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At least 19 recordsLinked to original sources
PubMed1987

Veratridine-induced activation of choline-O-acetyltransferase activity in rat hippocampal tissue: relationship to the veratridine-induced release of acetylcholine.

The effect of veratridine depolarization on the activity of 3 choline-O-acetyltransferase (ChAT) fractions in rat hippocampal tissue was investigated. Those concentrations of veratridine which augmented acetylcholine (ACh) release also increased the activity of water and detergent soluble ChAT fractions. These results may suggest that the depolarization induced release of ACh is linked to an activation of ChAT activity.

Acetylcholine↗
PubMed1992

Relation between veratridine reaction dynamics and macroscopic Na current in single cardiac cells.

Veratridine modification of Na current was examined in single dissociated ventricular myocytes from late-fetal rats. Extracellularly applied veratridine reduced peak Na current and induced a noninactivating current during the depolarizing pulse and an inward tail current that decayed exponentially (tau = 226 ms) after repolarization. The effect was quantitated as tail current amplitude, Itail (measured 10 ms after repolarization), relative to the maximum amplitude induced by a combination of 100 microM veratridine and 1 microM BDF 9145 (which removes inactivation) in the same cell. Saturation curves for Itail were predicted on the assumption of reversible veratridine binding to open Na channels during the pulse with reaction rate constants determined previously in the same type of cell at single Na channels comodified with BDF 9145. Experimental relationships between veratridine concentration and Itail confirmed those predicted by showing (a) half-maximum effect near 60 microM veratridine and no saturation up to 300 microM in cells with normally inactivating Na channels, and (b) half-maximum effect near 3.5 microM and saturation at 30 microM in cells treated with BDF 9145. Due to its known suppressive effect on single channel conductance, veratridine induced a progressive, but partial reduction of noninactivating Na current during the 50-ms depolarizations in the presence of BDF 9145, the kinetics of which were consistent with veratridine association kinetics in showing a decrease in time constant from 57 to 22 and 11 ms, when veratridine concentration was raised from 3 to 10 and 30 microM, respectively. As predicted for a dissociation process, the tail current time constant was insensitive to veratridine concentration in the range from 1 to 300 microM. In conclusion, we have shown that macroscopic Na current of a veratridine-treated cardiomyocyte can be quantitatively predicted on the assumption of a direct relationship between veratridine binding dynamics and Na current and as such can be successfully used to analyze molecular properties of the veratridine receptor site at the cardiac Na channel.

Animals↗
PubMed1981

On the mechanism by which veratridine causes a calcium-independent release of gamma-aminobutyric acid from brain slices.

1 The mechanisms by which veratridine increases the release of gamma-aminobutyric acid (GABA) from brain slices have been studied.2 Exposure of superfused cerebro-cortical, nigral or cerebellar slices to veratridine (5 muM) or KCl (50 mM) caused large increases in the efflux of [(3)H]-GABA.3 Reduction of the external Ca concentration [Ca](o) to zero had strikingly different effects on the veratridine and K-evoked release of [(3)H]-GABA. The K-evoked release from all three areas was greatly reduced in Ca-free medium, but the veratridine-evoked release from cerebeller slices was not affected, and the release of [(3)H]-GABA from cortical and nigral slices was increased three fold. The potentiation of the veratridine evoked release of GABA which occurred in Ca-free medium was not due to the reduction in divalent ions, because it still occurred in medium in which the Ca was replaced by an equivalent amount of Mg.4 The veratridine-evoked release of [(14)C]-glycine from slices of spinal cord was also significantly increased in Ca-free medium. In contrast, the release of cortical [(3)H]-noradrenaline and [(14)C]-acetylcholine caused by the alkaloid was greatly diminished in Ca-free medium.5 The veratridine but not the K-evoked release of [(3)H]-GABA was abolished when the external Na concentration [Na](o) was reduced to zero and by tetrodotoxin (TTX) (0.2 muM). Cl-free medium did not affect the veratridine-evoked release of [(3)H]-GABA or its potentiation by Ca-free medium.6 Exposure of the tissue to depolarizing concentrations of external K ([K](o) = 120 mM) did not abolish the veratridine evoked release of [(3)H]-GABA or its potentiation by Ca-free medium.7 Pre-incubation of cortical slices with L-2,4, diaminobutyric acid (DABA), or substitution of Na in the superfusion medium with Li, did not affect the veratridine-evoked release of [(3)H]-GABA, indicating that the alkaloid does not stimulate GABA efflux by a carrier-mediated transport process.8 Exposure of the tissue to ruthenium red (10 muM) increased the veratridine evoked release of [(3)H]-GABA in both normal and in Ca-free medium but almost abolished the K-evoked release.9 It is suggested that veratridine causes GABA release by increasing the permeability of the nerve terminals to Na. In normal medium, the resulting influx of Ca(2+) ions through voltage-dependent Ca(2+) channels may be involved in triggering the release of GABA. However, a major part of the GABA efflux appears to be triggered by the release of Ca(2+) ions from intraterminal mitochondria, which results from the increase in[Na](i). Since Ca(2+) ions antagonize the action of veratridine, the potentiation of the drug-evoked release of GABA that occurs in Ca-free medium, might be due to the absence of the antagonistic Ca(2+) ions. The resulting greater increase in Na entry and [Ca](i) caused by Ca release from intracellular stores, must presumably more than balance the contribution normally made by any influx of extracellular Ca(2+).

