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PubMed1987

Changes in adrenergic pressor responses by calcium channel modulation in conscious dogs.

The influence of the slow channel calcium entry blocker, nifedipine, and the slow channel calcium entry promoter, BAY-K 8644, on receptor-mediated hemodynamic responses was studied in chronically instrumented, conscious dogs. Following ganglionic, cholinergic, and beta-adrenergic blockade, equipressor doses of phenylephrine (0.6 microgram/kg iv), a selective alpha 1-adrenoceptor agonist, and B-HT 933 (20 micrograms/kg iv), a selective alpha 2-adrenoceptor agonist, as well as a nonadrenergic vasoconstrictor, vasopressin (0.003 IU/kg) were administered before and after infusions of nifedipine or BAY-K 8644 (0.25, 0.5, 1.0, and 2.0 micrograms X kg-1 X min-1). In doses producing minimal or no haemodynamic effects, nifedipine caused dose-related attenuation from control of phenylephrine- (from 26 +/- 3 to 8 +/- 1 mmHg), B-HT 933- (from 30 +/- 2 to 5 +/- 2 mmHg), and vasopressin- (24 +/- 1 to 2 +/- 2 mmHg) mediated changes in mean arterial pressure. In contrast, BAY-K 8644 produced dose-related potentiation from control of the same pressor responses (phenylephrine, 24 +/- 2 to 41 +/- 3 mmHg; B-HT 933, 28 +/- 3 to 46 +/- 2 mmHg; vasopressin, 25 +/- 3 to 45 +/- 5 mmHg). In addition, BAY-K 8644 produced a marked increase in the duration of the pressor response produced by all three agonists. Thus, in conscious dogs, alpha 1-, alpha 2-, and vasopressin-mediated pressor responses are strongly modulated by transmembrane calcium flux and can be influenced by dihydropyridine slow channel calcium agonists and antagonists.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Depolarization shifts the voltage dependence of cardiac sodium channel and calcium channel gating charge movements.

In cardiac ventricular myocytes, membrane depolarization leads to the inactivation of the Na channel and Ca channel ionic currents. The inactivation of the ionic currents has been associated with a reduction of the gating charge movement ("immobilization") which governs the activation of Na channels and Ca channels. The nature of the apparent "immobilization" of the charge movement following depolarization was explored in embryonic chick ventricular myocytes using voltage protocols applied from depolarized holding potentials. It was found that although all of the charge was mobile following inactivation, the voltage dependence of its movement was shifted to more negative potentials. In addition, the shift in the distribution of the Na channel charge could be differentiated from that of the Ca channel charge on the basis of kinetic as well as steady-state criteria. These results suggest that the voltage-dependent activation of Na channel and Ca channel charge movements leads to conformational changes and charge rearrangements that differentially bias the movements of these voltage sensors, and concomitantly produce channel inactivation.

Animals↗
PubMed2002

Calcium channel blockers for inhibiting preterm labour.

BACKGROUND: Preterm birth is a major contributor to perinatal mortality and morbidity and affects approximately six to seven per cent of births in developed countries. Tocolytics are drugs used to suppress uterine contractions. The most widely tested tocolytics are betamimetics. Although they have been shown to delay delivery, betamimetics have not been shown to improve perinatal outcome, and they have a high frequency of unpleasant and even fatal maternal side effects. There is growing interest in calcium channel blockers as a potentially effective and well tolerated form of tocolysis. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of calcium channel blockers, administered as a tocolytic agent, to women in preterm labour. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's specialised register of controlled trials, the Cochrane Controlled Trials Register (February 2002), MEDLINE, EMBASE, and Current Contents. We also contacted recognised experts and cross referenced relevant material. SELECTION CRITERIA: All published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in labour between 20 and 36 weeks gestation. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group were used. Evaluation of methodological quality and trial data extraction were undertaken independently by three authors. Additional information was sought to enable assessment of methodology and conduct of intention-to-treat analyses. Meta-analysis was conducted assessing the effects of calcium channel blockers compared with any other tocolytic agent. Results are presented using relative risk for categorical data and weighted mean difference for continuous data. MAIN RESULTS: Eleven randomised controlled trials involving 870 women were included. When compared with any other tocolytic agent (mainly betamimetics), calcium channel blockers reduced the number of women giving birth within 48 hours (relative risk (RR) 0.73; 95% confidence interval (CI) 0.54, 0.98) and within seven days (RR 0.76; 95% CI 0.59, 0.99). Calcium channel blockers also reduced the requirement for women to have treatment ceased for adverse drug reaction (RR 0.15; 95% CI 0.06, 0.43), the frequency of neonatal respiratory distress syndrome (RR 0.64; 95% CI 0.45, 0.91) and neonatal jaundice (RR 0.73; 95% CI 0.57, 0.93). REVIEWER'S CONCLUSIONS: When tocolysis is indicated for women in preterm labour, calcium channel blockers are preferable to betamimetic agents. Further research should address the effects of different dosage regimens and formulations of nifedipine on maternal and neonatal outcomes.

