`Wide-spectrum Ca2+ channel antagonists': lipophilicity, inhibition, and recovery of secretion in chromaffin cells

Lara, Baldomero; Gandı́a, Luis; Torres, Andrés; Olivares, Román; Martinez-Sierra, R.; Garcı́a, Antonio G.; López, Manuela G.

doi:10.1016/s0014-2999(97)00108-8

Cited by 26 publications

(7 citation statements)

References 26 publications

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“…The first emerges from the cytotoxic effects of penfluridol at 3–10 μM and the lack of cytotoxic effects of lubeluzole. This could be explained on the basis of differences in lipophilicity; thus, the octanol/water partition coefficient of penfluridol is 7.6 while that of lubeluzole is 4.6 (Lara et al , 1997). The prompt reversibility of the effects of lubeluzole on I Na , I Ba and [Ca 2+ ] i and the ‘irreversible’ or long‐lasting actions of penfluridol are in line with this different lipophilicity.…”

Section: Discussionmentioning

confidence: 99%

“…Na + as well as Ca 2+ channels are known to be involved in the cytotoxic effects of veratridine in bovine chromaffin cells (Maroto et al , 1994; 1996). For comparative purposes, penfluridol, a highly lipophilic compound that has recently been shown to block Ca 2+ entry (Villarroya et al , 1997) and secretion (Lara et al , 1997) in bovine chromaffin cells was also used. Attempts to correlate the veratridine cytotoxic effects as well as the cytoprotecting actions of lubeluzole, with cell Na + and Ca 2+ homeostasis were also made.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of the neuroprotectant lubeluzole on the cytotoxic actions of veratridine, barium, ouabain and 6‐hydroxydopamine in chromaffin cells

Cano‐Abad

López

Hernández‐Guijo

et al. 1998

British J Pharmacology

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1 Incubation of bovine adrenal chroma n cells with veratridine (10 ± 100 mM) during 24 h, caused a concentration-dependent release of the cytosolic lactate dehydrogenase (LDH) into the bathing medium, an indicator of cell death. Lubeluzole or its R(7) enantiomer, R91154, did not enhance LDH release. Both lubeluzole and R91154 (0.3 ± 10 mM) decreased the veratridine-induced LDH release. 2 Pen¯uridol did not increase LDH release at concentrations 0.003 ± 1 mM; 3 ± 10 mM increased LDH release to 50 ± 60%, after 24 h exposure. Pen¯uridol (0.03 ± 0.3 mM) did not protect against the cytotoxic e ects of veratridine; at 1 mM, 15% protection was produced. Higher concentrations (3 ± 10 mM) enhanced the cytotoxic e ects of veratridine. 3 Ba 2+ ions caused a concentration-dependent increase of LDH release. This cytotoxic e ect was partially prevented by 3 mM lubeluzole and fully counteracted by 1 mM pen¯uridol. R91154 was less potent than lubeluzole and only protected against the lesion induced by 0.5 mM Ba 2+ . 4 Ouabain (10 mM during 24 h) increased LDH release to about 30%. Both lubeluzole (0.3 ± 10 mM) and the lower concentrations of pen¯uridol (0.003 ± 0.3 mM) prevented the ouabain cytotoxic e ects. At higher concentrations (3 mM), pen¯uridol increased drastically the ouabain cytotoxic e ects. 5 6-Hydroxydopamine (6-OHDA) caused signi®cant cytotoxic e ects at 30 and 100 mM. Lubeluzole (3 ± 10 mM) or pen¯uridol (0.03 ± 0.3 mM) had no cytoprotective e ects against 6-OHDA. 6 Lubeluzole (3 mM), R91154 (3 mM) and pen¯uridol (1 mM) blocked the current through Na + channels in voltage-clamped chroma n cells (I Na ) by around 20 ± 30%. Ca 2+ current through Ca 2+ channels (I Ca ) was inhibited 57% by lubeluzole and R91154 and 50% by pen¯uridol. The e ects of pen¯uridol were not washed out, but those of lubeluzole and R91154 were readily reversible. 7 Lubeluzole (3 mM) induced reversible blockade of the oscillations of the cytosolic Ca 2+ , [Ca 2+ ] i , in fura-2-loaded cells exposed to 30 or 100 mM veratridine. Pen¯uridol (1 mM) inhibited those oscillations in an irreversible manner. 8 The results suggest that lubeluzole and its R-isomer caused cytoprotection against veratridine cell damage, by blocking the veratridine stimulated Na + and Ca 2+ entry, as well as the [Ca 2+ ] i oscillations. The Ba 2+ and ouabain cytotoxic e ects were prevented more e ciently by pen¯uridol, likely by blocking the plasmalemmal Na + /Ca 2+ exchanger. It remains dubious whether these ®ndings are relevant to the reported neuroprotective action of lubeluzole in stroke; the doubt rests in the stereoselective protecting e ects of lubeluzole in in vivo stroke models, as opposed to its lack of stereoselectivity in the in vitro model reported here.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of the neuroprotectant lubeluzole on the cytotoxic actions of veratridine, barium, ouabain and 6‐hydroxydopamine in chromaffin cells