Acetylcholine↗
PubMed1990

Sodium channel comodification with full activator reveals veratridine reaction dynamics.

Veratridine association and dissociation rates were determined at single sodium channels in outside-out patches of cultured ventricular myocytes obtained from late-fetal rat hearts. In single cardiac sodium channels depolarized from -110 to -30 mV, intracellular veratridine induced a long lasting (tau = 0.48 sec) open state with small current amplitude (-0.3 pA, i.e., 1/4 of normal) and frequent closing transitions, giving it a burstlike appearance, in agreement with reports on other types of sodium channel. Veratridine-associated and veratridine-free states of a single sodium channel were monitored by comodifying it with an allosteric activator, BDF 9145 (1 microM), that induced a burst with normal open channel current amplitude (-1.2 pA at -30 mV) upon veratridine dissociation. Veratridine and BDF 9145 interacted with reciprocal synergism at the single sodium channel such that veratridine-induced bursts (called P-bursts for partially activated) alternated with BDF 9145-induced bursts (called F-bursts for fully activated) many times following a single depolarization to -30 mV. P-bursts and F-bursts within such trains of bursts had exponentially distributed durations. The reciprocal time constant for F-bursts, tau F-1, increased linearly with veratridine concentration (0.3-30 microM), whereas tau P was insensitive. We conclude, therefore, that P-bursts reflect veratridine occupancy and F-bursts reflect the veratridine-free state; if veratridine and BDF 9145 bind to a sodium channel simultaneously, veratridine exerts conformational dominance, i.e., retains its property to reduce channel conductance. For the single cardiac sodium channel activated (i.e., deprived of inactivation) by BDF 9145, we have determined a veratridine association rate constant k1 = 4.3 x 10(6) M0-1 sec-1, dissociation rate constant K-1 = 2.2 sec-1 and equilibrium dissociation constant KD = 5.1 x 10(-7) M (20 degrees, -30 mV membrane potential).

Allosteric Regulation↗
PubMed1975

The relation between the effects of veratridine on action potential and contraction in mammalian ventricular myocardium.

In the isolated papillary muscle of the guinea pig veratridine produces an increase of the force of contraction by increasing the rate of force development. Time to peak force is slightly reduced, whereas relaxation time is markedly prolonged. Threshold, half-maximally and maximally effective concentrations for the positive inotropic effect are 0.1, 0.4 and 1.6 muM, respectively. 2. The positive inotropic effect of the maximally effective concentration of veratridine amounts to 68% of the maximum positive inotropic effect of dihydro-ouabain tested on the same muscle (N = 12). 3. Veratridine prolongs the action potential (AP) by delaying repolarization. The effect is concentration-dependent (range: 0.4--3.2 muM); it requires 1--2 hrs of maintained exposure to reach a steady state and is only slowly reversible upon removal of the drug. A concentration causing a nearly maximal positive inotropic effect (0.8 muM) does not affect resting potential or rate of rise of the AP; the overshoot is slightly depressed. 4. Tetrodotoxin (5--16 muM) reversibly inhibits both AP prolongation and positive inotropic effect of veratridine by shifting the concentration-effect curves for these effects to higher concentrations of veratridine. It also prevents veratridine-induced spontaneous activity. 5. Dihydro-ouabain or reduction of [K]o below 5.9 mM augument the positive inotropic effect of veratridine, while the interaction between veratridine and noradrenaline is additive. 6. The positive inotropic effect of 1.6 muM veratridine declines progressively when the contraction frequency is reduced below 0.5 Hz; rested-state contractions (at 0.004 Hz) are not increased by 1.6 muM veratridine. 7. It is concluded that (a) veratridine delays repolarization by prolonging the Na permeability component which is mediated by the fast Na channels; (b) this specific sarcolemmal effect of veratridine is the sole cause for its positive inotropic action by effecting an increase of [Na]i which probably leads to a subsequent increase of Ca uptake.