Calcium Channel Blockers↗
PubMed1995

Role of calcium channel subtypes in calcium transients in hippocampal CA3 neurons.

Multiple subtypes of voltage-gated calcium channels are differentially localized in brain neurons suggesting that they serve distinct roles in neuronal excitation and signaling. In organotypic hippocampal slice cultures, class D (L-type) calcium channels are predominantly located in the cell bodies of CA3 neurons while class B (N-type) and class A (P or Q-type) are localized in dendrites and associated presynaptic terminals with relatively low somal expression. Using specific antagonists to inhibit calcium transients recorded in CA3 neuronal cell bodies, we found that L-type calcium channels have a predominant role in somal calcium transients elicited by trains of strong stimuli applied to either the soma or the distal apical dendrite while class A calcium channels make a smaller contribution. Presynaptic class B (N-type) and class A (P- and/or Q-type) calcium channels are critical for glutamate-mediated synaptic transmission onto the dendrites of CA3 neurons. Postsynaptic class A and B calcium channels detected on the dendritic shaft by immunocytochemistry were not found to contribute substantially to somal calcium transients during repetitive stimulation of distal dendrites, but sodium channels were required for calcium transients elicited by somatic or dendritic stimulation. Our results show that the different calcium channel subtypes serve distinct roles in cellular activation and transmission of signals in CA3 neurons, consistent with their differential subcellular localization.

Animals↗
PubMed2000

L-Type calcium channels mediate calcium oscillations in early postnatal Purkinje neurons.

Ca(2+) signaling is important in many fundamental neuronal processes including neurotransmission, synaptic plasticity, neuronal development, and gene expression. In cerebellar Purkinje neurons, Ca(2+) signaling has been studied primarily in the dendritic region where increases in local Ca(2+) have been shown to occur with both synaptic events and spontaneous electrical activity involving P-type voltage-gated Ca(2+) channels (VGCCs), the predominant VGCC expressed by Purkinje neurons. Here we show that Ca(2+) signaling is also a prominent feature of immature Purkinje neurons at developmental stages that precede expression of dendritic structure and involves L-type rather than P-type VGCCs. Immature Purkinje neurons acutely dissociated from postnatal day 4-7 rat pups exhibit spontaneous cytoplasmic Ca(2+) oscillations. The Ca(2+) oscillations require entry of extracellular Ca(2+), are blocked by tetrodotoxin, are communicated to the nucleus, and correlate closely with patterns of endogenously generated spontaneous and evoked electrical activity recorded in the neurons. Immunocytochemistry showed that L-, N-, and P/Q-types of VGCCs are present on the somata of the Purkinje neurons at this age. However, only the L-type VGCC antagonist nimodipine effectively antagonized the Ca(2+) oscillations; inhibitors of P/Q and N-type VGCCs were relatively ineffective. Release of Ca(2+) from intracellular Ca(2+) stores significantly amplified the Ca(2+) signals of external origin. These results show that a somatic signaling pathway that generates intracellular Ca(2+) oscillations and involves L-type VGCCs and intracellular Ca(2+) stores plays a prominent role in the Ca(2+) dynamics of early developing Purkinje neurons and may play an important role in communicating developmental cues to the nucleus.

Action Potentials↗
PubMed1996

Voltage-sensitive calcium channels mediate calcium entry into cultured mammalian sympathetic neurons following neurite transection.

