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PubMed2004

Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling.

Neuronal activity in the brain is thought to be coupled to cerebral arterioles (functional hyperemia) through Ca2+ signals in astrocytes. Although functional hyperemia occurs rapidly, within seconds, such rapid signaling has not been demonstrated in situ, and Ca2+ measurements in parenchymal arterioles are still lacking. Using a laser scanning confocal microscope and fluorescence Ca2+ indicators, we provide the first evidence that in a brain slice preparation, increased neuronal activity by electrical stimulation (ES) is rapidly signaled, within seconds, to cerebral arterioles and is associated with astrocytic Ca2+ waves. Smooth muscle cells in parenchymal arterioles exhibited Ca2+ and diameter oscillations ("vasomotion") that were rapidly suppressed by ES. The neuronal-mediated Ca2+ rise in cortical astrocytes was dependent on intracellular (inositol trisphosphate [IP3]) and extracellular voltage-dependent Ca2+ channel sources. The Na+ channel blocker tetrodotoxin prevented the rise in astrocytic [Ca2+]i and the suppression of Ca2+ oscillations in parenchymal arterioles to ES, indicating that neuronal activity was necessary for both events. Activation of metabotropic glutamate receptors in astrocytes significantly decreased the frequency of Ca2+ oscillations in parenchymal arterioles. This study supports the concept that astrocytic Ca2+ changes signal the cerebral microvasculature and indicate the novel concept that this communication occurs through the suppression of arteriolar [Ca2+]i oscillations and corresponding vasomotion. The full text of this article is available online at http://circres.ahajournals.org.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2002

Epithelial Na channels and short-term renal response to salt deprivation.

To test the role of epithelial Na channels in the day-to-day regulation of renal Na excretion, rats were infused via osmotic minipumps with the Na channel blocker amiloride at rates that achieved drug concentrations of 2-5 microM in the lumen of the distal nephron. Daily Na excretion rates were unchanged, although amiloride-treated animals tended to excrete more Na in the afternoon and less in the late evening than controls. When the rats were given a low-Na diet, Na excretion rates were elevated in the amiloride-treated group within 4 h and remained higher than controls for at least 48 h. Adrenalectomized animals responded similarly to the low-Na diet. In contrast, rats infused with polythiazide at rates designed to inhibit NaCl transport in the distal tubule were able to conserve Na as well as did the controls. Injection of aldosterone (2 microg/100 g body wt) decreased Na excretion in control animals after a 1-h delay. This effect was largely abolished in amiloride-treated rats. On the basis of quantitative analysis of the results, we conclude that activation of amiloride-sensitive channels by mineralocorticoids accounts for 50-80% of the immediate natriuretic response of the kidney to a reduction in Na intake. Furthermore, the channels are necessary to achieve minimal rates of Na excretion during more chronic Na deprivation.

Aldosterone↗
PubMed2005

Small-cell lung cancer (human): potentiation of endocytic membrane activity by voltage-gated Na(+) channel expression in vitro.

The possible functional role of voltage-gated Na(+) channel (VGSC) expression in controlling endocytic membrane activity in human small-cell lung cancer (SCLC) cell lines (H69, H209, H510) was studied using uptake of horseradish peroxidase (HRP). The normal human airway epithelial (16HBE14o) cell line was used in a comparative approach. Uptake of HRP was vesicular, strongly temperature-sensitive and suppressed by cytoskeletal poisons (cytochalasin D and colchicine), consistent with endocytosis. Compared with the normal cells, HRP uptake into SCLC cells was kinetically more efficient, resulting in more than four-fold higher uptake under optimized conditions. Importantly, HRP uptake into SCLC cells was inhibited significantly by the specific VGSC blocker tetrodotoxin, as well as lidocaine and phenytoin. These effects were dose-dependent. None of these drugs had any effect on the uptake into the 16HBE14o cells. Uptake of HRP into SCLC cells was reduced by approximately 66% in Na(+)-free medium and was partially ( approximately 30%) dependent on extracellular Ca(2+). The possibility that the endocytic activity in the H510 SCLC cells involved an endogenous cholinergic system was investigated by testing the effects of carbachol (a cholinergic receptor agonist) and eserine (an inhibitor of acetylcholinesterase). Both drugs inhibited HRP uptake, thereby suggesting that basal cholinergic activity occurred. It is concluded that VGSC upregulation could enhance metastatic cell behavior in SCLC by enhancing endocytic membrane activity.