Action Potentials↗
PubMed1997

Involvement of different calcium channels in K+- and veratridine-induced increases of cytosolic calcium concentration in rat cerebral cortical synaptosomes.

Intracellular calcium ion concentrations ([Ca2+]i) in rat cerebral cortical synaptosomes were measured, using the calcium chelating fluorescence dye fura-2. The synaptosomes were depolarized by elevation of the extracellular K+ concentration or by addition of veratridine, which opens voltage-dependent Na+-channels and prevents their inactivation. Both enhancement of the concentration of extracellular K+ (up to 60 mM) and veratridine (1-100 microM) increased the [Ca2+]i in a concentration-dependent manner. In the absence of extracellular Ca2+, the K+- and veratridine-induced increases in [Ca2+]i were abolished, indicating that the increase in [Ca2+]i was due to an influx of extracellular Ca2+. Tetrodotoxin (TTX), a blocker of the voltage-dependent Na+ channel, inhibited the veratridine-induced (10 microM) Ca2+ influx by more than 80%, while the K+-evoked (30 mM) increase of [Ca2+]i was TTX-resistant. Both the K+- and the veratridine-induced Ca2+ influx were not reduced by nifedipine (1 microM), a blocker of L-type Ca2+ channels. Blockade of the voltage dependent N-type Ca2+ channels with omega-conotoxin GVIA (omega-CTx GVIA; 0.1 microM) and of the voltage-dependent P/Q-type channels with omega-agatoxin IVA (omega-AgaTx IVA; 0.2 microM) inhibited the K+-induced increase in [Ca2+]i by about 30 and 55%, respectively; these effects were additive. Omega-conotoxin MVIIC (omega-CTx MVIIC) at a concentration of 0.2 microM, which may be assumed to block predominantly the Q-type Ca2+ channel, inhibited the K+-induced increase in [Ca2+]i by 50%. The veratridine-induced increase in [Ca2+]i was reduced by about 25% by omega-CTx GVIA (0.1 microM), but was resistant to omega-AgaTx IVA (0.2 microM) and omega-CTx MVIIC (0.2 omegaM). Mibefradil (former designation Ro 40-5967), a Ca2+ antagonist which blocks all types of voltage-dependent Ca2+ channels including the T and R channels, led to a concentration-dependent inhibition of the K+- and veratridine-induced increase in [Ca2+]i (abolition at 10 microM mibefradil). Ifenprodil, another non-specific blocker of voltage-dependent Ca2+ channels, also inhibited the K+- and veratridine-induced increase in [Ca2+]i in concentration-dependent manner and abolished it at 320 microM ifenprodil. In contrast, KB-R 7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulphonate; 1 and 3 microM), a highly potent and selective inhibitor of the Na+/Ca2+ exchanger (NCX1), failed to inhibit the K+- and veratridine-induced increase in [Ca2+]i. It is concluded that the K+-induced increase in free cytosolic Ca2+ results from Ca2+ influx through voltage-dependent N- and, above all, Q-type Ca2+ channels. N-type Ca2+ channels also play a minor role in the veratridine-induced increase in [Ca2+]i, but P/Q-type channels do not appear to be involved at all. The inhibition of the veratridine-induced, omega-CTx GVIA- and omega-AgaTx IVA-resistant increase in [Ca2+]i by mibefradil and the failure of KB-R 7943 to inhibit this response are compatible with the suggestion that in rat cerebral cortical synaptosomes, Ca2+ influx via the R-type Ca2+ channel and/or another so far uncharacterized Ca2+ channel may substantially contribute to the veratridine-induced increase in [Ca2+]i.

Adenosine Triphosphatases↗
PubMed1986

Veratridine-induced breakdown of cytosolic acetylcholine in rat hippocampal minces: an intraterminal form of acetylcholinesterase or choline O-acetyltransferase?

