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Ca2+ Channel Blocker (ca2+ + channel_blocker)
Selected AbstractsChemInform Abstract: Synthesis and Biological Evaluation of New 4-Arylpiperidines and 4-Aryl-4-piperidinols: Dual Na+ and Ca2+ Channel Blockers with Reduced Affinity for Dopamine D2 Receptors.CHEMINFORM, Issue 15 2002Hirokazu Annoura Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Abnormal Excitability of Hippocampal CA3 Neurons in Noda Epileptic Rat (NER): Alteration of Seizure with AgingEPILEPSIA, Issue 2000Ryosuke Hanaya Purpose: Noda epileptic rat (NER), a mutant found in thc colony of Crj:Wistar rats, spontaneously shows tonic-clonic convulsions approximately once every 30 hours from 8,16 weeks of age. A long-lasting dcpolarization shift accompanied by repetitivc firings are observed in hippocampal CA3 pyramidal neurons of NER with seizures. Using hippocampal slice preparations of NER, the present electrophysiologi- cal study was performed to elucidate whether this abnormal firing in CA3 neurons developed with age and if abnormality of Ca2+ channel was involved. Methods: Hippocampal slices (40Opm) werc prepared from NER and normal Wistar rats (age; 4,29 weeks). A single rectangular pulse stimulus composed of 0.1-ms duration was delivered to the mossy fibers every 5 seconds though a bipolar electrode placed in the granular cell layer of the dentate gyrus. Intracellular recording was made from the CA3 pyramidal cell using a microelectrode containing 3M KCI intracellular recordings. A Ca2+ spike was elicited by applying a depolarizing pulse (InA, 120ms) in the cell through the recording electrode under a blockadc of Na+ and K+ channels using 1 pM tetrodotoxin and I 0mM tctraethylammonium added to the artificial CSF, respectivcly. Nicardipine (I-IOOnM), a Ca2+ channel blocker, was applicd to the bath. Results: Thirty-seven slices from I9 NER and 6 slices from 4 normal Wishe rats were used. There were no obvious changes in the resting membrane potentials of CA3 neurons between NER and Wistar rats tested. When a single stimulus was delivered to the mossy fibers, a long-lasting depolarization shift accompanied by repetitive firings followed by after-hyperpolarization werc also obtained i n hippocampal CA3 neurons of young NER (4,5 weeks of age) before occurrence of any seizurcs, although the depolarization shift in younger NER was shorter than that in NER aged more than 6 weeks. These abnormal firings werc evokcd in 58% and 30% of all CA3 neurons tested in the younger and mature NER (6,1 5 weeks of age), respectively. Furthermore, abnormal firing was not elicited in NER aged after I6 weeks. Agc-matched Wistar rats showed only single action potentials without any depolarization shift with single mossy fiber stimulation. Bath application of nicardipine (IOnM) inhibited this long-lasting depolarization shift and the accompanying repetitive firing followed by afterhypcrpolarization without affecting the first spike induced by mossy fiber stimulations. Furthermore, nicai-dipine (IOnM) inhibited the Ca2+ spikes elicited by applying a depolarizing pulse in the neurons of NER with seizures, although a higher dose (100nM) did not affect those in Wistar rats. Conclusions: These findings indicate that abnormal excitability of the NER CA3 pyramidal neurons is probably due to abnormality in the Ca2+ channcls. The abnorinal excitability was observed in NER at an age when tonic-clonic convulsions were not detected, suggesting that thc hippocampus may probably scrve as an epileptogenic focus in younger NER and the seizure impulses originating i n this area are transinittcd to the new other seizurc foci in mature NER. [source] L-type calcium channels are involved in fast endocytosis at the mouse neuromuscular junctionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2008Paula P. Perissinotti Abstract We used fluorescence microscopy of FM dyes-labeled synaptic vesicles and electrophysiological recordings to examine the functional characteristics of vesicle recycling and study how different