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PubMed2002

L-type Ca2+ channels in fetal and adult ovine cerebral arteries.

Recently, we reported that, whereas in cerebral arteries of the adult a majority of norepinephrine (NE)-induced increase in intracellular Ca2+ concentration ([Ca2+]i) comes from release of the sarcoplasmic reticulum (SR) Ca2+ stores, in the fetus the SR Ca2+ stores are relatively small, and NE-induced increase in [Ca2+]i results mainly from activation of plasma membrane L-type Ca2+ channels (20). In an effort to establish further the role of L-type Ca2+ channels in the developing cerebral arteries, we tested the hypothesis that, in the fetus, increased reliance on plasmalemmal L-type Ca2+ channels is mediated, in part, by increased L-type Ca2+ channel density. We used 3H-labeled (+)isopropyl-4-(2,1,3-benzoxadiazol-4-y1)-1,4-dihydro-(2,6-dimethyl-5-methoxycarbonyl)pyridine-3-carboxylate (PN200-110, isradipine) to measure L-type Ca2+ channel density (Bmax) in the cerebral arteries, common carotid artery (CCA), and descending aortae of fetal (approximately 140 gestation days), newborn (7-10 days), and adult sheep. In the cerebral and common carotid arteries, B(max) values (fmol/mg protein) of fetuses and newborns were significantly greater than those of adults. Western immunoblotting assay also revealed that the density of L-type Ca2+ channel protein in the cerebral arteries and CCA was about twofold greater in the fetus than the adult. Finally, compared with the adult, fetal cerebral arteries demonstrated a significantly greater maximum tension and [Ca2+]i in response to stimulation with the L-type Ca2+ channel agonist Bay K 8644. In addition, Bay K 8644-stimulated fetal vessels demonstrated a maximal tension and [Ca2+]i similar to that observed in response to stimulation with 10(-4) NE. These results support the idea that fetal cerebrovascular smooth muscle relies more on extracellular Ca2+ and L-type Ca2+ channels for contraction than does the adult and that this increased reliance is mediated, in part, by greater L-type Ca2+ channel density. This may have important implications in the regulation of cerebral blood flow in the developing organism.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Agonist-induced intracellular Ca2+ transients in HT29 cells.

In the present study we have investigated the mechanism of intracellular Ca2+ activity ([Ca2+]i) changes in HT29 cells induced by adenosine triphosphate (ATP), carbachol (CCH), and neurotensin (NT). [Ca2+]i was measured with the fluorescent Ca2+ indicator fura-2 at the single-cell level or in small cell plaques with high time resolution (1-40Hz). ATP and CCH induced not only a dose-dependent [Ca2+]i peak response, but also changes of the plateau phase. The [Ca2+]i plateau was inversely dependent on the ATP concentration, whereas the CCH-induced [Ca2+]i plateau increased at higher CCH concentrations. NT showed (from 10(-10) to 10(-7) mol/l) in most cases only a [Ca2+]i spike lasting 2-3 min. The [Ca2+]i plateau induced by ATP (10(-6) mol/l) and CCH (10(-5) mol/l) was abolished by reducing the Ca2+ activity in the bath from 10(-3) to 10(-4) mol/l (n = 7). In Ca(2+)-free bathing solution the [Ca2+]i peak value for all three agonists was not altered. Using fura-2 quenching by Mn2+ as an indicator of Ca2+ influx the [Ca2+]i peak was always reached before Mn2+ influx started. Every agonist showed this delayed stimulation of the Ca2+ influx with a lag time of 23 +/- 1.5 s (n = 15) indicating a similar mechanism in each case. Verapamil (10(-6)-10(-4) mol/l) blocked dose dependently both phases (peak and plateau) of the CCH-induced [Ca2+]i increase. Short pre-incubation with verapamil augmented the effect on the [Ca2+]i peak, whereas no further influence on the plateau was observed. Ni2+ (10(-3) mol/l) reduced the plateau value by 70%.

Adenosine Triphosphate↗
PubMed2000

Transmission of information from cardiac dihydropyridine receptor to ryanodine receptor: evidence from BayK 8644 effects on resting Ca(2+) sparks.