Carbachol↗
PubMed2000

Seizures and neurodegeneration induced by 4-aminopyridine in rat hippocampus in vivo: role of glutamate- and GABA-mediated neurotransmission and of ion channels.

Infusion of the K(+) channel blocker 4-aminopyridine in the hippocampus induces the release of glutamate, as well as seizures and neurodegeneration. Since an imbalance between excitation and inhibition, as well as alterations of ion channels, may be involved in these effects of 4-aminopyridine, we have studied whether they are modified by drugs that block glutamatergic transmission or ion channels, or drugs that potentiate GABA-mediated transmission. The drugs were administered to anesthetized rats subjected to intrahippocampal infusion of 4-aminopyridine through microdialysis probes, with simultaneous collection of dialysis perfusates and recording of the electroencephalogram, and subsequent histological analysis. Ionotropic glutamate receptor antagonists clearly diminished the intensity of seizures and prevented the neuronal damage, but did not alter substantially the enhancement of extracellular glutamate induced by 4-aminopyridine. None of the drugs facilitating GABA-mediated transmission, including uptake blockers, GABA-transaminase inhibitors and agonists of the A-type receptor, was able to reduce the glutamate release, seizures or neuronal damage produced by 4-aminopyridine. In contrast, nipecotate, which notably increased extracellular levels of the amino acid, potentiated the intensity of seizures and the neurodegeneration. GABA(A) receptor antagonists partially reduced the extracellular accumulation of glutamate induced by 4-aminopyridine, but did not exert any protective action. Tetrodotoxin largely prevented the increase of extracellular glutamate, the electroencephalographic epileptic discharges and the neuronal death in the CA1 and CA3 hippocampal regions. Valproate and carbamazepine, also Na(+) channel blockers that possess general anticonvulsant action, failed to modify the three effects of 4-aminopyridine studied. The N-type Ca(2+) channel blocker omega-conotoxin, the K(+) channel opener diazoxide, and the non-specific ion channel blocker riluzole diminished the enhancement of extracellular glutamate and slightly protected against the neurodegeneration. However, the two former compounds did not antagonize the 4-aminopyridine-induced epileptiform discharges, and riluzole instead markedly increased the intensity and duration of the disharges. Moreover, at the highest dose tested (8mg/kg, i.p.), riluzole caused a 75% mortality of the rats. We conclude that 4-aminopyridine stimulates the release of glutamate from nerve endings and that the resultant augmented extracellular glutamate is directly related to the neurodegeneration and is involved in the generation of epileptiform discharges through the concomitant overactivation of glutamate receptors. Under these conditions, a facilitated GABA-mediated transmission may paradoxically boost neuronal hyperexcitation. Riluzole, a drug used to treat amyotrophic lateral sclerosis, seems to be toxic when combined with neuronal hyperexcitation.

4-Aminopyridine↗
PubMed2000

[Current classification of anti-arrhythmia agents].