types of voltage-dependent Ca2+ channels (VDCCs) regulate the coupling of exocytosis and endocytosis at mouse neuromuscular junction. Our results demonstrate the presence of at least two different pools of recycling vesicles: a high-probability release pool (i.e. a fast destaining vesicle pool), which is preferentially loaded during the first 5 s (250 action potentials) at 50 Hz; and a low-probability release pool (i.e. a slow destaining vesicle pool), which is loaded during prolonged stimulation and keeps on refilling after end of stimulation. Our results suggest that a fast recycling pool mediates neurotransmitter release when vesicle use is minimal (i.e. during brief high-frequency stimulation), while vesicle mobilization from a reserve pool is the prevailing mechanism when the level of synaptic activity increases. We observed that specific N- and L -type VDCC blockers had no effect on evoked transmitter release upon low-frequency stimulation (5 Hz). However, at high-frequency stimulation (50 Hz), L -type Ca2+ channel blocker increased FM2-10 destaining and at the same time diminished quantal release. Furthermore, when L -type channels were blocked, FM2-10 loading during stimulation was diminished, while the amount of endocytosis after stimulation was increased. Our experiments suggest that L -type VDCCs promote endocytosis of synaptic vesicles, directing the newly formed vesicles to a high-probability release pool where they compete against unused vesicles. [source] Properties of LTD and LTP of retinocollicular synaptic transmission in the developing rat superior colliculusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002Fu-Sun Lo Abstract The developing retinocollicular pathway undergoes synaptic refinement in order to form the precise retinotopic pattern seen in adults. To study the mechanisms which underlie refinement, we investigated long-term changes in retinocollicular transmission in rats aged P0,P25. Field potentials (FPs) in the superior colliculus (SC) were evoked by stimulation of optic tract fibers in an in vitro isolated brainstem preparation. High intensity stimulation induced long-term depression (LTD) in the SC after both low (1000 stimuli at 1 Hz) and higher (1000 stimuli at 50 Hz) frequency stimulation. The induction of LTD was independent of activation of NMDA and GABAA receptors, because d -APV (100 µM) and bicuculline (10 µM) did not block LTD. Induction of LTD was dependent upon activation of l -type Ca2+ channels as 10 µM nitrendipine, an l -type Ca2+ channel blocker, significantly decreased the magnitude of LTD. LTD was down-regulated during development. LTD magnitude was greatest in rats aged P0,P9 and significantly less in rats aged P10,P25. Long-term potentiation (LTP) was induced by low intensity stimulation and only after high frequency tetanus (1000 stimuli at 50 Hz). LTP was NMDA receptor dependent because d -APV (100 ,M) completely abolished it. LTP induction was also blocked by the l -type Ca2+ channel blocker nitrendipine. The magnitude of LTP first increased with age, being significantly greater at P7,P13 than at P0,3 and then decreased at P23,25. In summary, both LTD and LTP are present during retinocollicular pathway refinement, but have different transmitter and ionic mechanisms and time courses of expression. [source] The potato StLTPa7 gene displays a complex Ca2+ -associated pattern of expression during the early stage of potato,Ralstonia solanacearum interactionMOLECULAR PLANT PATHOLOGY, Issue 1 2009GANG GAO SUMMARY Although nonspecific lipid transfer proteins (nsLTPs) are widely expressed during plant defence responses to pathogens, their functions and regulation are not fully understood. In this article, we report the isolation of a cDNA for the new nsLTP, StLTPa7, from cultivated potato (Solanum tuberosum) infected with Ralstonia solanacearum. The cDNA was predicted to encode a type 1 nsLTP containing an N-terminal signal sequence and possessing the characteristic features of nsLTPs. A phylogenetic analysis showed that the encoded amino acid