Coupling between L-type Ca(2+) channels (dihydropyridine receptors, DHPRs) and ryanodine receptors (RyRs) plays a pivotal role in excitation-contraction (E-C) coupling in cardiac myocytes, and Ca(2+) influx is generally accepted as the trigger of sarcoplasmic reticulum (SR) Ca(2+) release. The L-type Ca(2+) channel agonist BayK 8644 (BayK) has also been reported to alter RyR gating via a functional linkage between DHPR and RyR, independent of Ca(2+) influx. Here, the effect of rapid BayK application on resting RyR gating in intact ferret ventricular myocytes was measured as Ca(2+) spark frequency (CaSpF) by confocal microscopy and fluo 3. BayK increased resting CaSpF by 401+/-15% within 10 seconds in Ca(2+)-free solution, and depolarization had no additional effect. The effect of BayK on CaSpF was dose-dependent, but even 50 nmol/L BayK induced a rapid 245+/-12% increase in CaSpF. Nifedipine (5 micromol/L) had no effect by itself on CaSpF, but it abolished the BayK effect (presumably by competitive inhibition at the DHPR). The nondihydropyridine Ca(2+) channel agonist FPL-64176 (1 micromol/L) did not alter CaSpF (despite rapid and potent enhancement of Ca(2+) current, I(Ca)). In striking contrast to the very rapid and depolarization-independent effect of BayK on CaSpF, BayK increased I(Ca) only slowly (tau=18 seconds), and the effect was greatly accelerated by depolarization. We conclude that in ferret ventricular myocytes, BayK effects on I(Ca) and CaSpF both require drug binding to the DHPR, but postreceptor pathways may diverge in transmission to the gating of the L-type Ca(2+) channel and RyR.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Dihydropyridine ligands influence the evoked release of oxytocin and vasopressin dependent on stimulation conditions.

The effects of dihydropyridine ligands on the electrically evoked release of neurohypophysial hormones from isolated, rat neurointermediate lobes were investigated as a function of all combinations of two pulse widths (0.2 and 2 ms) and three stimulation frequencies (6.5, 13 and 30 Hz). The dihydropyridine agonist (S)-(+)-202-791 potentiated concentration dependently the release of both oxytocin and vasopressin at a pulse width of 2 ms and a frequency of 6.5 Hz. This effect of (S)-(+)-202-791 was abolished by the antagonist (-)-nitrendipine and stereospecifically by (R)-(-)-202-791 (only vasopressin). The antagonist (R)-(-)-202-791 alone inhibited the release of oxytocin at 13 Hz and 2 ms. The results presented show that the effects of the dihydropyridine ligands are dependent on the stimulation conditions, and thus demonstrate that the entry of Ca2+ through the dihydropyridine sensitive L-type Ca2+ channel is associated with electrically evoked release of neurohypophysial hormones under certain conditions.

Animals↗
PubMed1996

Palmitoyl-CoA potentiates the Ca2+ release elicited by cyclic ADP-ribose.

Cyclic ADP-ribose (cADPR) is a potent mediator of Ca2+ mobilization from intracellular stores in sea urchin eggs that ultimately activates the ryanodine channel. We now report that certain long-chain acyl-CoA derivative metabolites (14-18 carbons in length), such as palmitoyl-CoA, greatly potentiate the effect of cADPR on Ca2+ release. Furthermore, in higher concentrations, palmitoyl-CoA and other closely related long-chain acyl-CoA derivatives trigger Ca2+ release apparently through the ryanodine channel in sea urchin egg homogenates. Palmitoyl-CoA-induced Ca2+ release was suppressed by ruthenium red, spermine, and the calmodulin antagonist N-(6-aminohexyl)-1-naphthalenesulfonamide, which all prevent activation of the ryanodine channel, but not by heparin or thionicotinamide-NADP. In addition, cADPR was able to desensitize the sea urchin egg homogenates to the subsequent Ca2+ release induced by palmitoyl-CoA and vice versa. In contrast, neither inositol 1,4,5-trisphosphate (IP3) nor the newly identified Ca2+ release agonist nicotinate adenine dinucleotide phosphate was able to desensitize the homogenate to palmitoyl-CoA, indicating that palmitoyl-CoA probably acts selectively by activating the ryanodine channel, but, unlike cADPR, palmitoyl-CoA might act directly on this channel. Finally, we found that palmitoyl-CoA was able to counteract the inhibitory effect of Mg2+ and spermine, which, in physiological concentrations, suppress specifically the cADPR-induced Ca2+ release. We propose that palmitoyl-CoA, present in micromolar concentrations, may trigger Ca2+ release through the ryanodine channel and, in lower concentrations, may increase the sensitivity of the Ca2+ release system to cADPR. Thus palmitoyl-CoA may serve as a regulatory link between the intermediary metabolism and the cADPR-induced Ca2+ release signaling pathway.