Antiarrhythmic drugs can be divided into four Vaughan Williams classes (I-IV) according to defined electrophysiological effects on the myocardium. Thus, the Vaughan Williams classification also coincides with the main myocardial targets of the antiarrhythmics, i.e., myocardial sodium-, potassium-, and calcium-channels or beta-adrenergic receptors. A more detailed characterization which is also based on the myocardial targets of a drug is given by the "Sicilian Gambit" approach of classification. Nevertheless, the appropriate drug for the management of a given clinical arrhythmia has to be chosen according to the electrophysiological effects of the respective drug. A main determinant of the antiarrhythmic or proarrhythmic properties of a drug is the frequency dependence of its electrophysiological effects. The sodium-channel blockade induced by class-I substances is enhanced with increasing heart rates. Thus, class-I antiarrhythmics can be subclassified as substances showing a more exponential, an approximately linear, or rather saturated block-frequency relation. Class-III antiarrhythmics (potassium-channel blockade) can be further differentiated according to the component of the delayed rectifier potassium current (IK) which is inhibited by a drug. Class-III drugs inhibiting selectively the rapidly activating and deactivating IKr component exhibit a marked reverse rate dependence, i.e., the drug induced prolongation of the cardiac action potential is minimized at high rates. On the other hand, during bradycardia the pronounced action potential prolongation may cause early afterdepolarizations and triggered activity leading to torsades de pointes arrhythmias (acquired QT syndrome). Class-III substances inhibiting the slowly activating IKs component are currently under investigation and are expected to show a direct rate dependence. Experimental data available so far point to an action potential prolonging effect at least independent of rate. However, it is uncertain whether proarrhythmic effects can be thus avoided, especially in light of the fact that one form of congenital QT syndrome (LQT1) seems to be linked to dysfunction of the IKs-channel.

Adrenergic beta-Antagonists↗
PubMed1999

On the molecular basis of ion permeation in the epithelial Na+ channel.

The epithelial Na+ channel (ENaC) is highly selective for Na+ and Li+ over K+ and is blocked by the diuretic amiloride. ENaC is a heterotetramer made of two alpha, one beta, and one gamma homologous subunits, each subunit comprising two transmembrane segments. Amino acid residues involved in binding of the pore blocker amiloride are located in the pre-M2 segment of beta and gamma subunits, which precedes the second putative transmembrane alpha helix (M2). A residue in the alpha subunit (alphaS589) at the NH2 terminus of M2 is critical for the molecular sieving properties of ENaC. ENaC is more permeable to Li+ than Na+ ions. The concentration of half-maximal unitary conductance is 38 mM for Na+ and 118 mM for Li+, a kinetic property that can account for the differences in Li+ and Na+ permeability. We show here that mutation of amino acid residues at homologous positions in the pre-M2 segment of alpha, beta, and gamma subunits (alphaG587, betaG529, gammaS541) decreases the Li+/Na+ selectivity by changing the apparent channel affinity for Li+ and Na+. Fitting single-channel data of the Li+ permeation to a discrete-state model including three barriers and two binding sites revealed that these mutations increased the energy needed for the translocation of Li+ from an outer ion binding site through the selectivity filter. Mutation of betaG529 to Ser, Cys, or Asp made ENaC partially permeable to K+ and larger ions, similar to the previously reported alphaS589 mutations. We conclude that the residues alphaG587 to alphaS589 and homologous residues in the beta and gamma subunits form the selectivity filter, which tightly accommodates Na+ and Li+ ions and excludes larger ions like K+.

Amiloride↗
PubMed1998

Differential effects of phorbol ester (PMA) on blocker-sensitive ENaCs of frog skin and A6 epithelia.

Activation of protein kinase C with phorbol 12-myristate 13-acetate (PMA) caused complex transient perturbations of amiloride-sensitive short-circuit Na+ currents (INa) in A6 epithelia and frog skins that were tissue and concentration dependent. A noninvasive channel blocker pulse method of noise analysis (18) was used to investigate how PMA caused time-dependent changes of apical membrane epithelial Na+ channel (ENaC) single-channel currents, channel open probabilities (Po), and channel densities (NT). In A6 epithelia, 5 and 50 nM PMA caused within 7 min concentration-dependent sustained decreases of Po (approximately 55% below control, 50 nM) and rapid compensatory transient increases of NT within 7 min ( approximately 220% above control, 50 nM), resulting in either small transient increases of INa at 5 nM PMA or small biphasic decreases of INa at 50 nM PMA. In contrast to A6 epithelia, 50 and 500 nM PMA in frog skin caused after a delay of at least 10 min transient increases of NT to approximately 60-70% above control at 30-60 min. Unlike A6 epithelia, Po was increased approximately 15% above control within 7 min and remained within +/-10-15% of control for the duration of the 2-h experiments. Despite differences in the time courses of secondary inhibition of transport in A6 epithelia and frog skin, the delayed downregulation of transport was due to time-dependent decreases of NT from their preelevated levels in both tissues. Whereas Po is decreased within minutes in A6 epithelia as measured by noise analysis or by patch clamp (8), the discrepancy in regulation of NT in A6 epithelia as measured by noise analysis and patch clamp is most likely explained by the inability of on-cell patches formed before treatment of tissues with PMA to respond to regulation of their channel densities.