sequence of the nsLTP was similar to those of other previously reported plant nsLTPs, which contain a putative calmodulin-binding site consisting of approximately 12 highly conserved amino acid residues. The expression of the StLTPa7 gene was studied during the early stages of potato,R. solanacearum interaction using real-time quantitative polymerase chain reaction (qRT-PCR) and Northern analyses, and a complex calcium (Ca2+)-associated pattern of expression was observed with the following features: (i) transcripts of the StLTPa7 gene were systemically up-regulated by infection with R. solanacearum; (ii) the StLTPa7 gene was stimulated by salicylic acid, methyl jasmonate, abscisic acid and Ca2+; (iii) qRT-PCR showed that, during the early stage of R. solanacearum infection, nsLTP transcripts accumulated over a time course that paralleled that of Ca2+ accumulation, detected using environmental scanning electron microscopy and energy-dispersive X-ray (EDAX) spectrometry; and (iv) the Ca2+ channel blocker, ruthenium red, partially blocked R. solanacearum -induced StLTPa7 expression. This report represents the first use of EDAX analysis to establish a synchrony between Ca2+ accumulation and nsLTP expression in response to potato,R. solanacearum interactions. Collectively, these results suggest that StLTPa7 may be a pathogen- and Ca2+ -responsive plant defence gene. [source] Mitochondrial modulation of Ca2+ sparks and transient KCa currents in smooth muscle cells of rat cerebral arteriesTHE JOURNAL OF PHYSIOLOGY, Issue 3 2004Serguei Y. Cheranov Mitochondria sequester and release calcium (Ca2+) and regulate intracellular Ca2+ concentration ([Ca2+]i) in eukaryotic cells. However, the regulation of different Ca2+ signalling modalities by mitochondria in smooth muscle cells is poorly understood. Here, we investigated the regulation of Ca2+ sparks, Ca2+ waves and global [Ca2+]i by mitochondria in cerebral artery smooth muscle cells. CCCP (a protonophore; 1 ,m) and rotenone (an electron transport chain complex I inhibitor; 10 ,m) depolarized mitochondria, reduced Ca2+ spark and wave frequency, and elevated global [Ca2+]i in smooth muscle cells of intact arteries. In voltage-clamped (,40 mV) cells, mitochondrial depolarization elevated global [Ca2+]i, reduced Ca2+ spark amplitude, spatial spread and the effective coupling of sparks to large-conductance Ca2+ -activated potassium (KCa) channels, and decreased transient KCa current frequency and amplitude. Inhibition of Ca2+ sparks and transient KCa currents by mitochondrial depolarization could not be explained by a decrease in intracellular ATP or a reduction in sarcoplasmic reticulum Ca2+ load, and occurred in the presence of diltiazem, a voltage-dependent Ca2+ channel blocker. Ru360 (10 ,m), a mitochondrial Ca2+ uptake blocker, and lonidamine (100 ,m), a permeability transition pore (PTP) opener, inhibited transient KCa currents similarly to mitochondrial depolarization. In contrast, CGP37157 (10 ,m), a mitochondrial Na+,Ca2+ exchange blocker, activated these events. The PTP blockers bongkrekic acid and cyclosporin A both reduced inhibition of transient KCa currents by mitochondrial depolarization. These results indicate that mitochondrial depolarization leads to a voltage-independent elevation in global [Ca2+]i and Ca2+ spark and transient KCa current inhibition. Data also suggest that mitochondrial depolarization inhibits Ca2+ sparks and transient KCa currents via PTP opening and a decrease in intramitochondrial [Ca2+]. [source] Long-lasting contractile action and the inhibitory action of cupric ions on ileal longitudinal muscleAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2004K. Miyazaki Summary 1 Cupric ions (Cu2+), at concentrations above 0.03 mm, induced a progressive increase in the tonic contraction of guinea-pig ileal longitudinal muscle. Maximal contraction of 0.1 mm Cu2+ attained a level above that of the 60-mm K+ -induced tonic response, within 20 min of application. The tension induced by Cu2+ persisted for more than several hours. Tetrodotoxin (3 × 10,6 m) had no effect on the contraction induced by 0.1 mm Cu2+. 