Adenosine Diphosphate Ribose↗
PubMed1991

Ca2+ channel agonists enhance thyrotropin-releasing hormone-induced inositol phosphates and prolactin secretion.

The dihydropyridine Ca2+ channel activator BAY K 8644 (1 microM) stimulated basal prolactin secretion from perifused primary cultures of anterior pituitary cells and potentiated the stimulation of prolactin secretion by 1 microM thyrotropin-releasing hormone (TRH) 5-fold over 30 min. This potentiation was mimicked by other dihydropyridine agonists CGP 28392 and (+)-SDZ 202-791 and by (-)-BAY K 8644 (1 microM), but not by (+)-BAY K 8644. The Ca2+ channel antagonist nimodipine, at a concentration sufficient to block BAY K 8644-stimulated 45Ca2+ uptake in GH4C1 anterior pituitary tumor cells, decreased basal prolactin secretion and blocked the enhancement of basal and TRH-stimulated secretion by BAY K 8644. These results suggest that dihydropyridine agonists potentiate TRH-induced secretion through interaction with known stereospecific sites on Ca2+ channels. In GH4C1 cells, BAY K 8644 alone did not affect inositol polyphosphate accumulation, but potentiated TRH-stimulated accumulation of inositol 1,3,4-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Accumulation of the Ca(2+)-mobilizing isomer inositol 1,4,5-trisphosphate was not potentiated, suggesting that potentiation of TRH-stimulated hormone secretion by BAY K 8644 does not result from synergistic stimulation of phospholipase C, but may correlate with enhanced inositol trisphosphate-3-kinase activity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

Mechanism of generation of spontaneous miniature outward currents (SMOCs) in retinal amacrine cells.

A subtype of retinal amacrine cells displayed a distinctive array of K(+) currents. Spontaneous miniature outward currents (SMOCs) were observed in the narrow voltage range of -60 to -40 mV. Depolarizations above approximately -40 mV were associated with the disappearance of SMOCs and the appearance of transient (I(to)) and sustained (I(so)) outward K(+) currents. I(to) appeared at about -40 mV and its apparent magnitude was biphasic with voltage, whereas I(so) appeared near -30 mV and increased linearly. SMOCs, I(to), and a component of I(so) were Ca(2+) dependent. SMOCs were spike shaped, occurred randomly, and had decay times appreciably longer than the time to peak. In the presence of cadmium or cobalt, SMOCs with pharmacologic properties identical to those seen in normal Ringer's could be generated at voltages of -20 mV and above. Their mean amplitude was Nernstian with respect to [K(+)](ext) and they were blocked by tetraethylammonium. SMOCs were inhibited by iberiotoxin, were insensitive to apamin, and eliminated by nominally Ca(2+)-free solutions, indicative of BK-type Ca(2+)-activated K(+) currents. Dihydropyridine Ca(2+) channel antagonists and agonists decreased and increased SMOC frequencies, respectively. Ca(2+) permeation through the kainic acid receptor had no effect. Blockade of organelle Ca(2+) channels by ryanodine, or intracellular Ca(2+) store depletion with caffeine, eradicated SMOCs. Internal Ca(2+) chelation with 10 mM BAPTA eliminated SMOCs, whereas 10 mM EGTA had no effect. These results suggest a mechanism whereby Ca(2+) influx through L-type Ca(2+) channels and its subsequent amplification by Ca(2+)-induced Ca(2+) release via the ryanodine receptor leads to a localized elevation of internal Ca(2+). This amplified Ca(2+) signal in turn activates BK channels in a discontinuous fashion, resulting in randomly occurring SMOCs.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Differential interactions of the C terminus and the cytoplasmic I-II loop of neuronal Ca2+ channels with G-protein alpha and beta gamma subunits. II. Evidence for direct binding.