Calcium ion entry following mechanical neurite transection was examined in cultured sympathetic neurons loaded with the Ca2+ indicator fluo-3. Neurite transection produced a rapid [Ca2+]i rise in the cell soma which preceded any [Ca2+]i rise in the neurite (n = 30). Blocking sodium channels with tetrodotoxin had no effect on the Ca2+ rise, but inactivating voltage-sensitive Ca2+ channels by bath-applying 140 mM potassium prior to the transection, and the simultaneous application of nimodipine and omega-conotoxin GVIA, blockers of L-type and N-type Ca2+ channels, respectively, considerably attenuated the Ca2+ rise in the soma and neurites. These data contradict the intuitive hypothesis that Ca2+ entry following mechanical neurite transection occurs via non-specific influx pathways produced by cell-membrane disruption and provide direct evidence in mammalian neurons that immediate, traumatically-induced, increases in neuronal [Ca2+]i are amenable to pharmacological manipulation.

Animals↗
PubMed1994

Role of L-type calcium channels on stimulated calcium influx and on proliferative activity of human coronary smooth muscle cells.

Dihydropyridine (DHP) calcium channel blockers are widely used in treatment of coronary artery disease. To evaluate the specific role of L-type calcium channels in the antianginal and possibly antiatherosclerotic properties of DHP inhibitors, we examined the effects of a 1,4-DHP agonist and antagonist on angiotensin II (ANG II)- and serum-stimulated calcium influx and proliferation of human coronary smooth muscle cells (cSMC). Fluorometry of fura-2 was used to measure changes in free cytosolic Ca2+ concentration ([Ca2+]i) in cSMC after short- and long-term pretreatment with the calcium agonist Bay K 8644 or the antagonist nitrendipine, respectively. Proliferative activity was quantified during exponential growth in serum-supplemented medium with or without both DHPs. Short- and long-term pretreatment with Bay K 8644 increased basal [Ca2+]i significantly in resting cells and augmented ANG II- and serum-induced sustained [Ca2+]i responses. Concordantly, proliferation rate was increased. In contrast, nitrendipine had no significant effect on basal or stimulated [Ca2+]i after short-term treatment, but decreased [Ca2+]i after 24-h incubation, attenuated the plateau phase of ANG II- and serum-evoked [Ca2+]i transients, and reduced proliferative activity of these cells. The results indicate that 1,4-DHPs modulate ANG II- and serum-induced Ca2+ influx in cSMC. Thus, L-type calcium channels may contribute to [Ca2+]i transients evoked by ANG II and serum. Moreover, the modulating effects of both DHPs on proliferative activity suggest involvement of DHP-sensitive calcium channels. Calcium influx through L-type channels may be one of the mechanisms that determine responsiveness to vasoconstrictors and proliferative activity of human cSMC.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Interactive effects of the GABABergic modulation of calcium channels and calcium-dependent potassium channels in lamprey.

The GABAB-mediated modulation of spinal neurons in the lamprey is investigated in this study. Activation of GABAB receptors reduces calcium currents through both low- (LVA) and high-voltage activated (HVA) calcium channels, which subsequently results in the reduction of the calcium-dependent potassium (KCa) current. This in turn will reduce the peak amplitude of the afterhyperpolarization (AHP). We used the modulatory effects of GABAB receptor activation on N-methyl-D-aspartate (NMDA)-induced, TTX-resistant membrane potential oscillations as an experimental model in which to separate the effects of GABAB receptor activation on LVA calcium channels from that on KCa channels. We show experimentally and by using simulations that a direct effect on LVA calcium channels can account for the effects of GABAB receptor activation on intrinsic membrane potential oscillations to a larger extent than indirect effects mediated via KCa channels. Furthermore, by conducting experiments and simulations on intrinsic membrane potential oscillations, we find that KCa channels may be activated by calcium entering through LVA calcium channels, providing that the decay kinetics of the calcium that enters through LVA calcium channels is not as slow as the calcium entering via NMDA receptors. A combined experimental and computational analysis revealed that the LVA calcium current also contributes to neuronal firing properties.

Animals↗
PubMed1991

Iminodipropionitrile-induced dyskinesia in mice: striatal calcium channel changes and sensitivity to calcium channel antagonists.