Cano‐Abad

López

Hernández‐Guijo

et al. 1998

British J Pharmacology

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“…They are particularly useful in cardiac and smooth muscle cells, where they exert negative inotropic and relaxing effects. Some piperazine derivatives (cinnarizine, flunarizine, dotarizine, R56865) also block L-type calcium channels, but they also block other subtypes of calcium channels and thus have been consid- ered "wide-spectrum" calcium channel blockers (164,234,389). The same is true for imidazole antimycotics (386).…”

Section: B L-type Channelsmentioning

confidence: 99%

Calcium Signaling and Exocytosis in Adrenal Chromaffin Cells

Garcı́a¹,

García-de-Diego²,

Gandı́a³

et al. 2006

Physiological Reviews

319

289

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At a given cytosolic domain of a chromaffin cell, the rate and amplitude of the Ca2+ concentration ([Ca2+]c) depends on at least four efficient regulatory systems: 1) plasmalemmal calcium channels, 2) endoplasmic reticulum, 3) mitochondria, and 4) chromaffin vesicles. Different mammalian species express different levels of the L, N, P/Q, and R subtypes of high-voltage-activated calcium channels; in bovine and humans, P/Q channels predominate, whereas in felines and murine species, L-type channels predominate. The calcium channels in chromaffin cells are regulated by G proteins coupled to purinergic and opiate receptors, as well as by voltage and the local changes of [Ca2+]c. Chromaffin cells have been particularly useful in studying calcium channel current autoregulation by materials coreleased with catecholamines, such as ATP and opiates. Depending on the preparation (cultured cells, adrenal slices) and the stimulation pattern (action potentials, depolarizing pulses, high K+, acetylcholine), the role of each calcium channel in controlling catecholamine release can change drastically. Targeted aequorin and confocal microscopy shows that Ca2+ entry through calcium channels can refill the endoplasmic reticulum (ER) to nearly millimolar concentrations, and causes the release of Ca2+ (CICR). Depending on its degree of filling, the ER may act as a sink or source of Ca2+ that modulates catecholamine release. Targeted aequorins with different Ca2+ affinities show that mitochondria undergo surprisingly rapid millimolar Ca2+ transients, upon stimulation of chromaffin cells with ACh, high K+, or caffeine. Physiological stimuli generate [Ca2+]c microdomains in which the local subplasmalemmal [Ca2+]c rises abruptly from 0.1 to approximately 50 microM, triggering CICR, mitochondrial Ca2+ uptake, and exocytosis at nearby secretory active sites. The fact that protonophores abolish mitochondrial Ca2+ uptake, and increase catecholamine release three- to fivefold, support the earlier observation. This increase is probably due to acceleration of vesicle transport from a reserve pool to a ready-release vesicle pool; this transport might be controlled by Ca2+ redistribution to the cytoskeleton, through CICR, and/or mitochondrial Ca2+ release. We propose that chromaffin cells have developed functional triads that are formed by calcium channels, the ER, and the mitochondria and locally control the [Ca2+]c that regulate the early and late steps of exocytosis.

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“…(Villarroya et al, 1995). This gradual blockade could be linked to a time dependent progressive accumulation of NNC and mibefradil at the plasmalemma of CCs, as the case is for R56865, dotarizine, and lubeluzole, as well as for another array of so-called wide-spectrum blockers of VACCs having a high octanol/water partition coefficient (Lara et al, 1997). In this context, the slow development of VACCs blockade exerted by mibefradil and particularly NNC, should be considered when using them as pharmacological probes to block a particular [Ca 2+ However, early (Thompson et al, 1997;Takeuchi et al, 2001;Adams et al, 1996) …”

Section: Discussionmentioning

confidence: 99%

Blockade by NNC 55-0396, mibefradil, and nickel of calcium and exocytotic signals in chromaffin cells: Implications for the regulation of hypoxia-induced secretion at early life

Fernández-Morales

Padín

Vestring

et al. 2015

European Journal of Pharmacology

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transients and secretion was also elicited by the three agents. However, the hypoxia-induced secretion (HIS) of catecholamine in RECCs was blocked substantially (75%) with thresholds concentrations of NCC (IC 20 to block I Ba ); this was not the case for mibefradil and Ni 2+ that required higher concentrations to block the HIS response. Thus, out of the three compounds, NNC seemed to be an adequate pharmacological tool to discern the contribution of T channels to the HIS response, without a contamination with high-VACCs blockade.

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`Wide-spectrum Ca2+ channel antagonists': lipophilicity, inhibition, and recovery of secretion in chromaffin cells

Cited by 26 publications

References 26 publications

Effects of the neuroprotectant lubeluzole on the cytotoxic actions of veratridine, barium, ouabain and 6‐hydroxydopamine in chromaffin cells

Effects of the neuroprotectant lubeluzole on the cytotoxic actions of veratridine, barium, ouabain and 6‐hydroxydopamine in chromaffin cells

Calcium Signaling and Exocytosis in Adrenal Chromaffin Cells

Blockade by NNC 55-0396, mibefradil, and nickel of calcium and exocytotic signals in chromaffin cells: Implications for the regulation of hypoxia-induced secretion at early life

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