The present study was designed to obtain evidence for direct interactions of G-protein alpha (Galpha) and beta gamma subunits (Gbeta gamma) with N- (alpha1B) and P/Q-type (alpha1A) Ca2+ channels, using synthetic peptides and fusion proteins derived from loop 1 (cytoplasmic loop between repeat I and II) and the C terminus of these channels. For N-type, prepulse facilitation as mediated by Gbeta gamma was impaired when a synthetic loop 1 peptide was applied intracellularly. Receptor agonist-induced inhibition of N-type as mediated by Galpha was also impaired by the loop 1 peptide but only when applied in combination with a C-terminal peptide. For P/Q-type channels, by contrast, the Galpha-mediated inhibition was diminished by application of a C-terminal peptide alone. Moreover, in vitro binding analysis for N- and P/Q-type channels revealed direct interaction of Galpha with C-terminal fusion proteins as well as direct interaction of Gbeta gamma with loop 1 fusion proteins. These findings define loop 1 of N- and P/Q-type Ca2+ channels as an interaction site for Gbeta gamma and the C termini for Galpha.

Amino Acid Sequence↗
PubMed2002

Different effects of mibefradil and amlodipine on coronary vessels and during beta-adrenergic stimulation in conscious dogs.

Coronary effects of Ca -channel blockers mibefradil and amlodipine were compared in conscious dogs. Ten dogs were instrumented for measurement of aortic and left ventricular pressures, circumflex coronary blood flow velocity (CBFv), and coronary diameter (CD). A permanent catheter was implanted in the circumflex coronary artery. At doses having no systemic effects (7.5-150 micro g/kg), mibefradil and amlodipine increased CBFv and CD dose dependently. At the same dose, mibefradil increased less CBFv than amlodipine. However, for a similar increase in CBFv induced by amlodipine, mibefradil increased CD more. BAY K8644, an L-type Ca -channel agonist, prevented the CBFv and CD responses to amlodipine, but minimally affected the coronary responses to mibefradil. Intracoronary isoproterenol (6 ng/kg) increased LV dP/dt max, CBFv, and CD. Amlodipine markedly altered these responses, while mibefradil did not affect LV inotropic response and slightly altered CBFv response to isoproterenol. Thus, in conscious dogs, both mibefradil and amlodipine exert coronary vasodilation, with different patterns on coronary conductance and resistance vessels and during beta-adrenergic stimulation. These differences could be related to their actions on different Ca channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMedDate not supplied

Properties of isolated gastric enterochromaffin-like cells.

The gastric enterochromaffin-like cell (ECL) has been studied in gastric fundic glands by confocal microscopy and as a purified cell preparation by video imaging of calcium signaling and measurements of histamine release. Regulation of gastric acid secretion is largely due to alterations of histamine activation of the H2 receptor on the parietal cell and can be divided into central neural regulation, with direct actions of neuronally released mediators and into peripheral regulation by substances released from other endocrine cells. Gastric neuronal stimulation of acid secretion by alteration of ECL cell function is probably mediated by pituitary adenylate cyclase activating peptide (PACAP) receptors on the ECL cell, which activate calcium signaling and histamine release. Peripheral stimulation of acid secretion via the ECL cell is largely mediated by gastrin stimulation of calcium signaling and histamine release. Gastric neuronal inhibition of ECL cell function is probably mediated by galanin inhibition of calcium signaling, and histamine release and peripheral inhibition of ECL cell function is mainly due to somatostatin release from D cells.

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

Enhancement of tamoxifen-induced E-cadherin function by Ca2+ channel antagonists in human breast cancer MCF7/6 cells.