Administration of 3,3'-iminodipropionitrile (IDPN) (1 g/kg, i.p. for 3 days) in mice leads to the development of a characteristic syndrome consisting of lateral and vertical head and neck movements, hyperactivity, random circling, increased locomotor activity, and increased startle response. Nifedipine, verapamil, and diltiazem (10 mg/kg) inhibited significantly the symptoms of IDPN-induced dyskinesia. However, there was no change in the affinity (KD) or the density of PN 200-110 binding sites (Bmax) in whole brains of IDPN-treated mice. Similarly, the K(+)-depolarization-dependent Ca2+ uptake in synaptosomes from whole brain, cortex, or striatum was not altered following IDPN treatment. However, IDPN caused a significant increase in the Bmax value (from 157 +/- 7 fmol/mg to 237 +/- 31 fmol/mg in control and treated groups, respectively) of PN 200-110 binding to the striatum without change of KD value (38 +/- 4.7 pM versus 33 +/- 1.6 pM). IDPN also caused a slight but significant decrease in the KD value (from 68 +/- 10.1 pM to 45 +/- 4.5 pM in control and treated groups, respectively), without significant change of Bmax value (563 +/- 51 fmol/mg versus 485 +/- 41 fmol/mg) of PN 200-110 binding to the cortex. IDPN did not alter omega-conotoxin binding in whole brain, striatum, or cortex. The behavioral effects of chronic IDPN treatment as inhibited by L-type calcium channel antagonists and this may be associated with the observed increase in striatal L-type calcium channels.

Animals↗
PubMed1991

Do calcium channel classifications account for neuronal calcium channel diversity?

Calcium (Ca2+) ions are involved in the development and control of a variety of neuronal properties and functions such as channel expression, synaptic transmission and neurosecretion. The main pathway by which Ca2+ enters the intracellular space is through voltage-activated Ca2+ channels that can be classified according to their different biophysical and pharmacological properties. Identification and characterization of these channel types are prerequisites for understanding the mechanisms that underlie Ca2(+)-controlled processes. In this article we summarize the efforts made to identify neuronal Ca2+ channel types, and we attempt to evaluate how useful existing classifications are in assigning specific properties and functions to distinct channel types in neurons.

Animals↗
PubMed1992

Molecular and cellular aspects of calcium channel antagonism.

Calcium fluxes play a key role in controlling many physiologic processes and responses in the body. The past few years have witnessed major advances in understanding of L-type calcium channels and their blockade with calcium channel antagonists. The L-type calcium channels comprise 5 subunits termed alpha 1, alpha 2, beta, gamma, and delta. Elucidation of the mechanisms of action of the calcium channel antagonists has been advanced by cloning and genetic manipulation of these subunits. The alpha 1 subunit appears to be responsible for channel opening and voltage dependency, and it contains receptors for calcium channel antagonists; these geographically distinct receptors correspond to each of the 3 different chemical classes of antagonists, exemplified by diltiazem, nifedipine, and verapamil. Diltiazem appears to have an inhibitory effect on mitochondrial sodium-calcium exchange that is unique among calcium channel antagonists. Preliminary data suggest that a diltiazem-specific receptor also exists in the endothelium. It appears, therefore, that despite advances in the understanding of L-type calcium channels, much remains to be learned about other possible receptors for the calcium channel antagonists.

Calcium Channel Blockers↗
PubMed1990

Effects of calcium channel blockade on calcium homeostasis in mild to moderate essential hypertension.

Calcium channel blockers may alter parathyroid hormone secretion in vitro, which would alter calcium homeostasis. To determine the chronic effect of calcium channel blockade in vivo, we conducted a randomized, double blind, 16 week study comparing the effects of two pharmacologic antihypertensive agents, the calcium channel blocker diltiazem and the angiotensin-converting enzyme inhibitor captopril on parameters of calcium homeostasis. Both diltiazem and captopril lowered blood pressure to a similar degree. Neither drug produced any significant change in blood levels of total and ionized calcium, magnesium, or phosphorus, which affect the regulation of parathyroid hormone and vitamin D. In addition, at eight or 16 weeks following initiation, neither drug altered the serum levels of parathyroid hormone (PTH) or 1,25-(OH)2-vitamin D3 (1,25-D). Chronic calcium channel blockade with diltiazem does not alter serum parameters of calcium homeostasis and, thus, should not affect bone mineralization.

Adult↗
PubMedDate not supplied

Sarcoplasmic reticulum contains adenine nucleotide-activated calcium channels.