Amiloride↗
PubMed2000

Na(+) current contribution to the diastolic depolarization in newborn rabbit SA node cells.

Isolated newborn, but not adult, rabbit sinoatrial node (SAN) cells exhibit spontaneous activity that (unlike adult) are highly sensitive to the Na(+) current (I(Na)) blocker TTX. To investigate this TTX action on automaticity, cells were voltage clamped with ramp depolarizations mimicking the pacemaker phase of spontaneous cells (-60 to -20 mV, 35 mV/s). Ramps elicited a TTX-sensitive current in newborn (peak density 0.89 +/- 0.14 pA/pF, n = 24) but not adult (n = 5) cells. When depolarizing ramps were preceded by steplike depolarizations to mimic action potentials, ramp current decreased 54.6 +/- 8.0% (n = 3) but was not abolished. Additional experiments demonstrated that ramp current amplitude depended on the slope of the ramp and that TTX did not alter steady-state holding current at pacemaker potentials. This excluded a steady-state Na(+) window component and suggested a kinetic basis, which was investigated by measuring TTX-sensitive I(Na) during long step depolarizations. I(Na) exhibited a slow but complete inactivation time course at pacemaker voltages (tau = 33.9 +/- 3.9 ms at -50 mV), consistent with the rate-dependent ramp data. The data indicate that owing to slow inactivation of I(Na) at diastolic potentials, a small TTX-sensitive current flows during the diastolic depolarization in neonatal pacemaker myocytes.

Action Potentials↗
PubMed1996

Differential response to Na+ channel blockade, beta-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects present in the long-QT syndrome.

The long-QT syndrome (LQTS) is a hereditary disorder characterized by an abnormally prolonged QT interval and by life-threatening arrhythmias. Recently, two of the genes responsible for LQTS have been identified: SCN5A, a voltage-dependent Na+ channel on chromosome 3 (LQT3), and HERG, responsible for the rapid component of the delayed rectifier current (IKr), on chromosome 7 (LQT2). We developed an in vitro model to attempt reproduction of the expected alterations in LQT3 and LQT2 patients. Guinea pig ventricular myocytes were exposed to anthopleura toxin A (anthopleurin), an inhibitor of the inactivation of the Na+ current, and to dofetilide, a selective blocker of IKr. Both interventions significantly prolonged action potential duration (APD), by 54 +/- 13 and 62 +/- 16 ms, respectively. Cells pretreated with anthopleurin significantly shortened APD in response to mexiletine, isoproterenol, and rapid pacing (from 264 +/- 38 to 226 +/- 32 ms after mexiletine, P < .001). On the contrary, cells exposed to dofetilide did not shorten the APD after mexiletine and even prolonged it after initial exposure to isoproterenol (from 280 +/- 25 to 313 +/- 20 ms, P < .001); during rapid pacing, APD was shortened but less (38 +/- 9 versus 60 +/- 11 ms, P < .05) than in anthopleurin-treated cells. This study shows that a cellular model for LQTS, based on the recent advances in molecular genetics, can provide adequate "phenotypes" of prolonged repolarization amenable to the testing of interventions of potential clinical relevance. We found differential responses to Na+ channel blockade, to beta-adrenergic stimulation, and to rapid pacing according to specific pretreatment with either anthopleurin (to mimic LQT3) or dofetilide (to mimic LQT2). These different responses in myocytes bear striking similarities with the differential response to analogous interventions in LQTS patients with mutations on the SCN5A and HERG genes.

Action Potentials↗
PubMed2002

Cn11, the first example of a scorpion toxin that is a true blocker of Na(+) currents in crayfish neurons.