Rat hippocampal minces were loaded with N-methyl-[3H]acetylcholine ([3H]ACh) in the presence of the 'poorly penetrating' acetylcholinesterase (EC 3.1.1.7, AChE) inhibitor echothiophate and the effect of the depolarizing agent veratridine determined on the subcellular storage and release of [3H]ACh and [3H]choline. Results indicated that veratridine stimulated the release of [3H]ACh from a crude vesicular fraction (P3) by a Ca2+-dependent process, while simultaneously accelerating the breakdown of cytosolic (S3) [3H]ACh. A portion of the [3H]choline derived from the hydrolyzed S3 [3H]ACh was donated to the P3 fraction for [3H]ACh formation and release. When the identical experiment was done using hippocampal minces from septal lesioned rats, veratridine did not stimulate either the Ca2+-dependent release of [3H]ACh or the hydrolysis of cytosolic [3H]ACh. Incubation of control hippocampal minces with paraoxon, an AChE inhibitor which can penetrate cholinergic nerve terminals more rapidly than echothiophate, prevented veratridine from stimulating the Ca2+-dependent release of [3H]ACh from the P3 fraction. Instead, it then stimulated the Ca2+-independent release of [3H]ACh from the S3 fraction. When minces were incubated with the choline O-acetyltransferase (EC 2.3.1.6, ChAT) inhibitor 4-(1-naphthyl)vinyl pyridine (NVP), veratridine was no longer able to stimulate the Ca2+-dependent release of labelled ACh either. Instead, veratridine stimulated the Ca2+-independent release of labelled ACh from the S3 fraction. NVP also abolished the veratridine-induced, Ca2+-dependent release of total ACh. Both paraoxon and NVP inhibited the reversible reaction of ionically bound ChAT prepared from rat brain when tested in vitro, yet paraoxon was much less potent than NVP, and was unable to inhibit this reaction at the low concentration which prevented the veratridine induced breakdown of S3 [3H]ACh during mince incubation. Veratridine depolarization of hippocampal minces stimulated the activity of a membrane-bound fraction of ChAT associated with the P3 fraction, but this fraction of ChAT did not become more sensitive to inhibition by paraoxon during tissue incubation. Veratridine depolarization of minces also increased the activity of membrane-bound AChE, but this enzyme was not inhibited by the low NVP concentration which prevented the veratridine-induced breakdown of S3 [3H]ACh. The veratridine-induced increase in membrane-bound ChAT activity was dependent on the presence of extracellular Ca2+ in the incubation medium.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed2000

Veratridine induces apoptotic death in bovine chromaffin cells through superoxide production.

The molecular mechanisms involved in veratridine-induced chromaffin cell death have been explored. We have found that exposure to veratridine (30 microM, 1 h) produces a delayed cellular death that reaches 55% of the cells 24 h after veratridine exposure. This death has the features of apoptosis as DNA fragmentation can be observed. Calcium ions play an important role in veratridine-induced chromaffin cell death because the cell permeant Ca(2+) chelator BAPTA-AM and extracellular Ca(2+) removal completely prevented veratridine-induced toxicity. Following veratridine treatment, there is a decrease in mitochondrial function and an increase in superoxide anion production. Veratridine-induced increase in superoxide production was blocked by tetrodotoxin (TTX; 10 microM), extracellular Ca(2+) removal and the mitochondrial permeability transition pore blocker cyclosporine A (10 microM). Veratridine-induced death was prevented by different antioxidant treatments including catalase (100 IU ml(-1)), N-acetyl cysteine (100 microM), allopurinol (100 microM) or vitamin E (50 microM). Veratridine-induced DNA fragmentation was prevented by TTX (10 microM). Veratridine produced a time-dependent increase in caspase activity that was prevented by Ca(2+) removal and TTX (10 microM). In addition, calpain and caspases inhibitors partially prevented veratridine-induced death. These results indicate that chromaffin cells share with neurons the molecular machinery involved in apoptotic death and might be considered a good model to study neuronal death during neurodegeneration.

Animals↗
PubMed1959

Renal effects of veratridine.