Despite its intensive use in adjuvant breast cancer therapy for more than 30 years, the exact mechanisms of action of tamoxifen have not yet been fully characterized. Tamoxifen was recently shown to restore the E-cadherin function of human breast cancer MCF7/6 cells and to suppress their invasive phenotype. Because tamoxifen interacts with targets implicated in Ca2+ homeostasis, we explored the possibility that the restoration of E-cadherin function in MCF7/6 cells induced by this drug could be affected by Ca2+ modulators. Two different Ca2+ channel antagonists (verapamil and nifedipine) potentiated the effect of tamoxifen on E-cadherin function, as evaluated with a fast cell aggregation assay. These molecules decreased the tamoxifen concentration needed to restore the E-cadherin function from 10(-6) M to 10(-7) M. When incubated with a Ca2+ channel agonist, Bay K8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methylphenyl)- pyridine-5-carboxylate), the effect of tamoxifen on E-cadherin function was completely abolished. These results demonstrate that the restoration of the E-cadherin function induced by tamoxifen depends, at least in part, on a Ca2+ pathway, and support the evidence of an effect of tamoxifen on Ca(2+)-dependent mechanisms. Our data also suggest that Ca2+ channel modulators could make it possible to decrease the dose of tamoxifen administered to patients without reducing the therapeutic effects.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Ca2+ channel modulation alters halothane-induced depression of ventricular myocytes.

PURPOSE: This study examined the direct myocardial depressant effect of halothane and determined whether an L-type Ca2+ channel agonist and antagonists altered the myocardial depression induced by halothane in cultured rat ventricular myocytes. METHODS: Ventricular myocytes were obtained from neonatal rats by enzymatic digestion with collagenase and then cultured for 6 to 7 days. The myocytes were stabilized in a serum-free medium, and the spontaneous beating rate and amplitude were measured. To assess the halothane-induced conformational changes in L-type Ca2+ channel, receptor binding study was performed using a dihydropyridine derivative, [3H] PN 200-110, in cardiac membrane preparation. RESULTS: Halothane (1%, 2%, 3%, 4%) decreased the beating rate and amplitude in a concentration-dependent manner (P < 0.05). The myocardial depressant effects of halothane were potentiated by nifedipine or verapamil (P < 0.05). Bay K 8644, an L-type Ca2+ channel agonist, completely prevented the halothane-induced depression in amplitude (P < 0.05), but affected the beating rate less. Adding halothane (2%) decreased (P < 0.05) the maximum binding site density for [3H] PN 200-110 (from 198.6 +/- 23.7 fmol.mg-1 protein to 115.3 +/- 21.6 fmol.mg-1 protein) but did not affect binding affinity (from 0.461 +/- 0.077 nM to 0.307 +/- 0.055 nM). CONCLUSION: The reduction of Ca2+ current via sarcolemmal L-type Ca2+ channel, probably due to conformational changes in dihydropyridine binding sites, plays an important role in halothane-induced myocardial depression in living heart cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Modulation of nicotine-induced analgesia by calcium agonist and antagonist in adult rats.

The involvement of calcium in nicotine-induced analgesia in male rats was explored using the tail-flick test. A single dose of nicotine (1 mg/kg SC) produced a maximal effect on tail-flick latency (15 s) within 8-10 min, which lasted for 4 min. Pretreatment with the calcium chelator, EDTA (250 microM/kg SC four injections at 15 min intervals), before the single dose of nicotine accelerated the onset and prolonged the duration of the nicotine-induced analgesia. The maximal effect on tail-flick latency occurred within 2 min and lasted for 10-20 min. Conversely, pretreatment with calcium chloride (1.5 mM/kg IP) attenuated nicotine-induced analgesia. It is suggested that nicotine may exert its antinociceptive effects via modulation of calcium fluxes across the neural membrane.

Analgesia↗
PubMed2001

Influence of Voltage-sensitive Ca(++) channel drugs on bupivacaine infiltration anesthesia in mice.