A novel crustacean toxin (Cn11) was isolated and characterized from the venom of the Mexican scorpion Centruroides noxius Hoffmann. It contains 63 amino acid residues and is stabilized by four disulphide bridges. It is lethal to crustaceans (Cambarellus montezumae), less toxic to insects (crickets) and non-toxic to mammals (mice) at the doses assayed. In neurons isolated from the X organ-sinus gland system of the crayfish Procambarus clarkii, it blocks the Na(+) currents with an estimated K(m) of 320 nmol l(-1), without affecting the Ca(2+) and K(+) currents. The voltage-gated tetrodotoxin-sensitive Na(+) current was recorded from X organ neurons in culture 24 h after plating using the whole-cell clamp configuration. The Na(+) current was isolated by blocking Ca(2+) currents with Cd(2+) and Cs(+) and K(+) currents with tetraethylammonium and 4-aminopyridine. Under control conditions, the Na(+) currents were activated at -40 mV with a maximum amplitude at 0 mV. In the presence of 1 micromol l(-1) Cn11, the Na(+) current amplitude was reduced by 75 % without apparent modifications to the gating mechanism. These findings suggest that Cn11 selectively blocks a Na(+) channel. It is the first representative of a new group of scorpion toxins specific for this molecular target.

Amino Acid Sequence↗
PubMed1996

On the nature of endogenous antiexcitatory factors in the cerebrospinal fluid of patients with demyelinating neurological disease.

The cerebrospinal fluid (CSF) of patients with demyelinating neurological disease, such as Guillain-Barré syndrome or multiple sclerosis, contains factors that inhibit the excitatory Na+ current. Such antiexcitatory factors are occasionally also detectable in CSF from patients with other neurological diseases but were absent from an artificial CSF containing all major CSF constituents (electrolytes, amino acids, vitamins, metabolites, albumin). In an attempt to characterize these factors, unphysiological pCa or pH values were excluded by the application of the Ca2+ chelator EGTA and the use of buffers. Heating the CSF for 10 min to 95 degrees C or digesting it with proteases did not destroy the antiexcitatory potency. Fractionation of the CSF contents according to molecular weight showed that the factors have a molecular weight < 3 kD. This excludes proteins, such as antibodies or cytokines, as candidates. Small peptides are known to be resistant to some proteases and heating.

Adolescent↗
PubMed2000

Anti-GM1 antibodies can block neuronal voltage-gated sodium channels.

Anti-GM1 antibodies, frequently found in the serum of patients with Guillain-Barré syndrome (GBS), have been suggested to interfere with axonal function. We report that IgG anti-GM1 antibodies, raised in rabbits, can reversibly block the voltage-gated Na(+) channels of nerve cells, thus causing a reduction of the excitatory Na(+) current. The block was, however, only substantial when the antibodies were applied together with rabbit complement factors. A solution containing anti-GM1 sera (dilution 1:100) and complement (1:50) reduced the Na(+) current to 0.5 +/- 0.2 times control (mean value +/- SD). Applications of the antibody by itself, complement by itself, or anti-GM2 or anti-GM4 antibodies (1:100) plus complement had little effect. The complexes of anti-GM1 antibodies and complement factors block the ion-conducting pore of the channel directly. In addition, they increase the fraction of channels that are inactivated at the resting potential and alter channel function by changing the membrane surface charge. The described effects may be responsible for conduction slowing and reversible conduction failure in some GBS patients.

Animals↗
PubMed2001

Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis.

A novel mutation in a family with hypokalemic periodic paralysis is described. The mutation R672S is located in the voltage sensor segment S4 of domain II in the SCN4A gene encoding the human skeletal muscle voltage-gated sodium channel. Functional expression of the R672S channels in human embryonic kidney 293 cells revealed a small but significant hyperpolarizing shift in the steady-state fast inactivation, and a dramatic enhancement in channel slow inactivation. These two defects are mainly due to a slow recovery of the mutant channels from fast and/or slow inactivation. Our data may help explain the mechanism underlying hypokalemic periodic paralysis and the patient's worsening from acetazolamide.