Veratridine hydrochloride injected subcutaneously into unanaesthetized rats inhibited water diuresis. A linear relationship between log dose and antidiuretic effect could be established over the dose range 50 to 200 mug./100 g. of body weight. When veratridine hydrochloride was injected intravenously in doses from 10 to 30 mug./100 g., this relationship was also linear. In terms of its antidiuretic action, the alkaloid was approximately five times as effective when given intravenously. Rats anaesthetized with urethane responded to an intravenous injection with a more pronounced inhibition than unanaesthetized animals. Protoveratrine injected intravenously into unanaesthetized rats showed no clear relationship between dose and magnitude of antidiuretic effect. Veratridine hydrochloride injected intravenously had a pronounced hypotensive effect in both anaesthetized and unanaesthetized rats. Treatment with atropine did not affect this hypotensive action significantly. Atropine given subcutaneously 30 min. before an intravenous injection of veratridine hydrochloride abolished or diminished the inhibitory effect of veratridine on water diuresis. Veratridine hydrochloride injected intravenously into unanaesthetized rats caused a marked depression of the clearance of inulin and p-aminohippurate. In unanaesthetized rats with an osmotic diuresis, veratridine hydrochloride produced its usual antidiuretic effect. The urine of rats injected with veratridine hydrochloride produced an antidiuretic effect when injected intravenously into other animals. The antidiuretic potency of such urines was not affected by treatment with thioglycollate. Animals injected with veratridine excreted small amounts of a veratridine-like substance in the urine. These results do not suggest that veratridine in antidiuretic and hypotensive doses stimulated the neurohypophysis in the rat.

Animals↗
PubMed1979

The effect of veratridine on the release of catecholamines from the perfused adrenal gland.

1. Experiments on perfused adrenal glands of guinea-pigs were carried out to study the catecholamine output induced by veratridine in the presence of hexamethonium and atropine. 2. Veratridine (10 micrometer to 200 micrometer) caused a dose-dependent increase in catecholamine output. 3. The addition of veratridine to the perfusion medium for a period of 3 min caused an increase in catecholamine output which reached a maximum 5 min to 10 min after withdrawal of the drug. The catecholamine output then gradually declined and reached near resting values within 30 minutes. It was never sustained for a longer period, even when veratridine was infused for 1 hour. 4. Veratridine failed to increase the catecholamine output in the absence of extracellular Ca2+. However, the addition of Ca2+ after an infusion of veratridine (100 micrometer) in the absence of Ca2+ caused an increase in the catecholamine output which was proportional to the concentration of Ca2+ (0.55 mM to 8.8 mM) used. 5. Veratridine did not increase the catecholamine output in the absence of extracellular Na+ ions, NaCl being replaced by equimolar choline chloride or LiCl. Veratridine also failed to evoke catecholamine output in a Na+-free solution in which Na+ was replaced by sucrose; this was the case even in the presence of a high concentration of Ca2+ (8.8 mM). 6. Tetrodotoxin (0.1 micrometer) and excess Mg2+ (20 mM) reversibly inhibited the catecholamine output induced by veratridine. 7. Ouabain (10 micrometer) significantly potentiated the veratridine-induced catecholamine output. 8. It is suggested that Na+-dependent Ca2+ influx as well as voltage-dependent Ca2+ influx mechanisms may be involved in the catecholamine output induced by veratridine.

Adrenal Glands↗
PubMed1986

Intracellular sodium and the positive inotropic effect of veratridine and cardiac glycoside in sheep Purkinje fibers.

Veratridine is a sodium channel toxin that exerts a powerful positive inotropic effect and prolongs the action potential duration in the heart. To determine the basis of the inotropic action of veratridine and to examine the effects of dissimilar methods of raising intracellular sodium activity on contractility, we measured twitch tension and intracellular sodium activity using sodium-sensitive microelectrodes in stimulated sheep Purkinje fibers exposed to veratridine and in voltage-clamped fibers exposed to veratridine and cardiac glycoside. In stimulated fibers, veratridine (0.1-1 microM) produced coincident increases in intracellular sodium activity, action potential duration, and tension. In voltage-clamped fibers, veratridine (1-2 microM) and acetylstrophanthidin (0.1 microM) raised intracellular sodium activity and tension to a comparable degree. Tetrodotoxin (10 microM) abolished the mechanical, electrophysiological, and ionic changes produced by veratridine. The relationship between intracellular sodium activity and tension in voltage-clamped fibers (n = 6) was indistinguishable for veratridine and acetylstrophanthidin and could be fitted either with a linear function with slopes of 122.8% and 124.2%, respectively, or with a power function with slopes of 4.60 and 4.54, respectively, where the slope represents the exponential power of intracellular sodium activity to which tension is proportional. These results indicate that the positive inotropic action of veratridine is entirely accounted for by accumulation of intracellular sodium, which increases intracellular calcium available for contraction by sodium-calcium exchange. This study is the first direct demonstration that veratridine or any other sodium channel toxin affects intracellular sodium activity and suggests that the inotropic potency of veratridine and cardiac glycoside rely on the same mechanism, namely, elevation of intracellular sodium.