BACKGROUND: Local anesthesia has been traditionally associated with blockade of voltage-sensitive sodium (Na(+)) channels. Yet in vitro evidence indicates that local anesthetic mechanisms are more complex than previously understood. For example, local anesthetics bind and allosterically modify 1,4-dihydropyridine-sensitive Ca(++) channels and can reduce Ca(++) influx in tissues. The current study examines the influence of voltage-sensitive Ca(++) channels in bupivacaine infiltration anesthesia. METHODS: Baseline tail-flick latencies to radiant heat nociception were obtained before subcutaneous infiltration of bupivacaine and Ca(++)-modulating drugs in the tails of mice. No musculature is contained in the tail that could result in motor block. The magnitude of infiltration anesthesia over time, as well as the potency of bupivacaine alone or in the presence of Ca(++)-modulating drug, was assessed by obtaining test latencies. RESULTS: The 1,4-dihydropyridine L-type Ca(++) channel agonist S(-)-BayK-8644 reduced the duration of action and potency of bupivacaine anesthesia. In opposite fashion, nifedipine and nicardipine increased the effects of bupivacaine. Neither nifedipine nor nicardipine alone elicited anesthesia. Alternatively, the phenylalkylamine L-type blocker verapamil elicited concentration-dependent anesthesia. Other Ca(++) channel subtype blockers were investigated as well. The N-, T-, P-, and Q-type channel blockers, omega-conotoxin GVIA, flunarizine, omega-agatoxin IVA, and omega-conotoxin MVIIC, respectively, were unable to modify bupivacaine anesthesia. CONCLUSIONS: These results indicate that heat nociception stimulates Ca(++) influx through L-type channels on nociceptors in skin. Although other voltage-sensitive Ca(++) channels may be located on skin nociceptors, only the L-type channel drugs affected bupivacaine in the radiant heat test.

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

Comparison of the effects of perchlorate and Bay K 8644 on the dynamics of cytoplasmic Ca2+ concentration and insulin secretion in mouse beta-cells.

Non-inbred ob/ob mice were used to study the dynamics of cytoplasmic Ca2+ concentration ([Ca2+]i) in isolated pancreatic beta-cells using microfluorimetry with fura 2/AM as probe, and the dynamics of insulin secretion in isolated pancreatic islets. D-Glucose (20 mM) caused a transient peak increase in [CA2+]i which changed to either an oscillating or a flat, elevated phase. The lag-time before the first peak increase in [Ca2+]i was markedly shortened by 12 mM ClO4- and the glucose-stimulated level of [Ca2+]i after the first peak was clearly elevated by the anion. ClO4- did not change the basal [Ca2+]i at 3 mM glucose. Extracellular Ca2+ deficiency abolished the effect of high glucose and ClO4- on [Ca2+]i. This suggests that ClO4- acts as an amplifier of transmembrane Ca2+ inflow. The L-type Ca2+ channel agonist, Bay K 8644 (0.01-1.0 microM), strictly reproduced all the effects of perchlorate on the glucose-stimulated beta-cell [Ca2+]i. Both phases of insulin release (20 mM glucose) were markedly enhanced by ClO4- (12 mM) or Bay K 8644 (1.0 microM). The lag-time for glucose-stimulated insulin release was shortened by both agents. Taken together, these data strengthen the idea that perchlorate amplifies the glucose-stimulation of [Ca2+]i and insulin release by directly modifying the function of the L-type Ca2+ channel. This effect can induce both a more prompt onset of and an amplified level of beta-cell secretory activity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2005

Postsynaptic IP3 receptor-mediated Ca2+ release modulates synaptic transmission in hippocampal neurons.

Ca(2+)-dependent mechanisms are important in regulating synaptic transmission. The results herein indicate that whole-cell perfusion of inositol 1,4,5-trisphosphate receptor (IP(3)R) agonists greatly enhanced excitatory postsynaptic current (EPSC) amplitudes in postsynaptic hippocampal CA1 neurons. IP(3)R agonist-mediated increases in synaptic transmission changed during development and paralleled age-dependent increases in hippocampal type-1 IP(3)Rs. IP(3)R agonist-mediated increases in EPSC amplitudes were inhibited by postsynaptic perfusion of inhibitors of Ca(2+)/calmodulin, PKC and Ca(2+)/calmodulin-dependent protein kinase II. Postsynaptic perfusion of inhibitors of smooth endoplasmic reticulum (SER) Ca(2+)-ATPases, which deplete intracellular Ca(2+) stores, also enhanced EPSC amplitudes. Postsynaptic perfusion of the IP(3)R agonist adenophostin (AdA) during subthreshold stimulation appeared to convert silent to active synapses; synaptic transmission at these active synapses was completely blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Postsynaptic IP(3)R-mediated Ca(2+) release also produced a significant increase in spontaneous EPSC frequency. These results indicate that Ca(2+) release from intracellular stores play a key role in regulating the function of postsynaptic AMPARs.