2 After incubation in a Ca2+ -free medium, the ileal response to 0.1 mm Cu2+ was lost. Nifedipine, a L-type Ca2+ channel blocker, dose-dependently inhibited contractions induced by Cu2+. 3 As the duration of the first application of 0.1 mm Cu2+ increased above 30 min, after washing with normal medium, the contractile response to a second application of 0.1 mm Cu2+ decreased gradually. After 150 min of the first application of 0.1 mm Cu2+, a second application of Cu2+ could not evoke any contraction. 4 After the application of 0.1 mm Cu2+ for 150 min, when muscles were washed with a medium containing 1 mm EDTA, the response to 0.1 mm Cu2+ returned to a greater extent in the normal Ca2+ medium. 5 In conclusion, Cu2+ (0.1 mm) induced a maximal ileal tension above that of the K-induced tonic response within 20 min. The ileal contraction to Cu2+ persisted for more than several hours and depended on extracellular Ca2+ concentrations. It is possible that a part of Cu2+, bound to a EDTA-inaccessible site, also has a tension inhibitory effect. [source] Modulatory effects of static magnetic fields on blood pressure in rabbitsBIOELECTROMAGNETICS, Issue 6 2001Hideyuki Okano Abstract Acute effects of locally applied static magnetic fields (SMF) on pharmacologically altered blood pressure (BP) in a central artery of the ear lobe of a conscious rabbit were evaluated. Hypotensive and vasodilator actions were induced by a Ca2+ channel blocker, nicardipine (NIC). Hypertensive and vasoconstrictive actions were induced by a nitric oxide synthase (NOS) inhibitor, N, -nitro- L -arginine methyl ester (L-NAME). The hemodynamic changes in the artery exposed to SMF were measured continuously and analyzed by penetrating microphotoelectric plethysmography (MPPG). Concurrently, BP changes in a central artery contralateral to that of the exposed ear lobe were monitored. SMF intensity was 1,mT and the duration of exposure was 30,min. A total of 180 experimental trials were carried out in 34 healthy adult male rabbits weighing 2.6,3.8,kg. Six experimental procedures were chosen at random: (1) sham exposure without pharmacological treatment; (2) SMF exposure alone; (3) decreased BP induced by a single intravenous (iv) bolus injection of NIC (100,,M/kg) without SMF exposure; (4) decreased BP induced by injection of NIC with SMF exposure; (5) increased BP induced by a constant iv infusion of L-NAME (10,mM/kg/h) without SMF exposure; (6) increased BP induced by infusion of L-NAME with SMF exposure. The results demonstrated that SMF significantly reduced the vasodilatation with enhanced vasomotion and antagonized the reduction of BP via NIC-blocked Ca2+ channels in vascular smooth muscle cells. In addition, SMF significantly attenuated the vasoconstriction and suppressed the elevation of BP via NOS inhibition in vascular endothelial cells and/or central nervous system neurons. These results suggest that these modulatory effects of SMF on BP might, in part, involve a feedback control system for alteration in NOS activity in conjunction with modulation of Ca2+ dynamics. Bioelectromagnetics 22:408,418, 2001. © 2001 Wiley-Liss, Inc. [source] Block of cardiac delayed-rectifier and inward-rectifier K+ currents by nisoldipineBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2003Sergey Missan The objective of this study was to determine the concentration-dependent effects of nisoldipine, a dihydropyridine Ca2+ channel blocker, on K+ currents in guinea-pig ventricular myocytes. Myocytes in the conventional whole-cell configuration were bathed in normal Tyrode's solution or K+ -free Tyrode's solution for the measurement of the effects of 0.01,100 ,M nisoldipine on rapidly activating delayed-rectifier K+ current (IKr), slowly activating delayed-rectifier K+ current (IKs), inwardly rectifying K+ current (IK1), and reference L-type Ca2+ current (ICa,L). Nisoldipine inhibited IKr with an IC50 of 23 ,M, and IKs with an IC50 of 40 ,M. The drug also had weak