Action Potentials↗
PubMed1991

Veratridine-induced intoxication in the isolated left atrium of the rat: effects of some anti-ischemic compounds.

Veratridine-induced Na+ and Ca2+ uptake was used as a simulation of ischemia-induced Na+ and Ca2+ uptake. Therefore, electrically driven (1 Hz) isolated left atria of the rat were intoxicated with veratridine and the 45Ca2+ uptake was determined. Veratridine (10(-4) mol/l) increased the 45Ca2+ uptake from 575 +/- 13 to 2320 +/- 86 dpm/mg ww (n = 20). The total tissue content of 45Ca was elevated from 4328 +/- 132 to 5136 +/- 303 dpm/mg ww (n = 13). The veratridine-induced 45Ca2+ uptake was completely suppressed by tetrodotoxin (10(-7) and 10(-6) mol/l), whereas amiloride (6.10(-6) mol/l) and phentolamine (10(-6) and 10(-5) mol/l) exhibited no effect on the veratridine-induced 45Ca2+ uptake. Nifedipine (10(-7) and 10(-6) mol/l) was ineffective on veratridine-induced 45Ca2+ uptake. Verapamil (10(-5) mol/l) suppressed the veratridine-induced 45Ca2+ uptake, but the 45Ca2+ uptake in the absence of veratridine was also suppressed by verapamil (10(-6) and 10(-5) mol/l). The novel anti-ischemic compounds R 56865 (10(-8)-10(-5) mol/l) and R 59494 (10(-8)-10(-5) mol/l) totally abolished veratridine-induced 45Ca2+ uptake. It is speculated that Ca2+ enters the cell via a Na+ channel which changes its selectivity upon veratridine treatment. Consequently, R 56865 and R 59494 could display their protective effect by either inhibiting the modified Na+ channel or preventing the transition of the normal Na+ channel to its altered state.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Modulation by ouabain and diphenylhydantoin of veratridine-induced 22Na influx and its relation to 45Ca influx and the secretion of catecholamines in cultured bovine adrenal medullary cells.

The effects of ouabain and diphenylhydantoin on the secretion of catecholamines induced by veratridine were investigated in cultured bovine adrenal medullary cells with special reference to ion fluxes. Veratridine itself induced an influx of 22Na and 45Ca as well as secretion of catecholamines, which were antagonized by tetrodotoxin, a selective inhibitor of voltage dependent Na channels. The secretion of catecholamines caused by veratridine was not observed either in Na free or Ca free medium. Veratridine-induced influx of 45Ca did not occur in Na free medium, while veratridine-induced influx of 22Na occurred even in Ca free medium. Veratridine-induced influx of 22Na, 45Ca and secretion of catecholamines were all potentiated by ouabain, a potent inhibitor of Na,K-ATPase. Omission of K from the medium, a condition which suppresses the Na,K-ATPase activity, also augmented these cell responses caused by veratridine. On the contrary, diphenylhydantoin, which is known to decrease the intracellular concentration of Na, reduced the veratridine-induced influx of 22Na, 45Ca and secretion of catecholamines. The potentiating effects of ouabain on the veratridine-induced cell responses were all abolished by diphenylhydantoin. These findings imply that veratridine, ouabain and K removal as well as diphenylhydantoin modulate the intracellular accumulation of 22Na which is involved in the influx of 45Ca and the secretion of catecholamines.

Adrenal Medulla↗
PubMed2005

The regulation of veratridine-stimulated electrogenic ion transport in mouse colon by neuropeptide Y (NPY), Y1 and Y2 receptors.

