone receptor or potassium channel antagonists...
April 2016: Steroids
Eilis Hannon, Annisa N Chand, Mark D Evans, Chloe C Y Wong, Matthew S Grubb, Jonathan Mill
Direct manipulations of neuronal activity have been shown to induce changes in DNA methylation (DNAm), although little is known about the cellular signaling pathways involved. Using reduced representation bisulfite sequencing, we identify DNAm changes associated with moderate chronic depolarization in dissociated rat hippocampal cultures. Consistent with previous findings, these changes occurred primarily in the vicinity of loci implicated in neuronal function, being enriched in intergenic regions and underrepresented in CpG-rich promoter regulatory regions...
July 2015: Neuroepigenetics
Yu Chen, Hanmeng Zhang, Yanyan Zhang, Ni Lu, Lin Zhang, Lijun Shi
Exercise can be regarded as a drug for treating hypertension, and the 'dosage' (intensity/volume) is therefore of great importance. L-type voltage-gated Ca(2+) (Cav1.2) channels on the plasma membrane of vascular smooth muscle cells have a pivotal role in modulating the vascular tone, and the upregulation of Cav1.2 channels is a hallmark feature of hypertension. The present study investigated the beneficial and adverse effects of exercise at different intensities on the remodeling of the Cav1.2 channel in mesenteric arteries (MAs) of spontaneously hypertensive rats (SHRs)...
October 2015: Hypertension Research: Official Journal of the Japanese Society of Hypertension
John J Enyeart, Judith A Enyeart
In whole cell patch-clamp recordings, we characterized the L-type Ca(2+) currents in bovine adrenal zona fasciculata (AZF) cells and explored their role, along with the role of T-type channels, in ACTH- and angiotensin II (ANG II)-stimulated cortisol secretion. Two distinct dihydropyridine-sensitive L-type currents were identified, both of which were activated at relatively hyperpolarized potentials. One activated with rapid kinetics and, in conjunction with Northern blotting and PCR, was determined to be Cav1...
June 1, 2015: American Journal of Physiology. Cell Physiology
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