inhibitory effects on inward- and outward-directed IK1; the IC50 determined for outward-directed current was 80 ,M. Investigation of nisoldipine action on IKs showed that inhibition occurred in the absence of previous pulsing, and with little change in the time courses of activation and deactivation. However, the drug-induced inhibition was significantly weaker at +30 mV than at +10 mV. We estimate that nisoldipine is about 30 times less selective for delayed-rectifier K+ channels than for L-type Ca2+ channels in fully polarised guinea-pig ventricular myocytes, and several orders less selective in partially depolarised myocytes. British Journal of Pharmacology (2003) 140, 863,870. doi:10.1038/sj.bjp.0705518 [source] Nociceptin/orphanin FQ inhibits capsaicin-induced guinea-pig airway contraction through an inward-rectifier potassium channelBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2002Yanlin Jia Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid-like orphan receptor (NOP receptor, previously termed ORL1 receptor) agonist, has been found to inhibit capsaicin-induced bronchoconstriction in isolated guinea-pig lungs and in vivo. The underlying mechanisms are not clear. In the present studies, we tested the effect of N/OFQ on VR1 channel function in isolated guinea-pig nodose ganglia cells. Capsaicin increased intracellular Ca2+ concentration in these cells through activation of vanilloid receptors. Capsaicin-induced Ca2+ responses were attenuated by pretreatment of nodose neurons with N/OFQ (1 ,M). N/OFQ inhibitory effect on the Ca2+ response in nodose ganglia cells was antagonized by tertiapin (0.5 ,M), an inhibitor of inward-rectifier K+ channels, but not by verapamil, a voltage gated Ca2+ channel blocker, indicating that an inward-rectifier K+ channel is involved in N/OFQ inhibitory effect. In isolated guinea-pig bronchus, N/OFQ (1 ,M) inhibited capsaicin-induced airway contraction. Tertiapin (0.5 ,M) abolished the N/OFQ inhibition of capsaicin-induced bronchial contraction. Capsaicin (10 ,g) increased pulmonary inflation pressure in the isolated perfused guinea-pig lungs. This response was significantly attenuated by pretreatment with N/OFQ (1 ,M). Tertiapin also abolished the N/OFQ inhibitory effect on capsaicin-induced bronchoconstriction in perfused lungs. Capsaicin increased the release of substance P and neurokinin A from isolated lungs. N/OFQ (1 ,M) blocked the capsaicin-induced tachykinin release. These results indicate that N/OFQ-induced hyperpolarization of tachykinin containing airway sensory nerves, through an inward-rectifier K+ channel activation, accounts for the inhibition of capsaicin-evoked broncoconstriction. British Journal of Pharmacology (2002) 135, 764,770; doi:10.1038/sj.bjp.0704515 [source] Nonylphenol-induced cytosolic Ca2+ elevation and death in renal tubular cellsDRUG DEVELOPMENT RESEARCH, Issue 5 2009Jeng-Yu Tsai Abstract Nonylphenol is an environmental endocrine disrupter. The effect of nonylphenol on intracellular free Ca2+ levels ([Ca2+]i) and viability in Madin-Darby canine kidney (MDCK) cells was explored. Nonylphenol increased [Ca2+]i in a concentration-dependent manner (EC50,0.8,,M). Nonylphenol-induced Mn2+ entry demonstrated Ca2+ influx and removal of extracellular Ca2+ partly decreased the [Ca2+]i rise. The [Ca2+]i rise was inhibited by the protein kinase C activator, phorbol 13-myristate acetate (PMA) but not by L-type Ca2+ channel blockers. In Ca2+ -free medium, nonylphenol-induced [Ca2+]i rise was partly inhibited by pretreatment with 1,,M thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor). Conversely, nonylphenol pretreatment abolished thapsigargin-induced Ca2+ release. Nonylphenol-induced Ca2+ release was unaltered by inhibition of phospholipase C. At concentrations of 5,100,,M, nonylphenol killed cells in a concentration-dependent manner. The cytotoxic effect of 100,,M nonylphenol was not affected by preventing [Ca2+]i rises with BAPTA/AM. Collectively, this study shows that nonylphenol induced [Ca2+]i increase in MDCK cells via