JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ya Deau, J. T. Articles by Desravines, S. Search for Related Content PubMed PubMed Citation Articles by Ya Deau, J. T. Articles by Desravines, S. Related Collections Mechanisms Pharmacology

---

ANESTHETIC PHARMACOLOGY

Inhibition by Propofol of Intracellular Calcium Mobilization in Cultured Mouse Pituitary Cells

Anesthesiology Division, Hospital of Special Surgery, Weill Medical College of Cornell University, New York

Address correspondence to Jacques T. Ya Deau, Hospital for Special Surgery, Anesthesiology Division, Weill Medical College of Cornell University, 535 E 70 St., New York, NY 10021. Address e-mail to yadeauj{at}hss.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Propofol inhibited regulated secretion of the neuropeptide ß-endorphin from AtT-20 cells, a pituitary tumor cell line. Neuropeptide secretion depends on an increase of intracellular calcium (Ca²⁺) levels. We investigated the hypothesis that propofol altered intracellular Ca²⁺ levels in AtT-20 cells. Propofol (100 µM) did not inhibit Ca²⁺-induced secretion of ß-endorphin from digitonin-permeabilized cells. Thus, propofol did not inhibit neuropeptide secretion by blocking the effects of increased intracellular Ca²⁺. Intracellular Ca²⁺ was measured in intact cells using a Ca²⁺-sensitive dye. Ca²⁺ transients were generated by depolarization with KCl or by incubation with thapsigargin (an inhibitor of Ca²⁺ uptake into the endoplasmic reticulum). Propofol inhibited generation of Ca²⁺ transients in intact cells by KCl (half-maximal inhibitory concentration of 14.9 µM; P < 0.05). Nitrendipine also inhibited potassium-induced Ca²⁺ peaks. Propofol 50 µM reduced the thapsigargin-induced Ca²⁺ peak to 47% of control (P < 0.05). Thapsigargin-induced Ca²⁺ peaks were not affected by calcium channel blockade by nitrendipine. Propofol inhibited the stimulus-induced increase in intracellular Ca²⁺. Propofol inhibited thapsigargin-induced Ca²⁺ transients, but nitrendipine did not, indicating that propofol had effects on intracellular Ca²⁺ independent of blockade of L-type Ca²⁺ channels. Propofol may inhibit release of Ca²⁺ from intracellular stores. These results are consistent with the hypothesis that propofol inhibits neuropeptide secretion by inhibiting the stimulus-induced increase in intracellular Ca²⁺.

IMPLICATIONS: Propofol may block both entry of calcium into cells and release of calcium from intracellular stores, thereby inhibiting regulated secretion of neuropeptides. Study of the effects of propofol on intracellular calcium metabolism may increase understanding of how propofol alters brain function and may aid development of better IV anesthetics.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Propofol inhibited neuropeptide secretion from cells of a cultured mouse pituitary tumor line, AtT-20 (1). The effects of propofol were essentially the same, regardless of what compound was used to stimulate secretion of ß-endorphin. (The secretagogues studied were a cyclic adenosine monophosphate analog, a phorbol ester, barium, or a calcium channel agonist.) We proposed that propofol inhibited a step late in the intracellular pathways leading from a receptor in the cell membrane to neuropeptide secretion. Experiments described in this paper investigated the hypothesis that propofol inhibits Ca²⁺ transients in AtT-20 cells.

An increase of Ca²⁺ levels in response to stimuli plays an important role in regulating secretion (2). In human neuroblastoma cells, Ca²⁺ entry into cells was inhibited by propofol (3), but propofol increased intracellular Ca²⁺ in cells transfected with a vanilloid receptor (4). A detergent, digitonin, can be used to permeabilize the cell membranes to small molecules such as Ca²⁺. Digitonin interacts with cholesterol in the cell membrane and has little effect on exocytotic granules or Ca²⁺ stores (5). Permeabilized AtT-20 cells respond to an extracellular addition of Ca²⁺ by secreting neuropeptides (increased extracellular Ca²⁺ does not cause secretion from intact cells) (6). Digitonin-permeabilization of cells allows the study of the secretory pathway subsequent to the increase in intracellular Ca²⁺. If propofol inhibits steps subsequent to the Ca²⁺ increase, then propofol would inhibit Ca²⁺-induced secretion from permeabilized cells. If propofol inhibits secretion by preventing the stimulus-induced increase in intracellular Ca²⁺, then propofol would not inhibit Ca²⁺-induced secretion from permeabilized cells.

The Ca²⁺-sensitive dye Fura-2 measures intracellular Ca²⁺ levels in intact cells. Stimulation of AtT-20 cells with chemicals that induce secretion of neuropeptides (secretagogues) causes transient increases of intracellular Ca²⁺ (7). Both potassium and thapsigargin can be used to study intracellular Ca²⁺ regulation. Depolarization of cells with potassium activates voltage-dependent Ca²⁺ channels. The resultant Ca²⁺ entry triggers Ca²⁺ release from intracellular Ca²⁺ stores (8). Depolarization of AtT-20 cells with external potassium causes an increase of internal Ca²⁺ and ß-endorphin secretion (7). Thapsigargin inhibits the endoplasmic reticulum Ca²⁺-adenosine triphosphatase (9). Resting cytoplasmic Ca²⁺ levels reflect the balance of Ca²⁺ entry and Ca²⁺ efflux. Thapsigargin blocks Ca²⁺ uptake into the endoplasmic reticulum and can cause intracellular Ca²⁺ levels to increase. Propofol had no effect on thapsigargin-induced Ca²⁺ increases in smooth muscle cells (10).