2-Amino-5-phosphonovalerate↗
PubMed1995

Inhibitory effects of thiopental, ketamine, and propofol on voltage-dependent Ca2+ channels in porcine tracheal smooth muscle cells.

BACKGROUND: Intravenously administered anesthetics directly inhibit airway smooth muscle contraction. Because many anesthetic agents affect membrane ion channel function and sustained contraction of airway smooth muscle requires the influx of Ca2+ through voltage-dependent Ca2+ channels, it was hypothesized that intravenous anesthetics inhibit airway smooth muscle voltage-dependent Ca2+ channels. METHODS: Porcine tracheal smooth muscle cells were enzymatically dispersed and studied using whole-cell, patch-clamp techniques. The cells were exposed to thiopental (10(-7)-3 x 10(-4) M), ketamine (10(-6)-10(-3) M), or propofol (10(-7)-3 x 10(-4) M) while recording macroscopic voltage-activated Ca2+ currents (ICa). RESULTS: Each intravenous anesthetic tested significantly inhibited ICa in a dose-dependent manner with 3 x 10(-4) M thiopental, 10(-3) M ketamine, and 3 x 10(-4) M propofol each causing approximately 50% depression of peak ICa, but with no apparent shift in the voltage dependence of induced ICa. After pretreatment with the Ca2+ channel agonist Bay K 8644, thiopental, but not ketamine or propofol, shifted the maximum ICa to more positive potentials. All three anesthetics promoted the inactivated state of the channel at more negative potentials, but propofol was less effective than thiopental or ketamine in this regard. CONCLUSIONS: Three intravenous anesthetics evaluated in this study decreased the ICa of porcine tracheal smooth muscle cells but with subtle electrophysiologic differences. Hence, thiopental, ketamine, and propofol each inhibit L-type voltage-dependent Ca2+ channels of porcine tracheal smooth muscle cells but the molecular mechanisms involved may be agent specific. This inhibition may contribute to the airway smooth muscle relaxant effects of these agents observed in vitro at concentrations greater than those encountered clinically.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Interaction between L-type Ca2+ channels and sarcoplasmic reticulum in the regulation of vascular tone in isolated rat small arteries.

A dysfunction of the sarcoplasmic reticulum (SR) causes an increase in the myogenic tone of rat skeletal muscle small arteries (A(SK)), but not that of mesenteric small arteries (A(MS)). We hypothesized that the difference depends on the activity of voltage-dependent Ca2+ channels in these vessels. To test this, we measured the membrane potential of these vessels and examined ryanodine-induced constrictions by manipulating the activity of voltage-dependent Ca2+ channels. The isolated vessels were cannulated to control the transmural pressure. To assess the vascular tone, the inner diameter was measured with a video-digitizing system. The membrane potential of A(SK) was more depolarized between 20 to 100 mm Hg of transmural pressure. A(MS) was not constricted by the Ca2+ channel agonist Bay K 8644 (1 nM(-1) microM) alone, but substantially constricted in the presence of ryanodine (1 microM). Ryanodine also augmented the KCl (20 mM)-induced constriction. In A(SK), the Ca2+ channel blocker nisoldipine fully dilated the ryanodine-induced constriction: however, the ryanodine-induced constriction was less susceptible to nisoldipine than was the myogenic and phenylephrine-induced constriction caused mainly by increased Ca2+ influx. In conclusion, the contribution of the SR function to Ca2+ metabolism depends on the activity of dihydropyridine-sensitive Ca2+ channels. The dysfunction of SR by ryanodine may impair the Ca2+ extrusion rather than increase Ca2+ influx in rat small arteries.

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