evoking Ca2+ entry through protein kinase C-regulated Ca2+ channels, and releasing Ca2+ from endoplasmic reticulum and other stores in a phospholipase C-independent manner. Nonylphenol also killed cells in a Ca2+ -independent fashion. Drug Dev Res, 2009. © 2009 Wiley-Liss, Inc. [source] 5-HT inhibits N-type but not L-type Ca2+ channels via 5-HT1A receptors in lamprey spinal neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2003Russell H. Hill Abstract 5-HT is a potent modulator of locomotor activity in vertebrates. In the lamprey, 5-HT dramatically slows fictive swimming. At the neuronal level it reduces the postspike slow afterhyperpolarization (sAHP), which is due to apamin-sensitive Ca2+ -dependent K+ channels (KCa). Indirect evidence in early experiments suggested that the sAHP reduction results from a direct action of 5-HT on KCa channels rather than an effect on the Ca2+ entry during the action potential [Wallén et al., (1989) J. Neurophysiol., 61, 759,768]. In view of the characterization of different subtypes of Ca2+ channels with very different properties, we now reinvestigate if there is a selective action of 5-HT on a Ca2+ channel subtype in dissociated spinal neurons in culture. 5-HT reduced Ca2+ currents from high voltage activated channels. N-type, but not L-type, Ca2+ channel blockers abolished this 5-HT-induced reduction. It was also confirmed that 5-HT depresses Ca2+ currents in neurons, including motoneurons, in the intact spinal cord. 8-OH-DPAT, a 5-HT1A receptor agonist, also inhibited Ca2+ currents in dissociated neurons. After incubation in pertussis toxin, to block Gi/o proteins, 5-HT did not reduce Ca2+ currents, further indicating that the effect is caused by an activation of 5-HT1A receptors. As N-type, but not L-type, Ca2+ channels are known to mediate the activation of KCa channels and presynaptic transmitter release at lamprey synapses, the effects of 5-HT reported here can contribute to a reduction in both actions. [source] The role of calcium on protein secretion of the albumen gland in Helisoma duryi (Gastropoda)INVERTEBRATE BIOLOGY, Issue 4 2004Lana Kiehn Abstract. The albumen gland of the freshwater pulmonate snail Helisoma duryi produces and secretes the perivitelline fluid, which coats fertilized eggs and provides nutrients to the developing embryos. It is known that perivitelline fluid secretion is stimulated by dopamine through the activation of a dopamine D1 -like receptor, which in turn stimulates cAMP production leading to the secretion of perivitelline fluid. This paper examines the glandular release of perivitelline fluid and provides evidence for the role of Ca2+ in the regulated secretion of perivitelline fluid based on protein secretion experiments and inositol 1,4,5-trisphosphate assays. Dopamine-stimulated protein secretion by the albumen gland is reduced in Ca2+ -free medium or in the presence of plasma membrane Ca2+ channel blockers, although the Ca2+ channel subtype involved is unclear. In addition, dopamine-stimulated protein secretion does not directly involve phospholipase C-generated signaling pathways and Ca2+ release from intracellular stores. Sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase inhibitors had little effect on protein secretion when applied alone; however, they potentiated dopamine-stimulated protein secretion. Dantrolene, an inhibitor of ryanodine receptors, 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride, a nonspecific inhibitor of intracellular Ca2+ channels, and 2-aminoethyldiphenylborate, an inhibitor of inositol 1,4,5-trisphosphate receptors, did not suppress protein secretion, suggesting Ca2+ release from internal stores does not directly regulate protein secretion. Thus, the influx of Ca2+ from the extracellular space appears to be the major pathway mediating protein secretion by the albumen gland. The results are discussed with respect to the role of Ca2+ in controlling exocytosis of proteins from the albumen gland secretory cells. [source] Calcium channel blockers inhibit galvanotaxis in human keratinocytesJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2002Donna R. Trollinger Directed migration of keratinocytes is essential for wound healing. The migration of human keratinocytes in vitro is strongly influenced by the presence of a physiological electric field and these cells migrate towards the negative pole of such a field (galvanotaxis). We have previously shown that the depletion of extracellular calcium blocks the directional migration of cultured human keratinocytes in an electric field (Fang et al., 1998; J Invest Dermatol 111:751,756). Here we further investigate the role of calcium influx on the directionality and migration speed of keratinocytes during electric field exposure with the use of Ca2+ channel blockers. A constant, physiological electric field strength of 100 mV/mm was imposed on the cultured cells for 1 h. To determine the role of calcium influx during galvanotaxis we tested the effects of the voltage-dependent cation channel blockers, verapamil and amiloride, as well as the inorganic Ca2+ channel blockers, Ni2+ and Gd3+ and the Ca2+ substitute, Sr2+, on the speed and directionality of keratinocyte migration during galvanotaxis. Neither amiloride (10 ,M) nor verapamil (10 ,M) had any effect on the galvanotaxis response. Therefore, calcium influx through amiloride-sensitive channels is not required for galvanotaxis, and membrane depolarization via K+ channel activity is also not required. In contrast, Sr2+ (5 mM), Ni2+ (1,5 mM), and Gd3+ (100 ,M) all significantly inhibit the directional migratory response to some degree. While Sr2+ strongly inhibits directed migration, the cells exhibit nearly normal migration speeds. These findings suggest that calcium influx through Ca2+ channels is required for directed migration of keratinocytes during galvanotaxis and that directional migration and migration speed are probably controlled by separate mechanisms. J. Cell. Physiol. 193: 1,9, 2002. © 2002 Wiley-Liss, Inc. [source] A comparison of Ca2+ channel blocking mode between gabapentin and verapamil: implication for protection against hypoxic injury in rat cerebrocortical slicesBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003Michiko Oka The mode of Ca2+ channel blocking by gabapentin [1-(aminomethyl)cyclohexane acetic acid] was compared to those of other Ca2+ channel blockers, and the potential role of Ca2+ channel antagonists in providing protection against hypoxic injury was subsequently investigated in rat cerebrocortical slices. mRNA for the ,2, subunits of Ca2+ channels was found in rat cerebral cortex. Nitric oxide (NO) synthesis estimated from cGMP formation was enhanced by KCl stimulation, which was mediated primarily by the activation of N- and P/Q-type Ca2+ channels. Gabapentin blocked both types of Ca2+ channels, and preferentially reversed the response to 30 mM K+ stimulation compared with 50 mM K+ stimulation. In contrast, verapamil preferentially inhibited the response to depolarization by the higher concentration (50 mM) of K+. Gabapentin inhibited KCl-induced elevation of intracellular Ca2+ in primary neuronal culture. Hypoxic injury was induced in cerebrocortical slices by oxygen deprivation in the absence (severe injury) or presence of 3 mM glucose (mild injury). Gabapentin preferentially inhibited mild injury, while verapamil suppressed only severe injury. , -Conotoxin GVIA (, -CTX) and , -agatoxin IVA (, -Aga) were effective in both models. NO synthesis was enhanced in a manner dependent on the severity of hypoxic insults. Gabapentin reversed the NO synthesis induced by mild insults, while verapamil inhibited that elicited by severe insults. , -CTX and , -Aga were effective in both the cases. Therefore, the data suggest that gabapentin and verapamil cause activity-dependent Ca2+ channel blocking by different mechanisms, which are associated with their cerebroprotective actions and are dependent on the severity of hypoxic insults. British Journal of Pharmacology (2003) 139, 435,443. doi:10.1038/sj.bjp.0705246 [source] | |||||||||||||