Acetazolamide↗
PubMed2005

Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish.

This study documents the effects of puffer-fish poisoning on peripheral nerve. Excitability measurements investigated membrane properties of sensory and motor axons in four patients. The median nerve was stimulated at the wrist, with compound muscle potentials recorded from abductor pollicis brevis and compound sensory potentials from digit 2. Stimulus-responses, strength-duration time constant (tau(SD)), threshold electrotonus, and current-threshold relations were recorded. The urine of each patient tested positive for tetrodotoxin. Compared with controls, axons were of higher threshold, compound muscle action potentials and compound sensory nerve action potentials were reduced in amplitude, latency was prolonged, and tau(SD) was reduced. In recovery cycles, refractoriness, superexcitability, and late subexcitability were decreased. Threshold electrotonus of motor axons exhibited distinctive abnormalities with less threshold decline than normal on depolarization and greater threshold increase on hyperpolarization (p < 0.0005 for each patient). The changes in excitability were reproduced in a mathematical model by reducing sodium (Na(+)) permeabilities by a factor of two. This study confirms that the neurotoxic effects of puffer-fish poisoning can be explained by tetrodotoxin blockade of Na(+) channels. It demonstrates the ability of noninvasive nerve excitability studies to detect Na(+) channel blockade in vivo and also the utility of mathematical modeling to aid interpretation of altered excitability properties in disease.

Action Potentials↗
PubMed2004

Stereospecific synthesis of "para-hydroxymexiletine" and sodium channel blocking activity evaluation.

Both enantiomers of "para-hydroxymexiletine" (PHM), one of the main metabolites of mexiletine, were synthesized and fully characterized. Properties of (R)- and (S)-PHM, in terms of blocking potency and stereoselectivity on frog skeletal muscle Na(+) channels, were evaluated. The presence of a hydroxy group on the aryloxy moiety in the 4-position, as in PHM, reduced potency with respect to mexiletine in reducing I(Na max). However, PHM showed clear use-dependent behavior similar to that of mexiletine and, in contrast with what is observed with the parent compound, maintained its stereoselectivity during the use-dependent block. Chirality 16:72-78, 2004.

Animals↗
PubMed2005

Expression and distribution of TTX-sensitive sodium channel alpha subunits in the enteric nervous system.

The expression and distribution of TTX-sensitive voltage-gated sodium channel (VGSC) alpha subunits in the enteric nervous system (ENS) has not been described. Using RT-PCR, expression of Na(v)1.2, Na(v)1.3, Na(v)1.6, and Na(v)1.7 mRNA was detected in small and large intestinal preparations from guinea pigs. Expression of Na(v)1.1 mRNA as well as Na(v)1.1-like immunoreactivity (-li) were not observed in any intestinal region investigated. Na(v)1.2-li was primarily observed within the soma of the majority of myenteric and submucosal neurons, although faint immunoreactivity was occasionally observed in ganglionic and internodal fibers. Na(v)1.3-li was observed in dendrites, soma, and axons in a small group of myenteric neurons, as well as in numerous myenteric internodal fibers; immunoreactivity was rarely observed in the submucosal plexus. Na(v)1.6-li was primarily observed in the initial axonal segment of colonic myenteric neurons. Na(v)1.7-li was observed in dorsal root ganglia neurons but not in the myenteric plexus of the small and large intestine. In the ileum, 37% of Na(v)1.2-li cell bodies colocalized with calbindin-li while colocalization with calretinin-li was rare. In contrast, 22% of Na(v)1.3-li cell bodies colocalized with calretinin-li but colocalization with calbindin-li was not observed. In the colon, both Na(v)1.2-li and Na(v)1.3-li cell bodies frequently colocalized with either calretinin-li or calbindin-li. Na(v)1.2-li cell bodies also colocalized with the majority of NeuN-li cells in the small and large intestine. These data suggest that Na(v)1.1 may not be highly expressed in the ENS, but that Na(v)1.2, Na(v)1.3, and Na(v)1.6, and possibly Na(v)1.7, have broadly important and distinct functions in the ENS.

Animals↗