1 Neuropeptide Y (NPY) is a prominent enteric neuropeptide with prolonged antisecretory effects in mammalian intestine. Veratridine depolarises neurons consequently causing epithelial anion secretion across mouse colon mucosa. Our aim was to characterise functionally, veratridine-stimulated mucosal responses and to determine the roles for NPY, Y(1), and Y(2) receptors in modulating these neurogenic effects. 2 Colon mucosae (with intact submucous innervation) from wild-type mice (+/+) and knockouts lacking either NPY (NPY-/-), Y(1)-/- or Y(2)-/- were placed in Ussing chambers and voltage clamped at 0 mV. Veratridine-stimulated short-circuit current (I(sc)) responses in +/+, Y(1) or Y(2) antagonist pretreated +/+ colon, Y(1)-/- and NPY-/- colon were insensitive to cholinergic blockade by atropine (At; 1 microM) and hexamethonium (Hex; 10 microM). Tetrodotoxin (TTX, 100 nM) abolished veratridine responses, but had no effect upon carbachol (CCh) or vasoactive intestinal polypeptide (VIP)-induced secretory responses. 3 To establish the functional roles for Y(1) and Y(2) receptors, +/+ tissues were pretreated with either the Y(1) or Y(2) receptor antagonist (BIBO3304 (300 nM) or BIIE0246 (1 microM), respectively) and veratridine responses were compared with those from Y(1)-/- or Y(2)-/- colon. Neither BIBO3304 nor Y(1)-/- altered veratridine-induced secretion, but Y(1) agonist responses were abolished in both preparations. In contrast, the Y(2) antagonist BIIE0246 significantly amplified veratridine responses in +/+ mucosa. Unexpectedly, NPY-/- colon exhibited significantly attenuated veratridine responses (between 1 and 5 min). 4 We demonstrate that electrogenic veratridine responses in mouse colon are noncholinergic and that NPY can act directly upon epithelia, a Y(1) receptor effect. The enhanced veratridine response observed in +/+ tissue following BIIE0246, indicates that Y(2) receptors are located on submucosal neurons and that their activation by NPY will inhibit enteric noncholinergic secretory neurotransmission. 5 We also demonstrate Y(1) and Y(2) receptor-mediated antisecretory tone in +/+ colon and show selective loss of each in Y(1) and Y(2) null colon respectively. In NPY-/- tissue, only Y(1)-mediated tone was present, this presumably being mediated by endogenous endocrine peptide YY. Y(2) tone was absent from NPY-/- (and Y(2)-/-) colon and we conclude that NPY activation of neuronal Y(2) receptors attenuates secretory neurotransmission thereby providing an absorptive electrolyte tone in isolated colon.

Animals↗
PubMed1987

Sodium permeability of frog skeletal muscle in absence and presence of veratridine.

The effect of veratridine on the Na permeability of frog sartorius muscle was studied by means of ion flux measurements using radiolabeled sodium. Veratridine increases Na influx in a dose-dependent manner (apparent Kd = 160 +/- 7 microM when Vm congruent to -40 mV). The increase can be completely inhibited by tetrodotoxin (TTX) (apparent Ki = 8 +/- 2 nM), indicating that all veratridine-induced Na influx occurs via sodium channels. The time constant for the rate of onset of veratridine action is 1 h. Raising external pH one unit to 8.3 causes the rate of action of veratridine and the final level of Na influx to increase. The apparent Kd for veratridine depends on membrane voltage. Values obtained in 2.5 and 5 mM K Ringer (Vm congruent to -95 and -80 mV) were 579 +/- 279 and 35 +/- 8 microM, respectively. Veratridine-induced Na influx obeys the Goldman constant field flux equation and when veratridine concentration is 1 mM, sodium permeability is 1.5 X 10(-7) cm/s. This is much less than the maximum PNa (1.6 X 10(-3) cm/s) obtained from voltage-clamp measurements of peak Na conductance. Mg (52 mM) inhibits veratridine-induced influx by about half. Aspects of resting Na influx in the absence of veratridine (but in the presence of ouabain) were also characterized. Steady-state Na influx is unaffected by tetrodotoxin over the voltage range -90-0 mV, suggesting that no sodium channels are open in the resting state. Na influx is also insensitive to curare. It is linearly dependent on external sodium and larger at more negative membrane potentials.

Animals↗
PubMed1975

Activation of the action potential Na+ ionophore of cultured neuroblastoma cells by veratridine and batrachotoxin.