Rapid calcium efflux from the sarcoplasmic reticulum (SR) is a necessary step in excitation-contraction coupling in skeletal muscle and is thought to be mediated by a calcium channel. Calcium efflux has been studied in fragmented SR vesicles by radioisotope efflux and fluorescence measurements. Several laboratories have reported that adenine nucleotides can stimulate calcium efflux from SR. In recent reports, Ca2+ release with a first-order rate constant as high as 100 s-1 has been observed for nucleotide-stimulated Ca2+ release from SR vesicles. Also, radioisotope efflux was blocked by Mg2+ and micromolar concentrations of the polycationic dye, ruthenium red. These high rates of transport are difficult to reconcile with a mechanism other than passive diffusion through a nucleotide-activated 'calcium release channel'. Using the fusion technique for inserting SR proteins into planar lipid bilayers, we report here single-channel recordings of calcium release channels from purified 'heavy' SR membranes. Channels have been identified on the basis of their activation by adenine nucleotides, blockade by ruthenium red, and selectivity for divalent cations. Surprisingly, the channel studied here exhibits an unusually large conductance of 170 pS in 50 mM Ba2+ while still being capable of discriminating against monovalent cations by a permeability ratio, P(Ba)/P(Cs) = 11.4.

Adenosine Triphosphate↗
PubMed2003

Calcium fluxes in human trophoblast (BeWo) cells: calcium channels, calcium-ATPase, and sodium-calcium exchanger expression.

Although placental transfer of maternal calcium (Ca(2+)) is a crucial process for fetal development, the biochemical mechanisms are poorly understood. In the current study, we have investigated the characteristics of Ca(2+) fluxes in relation with cell Ca(2+) homeostasis in the human placental trophoblast cell line BeWo. Time-courses of Ca(2+) uptake by BeWo cells displayed rapid initial entry (initial velocity (V(i)) of 3.42 +/- 0.35 nmol/mg protein/min) and subsequent establishment of a plateau. Ca(2+) efflux studies with (45)Ca(2+)-loaded cells also showed rapid declined of cell-associated (45)Ca(2+) with a V(i) of efflux (Ve(i)) of 3.30 +/- 0.08 nmol/mg protein/min. Further identification of membrane gates for Ca(2+) entry in BeWo cells was carried out. Expression of Ca(2+) transporter/channel CaT1 and L-type alpha(1S) subunit was showed by RT-PCR. However, mRNA for CaT2 channel and L-type alpha(1C) and alpha(1D) subunits were not revealed. Membrane systems responsible for intracellular Ca(2+) extrusion from BeWo cells were also investigated. Plasma membrane Ca(2+)-ATPases (PMCA) and Na/Ca exchangers (NCX) were detected by Western blot in BeWo cells. Expression of specific isoforms of PMCA and NCX was further investigated by RT-PCR. Messenger RNAs of four isoforms of PMCA (PMCA 1-4) were detected. The presence of messenger RNAs of two NCX isoforms (NCX1 and NCX3) was observed. Ca(2+) flux studies in Na-free incubation medium indicated that NCX played a minimal role in the cell Ca(2+) fluxes. Inorganic ions such as cadmium and manganese did not modify the Ca(2+) fluxes, however, barium increased cell-associated (45)Ca(2+) by, in part, by reducing radiolabel exit.

Calcium↗
PubMed1999

Calcium channel activation stabilizes a neuronal calcium channel mRNA.

We have identified a calcium-dependent pathway in neurons that regulates expression levels of the alpha1B subunit and N channel current. When neurons are depolarized and voltage-gated calcium channels activated, the half-life of cellular N channel alpha1B mRNA is prolonged. This stabilizing effect of depolarization is mediated through the 3' untranslated region of a long form of the alpha1B mRNA and may represent a form of modulation of N-channel levels that does not require changes in gene transcription. Increases in N channel expression would affect several key neuronal functions controlled by calcium, including transmitter release and neurite outgrowth.

3' Untranslated Regions↗
PubMed2003

[Role of L-type calcium channels in the calcium response and interleukin 4 (IL-4) synthesis by Th2 lymphocytes]].

CD4+ T lymphocytes are divided in Th1 cells that produce interferon (IFN) gamma and Th2 cells that synthesize IL-4. These subsets may arise from a common precursor: a combination of IL-12 plus anti-IL-4 monoclonal antibody (mAb) drives Th1 cell differentiation while IL-4 plus anti-IFN gamma mAb favor Th2 cell development. TCR stimulation activates protein kinase C that controls a calcium entry through L type calcium channels in Th2 cells. L type calcium channels are induced during Th2 but not Th1 cell differentiation. In addition, L type calcium channel inhibitors may be successfully used in the treatment of an experimental model of Th2 cell-mediated immunopathology. Thus, this signaling pathway that characterizes Th2 cells can be a target for the treatment of Th2 diseases.

Animals↗