The activation of the action potential Na+ ionophore by veratridine and batrachotoxin is time- and concentration-dependent and completely reversible. Batrachotoxin acts more slowly than veratridine. The concentration dependence of activation at equilibrium suggests reversible interaction of each toxin with a single class of independent sites having dissociation constants at physiologic ion concentrations of 80 plus or minus 13 muM for veratridine and 0.4 plus or minus muM for batrachotoxin. The maximum velocity of Na+ uptake at 50 mM Na+ is 128 plus or minus 12 nmol/min/mg in the presence of batrachotoxin compared to 48 plus or minus 4 nmol/min/mg in the presence of veratridine. Treatment of cells with excess veratridine in addition to batrachotoxin inhibits batrachotoxin-dependent 22-Na+ uptake. The concentration dependence of this inhibition suggests that it reflects competitive displacement of batrachotoxin from its binding site by veratridine. The activation by veratridine and batrachotoxin is inhibited in a competitive manner by divalent cations. The inhibition by divalent cations exhibits significant ion specificity with Mn-2+ greater than Co-2+ greater than Ni-2+ greater than Ca-2+ greater than Mg-2+ greater than Sr-2+. The inhibition constants (KI) for Ca-2+ are 0.84 mM for veratridine-dependent 22-Na+ uptake and 1.2 mM for batrachotoxin-dependent 22-Na+ uptake. The activation by veratridine and batrachotoxin is inhibited in a noncompetitive manner by tetrodotoxin. The apparent KD for tetrodotoxin as 11 plus or minus 1 nM in the presence of 150 mM Na+ and approximately 8.5 nM in 50 mM Na+. Divalent cations do not affect the apparent KD for tetrodotoxin. A hypothesis is presented which suggests that batrachotoxin, veratridine, and divalent cations interact with an activation site associated with the action potential Na+ ionophore, whereas tetrodotoxin interacts with a physically and functionally independent site involved in the transport of monovalent cations by the ionophore.

Action Potentials↗
PubMed1994

Veratridine blocks voltage-gated potassium current in human T lymphocytes and in mouse neuroblastoma cells.

(i) Effects of veratridine on ionic conductances of human peripheral blood T lymphocytes have been investigated using the whole-cell patch-clamp technique. (ii) Veratridine reduces the net outward current evoked by membrane depolarizations. The reduction originates from block of a 4-aminopyridine-sensitive, voltage-gated K+ current. (iii) Human T lymphocytes do not appear to express voltage-gated Na+ channels, since inward currents are observed neither in control nor in veratridine- and bretylium-exposed lymphocytes. (iv) The effect of veratridine consists of an increase in the rate of decay of the voltage-gated K+ current and a reduction of the peak current amplitude. Both effects depend on veratridine concentration. Half-maximum block occurs at 97 microM and the time constant of decay is reduced by 50% at 54 microM of veratridine. (v) Possible mechanisms of veratridine action are discussed. The increased rate of K+ current decay is most likely due to open channel block. The decrease of current amplitude may involve an additional mechanism. (vi) In cultured mouse neuroblastoma N1E-115 cells, veratridine blocks a component of voltage-gated K+ current, in addition to its effect on voltage-gated Na+ current. This result shows that the novel effect of veratridine is not confined to lymphocytes.

4-Aminopyridine↗
PubMed1994

Effects of antiischemic drugs on veratridine-induced hypercontracture in rat cardiac myocytes.

The effects of different groups of substances (beta-adrenoceptor antagonists, Ca2+ channel blockers and vasodilators) which are known to have antiischemic properties were studied on veratridine-induced hypercontracture. Veratridine increases Na+ influx by slowing the inactivation process of the Na+ channel, thereby inducing a continuously increased Na+ entry in depolarized cells. Veratridine (6.3 x 10(-6) M) produced a change in cell shape from rod-shape to round, resulting from hypercontracture of cells. Before treatment with veratridine the proportion of rod-shaped cells was 70% and fell to 0% 5 min after the treatment with veratridine. dl-Propranolol, d-propranolol, l-penbutolol, d-penbutolol, nisoldipine, and dilazep all inhibited veratridine-induced hypercontracture dose dependently. In contrast, acebutolol, atenolol, timolol, nifedipine, diltiazem, and nitroglycerin did not inhibit the rounding of cells. Concomitantly with the rounding of cells, the [Ca2+]i was increased by veratridine. dl-Propranolol, d-propranolol and dilazep prevented the increase of [Ca2+]i induced by veratridine, whereas timolol and nitroglycerin did not. These results show that dl-propranolol, d-propranolol, l-penbutolol, d-penbutolol, nisoldipine, and dilazep possess Na+ channel blocking actions on the veratridine-modified Na+ channel, thereby preventing excessive Na+ influx and secondary Ca2+ overload.

Adrenergic beta-Antagonists↗