Neuropeptides (small proteins secreted by neuronal cells) alter the function of other neurons. They act as excitatory or inhibitory neurotransmitters and neuromodulators (11). Propofol-induced inhibition of neuropeptide secretion could explain some of the effects (or side effects) of propofol on the nervous system. Research into the mechanism by which propofol alters neuropeptide secretion could promote the development of better IV anesthetics.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
AtT-20 cells, grown in 12-well plates as previously described (1), were incubated for 1 h with 1 mL/well of physiological salt solution (145 mM of NaCl, 2.2 mM of CaCl₂, 5.6 mM of KCl, 5.6 mM of glucose, 0.5 mM of sodium ascorbate, 0.5 mM of MgCl₂, and 5 mM of HEPES, with a pH value of 7.4; bovine serum albumin, 1 mg/mL; 37°C) adjusted to 0, 20, 40, 60, 80, or 100 µM of propofol from stock solutions of propofol in dimethyl sulfoxide (DMSO). The DMSO concentration was the same in all cases. The cells were rinsed with permeabilization buffer (139 mM of potassium glutamate, 5 mM of MgCl₂, 5 mM of adenosine triphosphate, 5 mM of EGTA, 5 mM of glucose, 0.5 mM of sodium ascorbate, and 20 mM of PIPES, with a pH value of 6.6; bovine serum albumin, 0.5 mg/mL; 37°C) without Ca²⁺ and then exposed to 1 mL/well of permeabilization buffer ± Ca²⁺ (free concentration 10 µM; determined as previously described (12)), ± 3 µM of digitonin, 0 to 100 µM of propofol (n = 3 wells for no Ca²⁺ and no digitonin; n = 4 wells for other conditions). ß-endorphin release was measured by enzyme-linked immunosorbent assay, as previously described (1). This technique was modified from methods used to permeabilize chromaffin cells (13) or AtT-20 cells (6).

AtT-20 cells in 2 75-cm² flasks were incubated at 37°C for 30 min with 4 mL of culture media containing 25 µM of Fura-2-AM (from a stock solution of 50 µg/50 µL in DMSO). The cells were rinsed 3 times with Ca²⁺- and magnesium-free Dulbecco phosphate-buffered saline and 10 mM of glucose, with a pH value of 7.4 (DPBSg) and then suspended in 7 mL of Ca²⁺-free DPBSg. The cell suspension was adjusted to 1.5 mM of Ca²⁺, centrifuged, resuspended in Ca²⁺-containing DPBSg, and stored on ice. Aliquots were warmed to 37°C, transferred to a cuvette, and studied in a SLM 8000 Aminco fluorescence spectrofluorometer (Aminco, Urbana, IL). Emission was measured at 510 nm, with excitation at 340 and 380 nm, while stirring the cell suspension with a magnetic stir bar. A 2-min baseline was recorded, and then 1 M of KCl was added to increase the potassium concentration by 20, 30, 40, 50, 60, 70, 80, or 100 mM. Fluorescence maxima and minima, determined by the addition of 0.01% sodium dodecyl sulfate and 15 mM of ethylene glycol-bis(ß-amino ethyl ether)-tetraacetic acid, were used to calculate Ca²⁺ concentrations (14). The K_d of Fura for Ca²⁺ used was 224 nM. Data from three independent experiments for each set of conditions were computed as mean ± SD.

Fura-2-loaded AtT-20 cells were exposed for 5 min to propofol dissolved in DMSO (2 µL/2 mL of buffer), with a final propofol concentration of 0, 2.5, 5, 10, 20, 30, or 50 µM. The cells were depolarized with 60 mM of potassium, and the intracellular Ca²⁺ peak was measured, as described above.

Baseline fluorescence of Fura-loaded AtT-20 cells was measured for 30 s, and then cells were incubated for 5 min with either 15 µM of propofol or DMSO (2 µL of stock solution per 2 mL of buffer). The cells were depolarized by addition of KCl to increase the potassium concentration by 20, 40, 60, 80, or 100 mM, and the intracellular Ca²⁺ peak was measured.

Baseline fluorescence of Fura-loaded AtT-20 cells was measured for 30 s, and then cells were incubated for 5 min with nitrendipine dissolved in DMSO (2 µL/2 mL of buffer). KCl was added to increase the potassium concentration by 60 mM, and the intracellular Ca²⁺ peak was measured.

Preliminary experiments indicated that the magnitude of the thapsigargin-induced Ca²⁺ transient diminished with storage of Fura-2-loaded cells. For this reason, thapsigargin experiments were performed immediately after loading cells with Fura-2. AtT-20 cells were grown in 60-mm dishes for 3 days and incubated for 30 min at 37°C with 25 µM of Fura-2-AM dissolved in 1.5 mL/dish of culture media. After rinsing each dish 3 times with 1.5 mL/dish of Ca²⁺- and magnesium-free DPBSg, adherent cells were suspended in 2 mL of DPBSg and transferred to a cuvette. Cells were allowed to stabilize for 3 min while stirring at 37°C in the spectrophotometer. Baseline fluorescence was measured for 30 s. Two microliters per milliliter of propofol or nitrendipine dissolved in DMSO was added. Final propofol concentrations were 0, 25, 50, or 75 µM. Nitrendipine was studied at 10 µM. After incubation for 3-min, the cells were stimulated with 5 µM of thapsigargin (from 1 mM of stock solution in DMSO), and the intracellular Ca²⁺ peak was measured.

Data were analyzed with the aid of SigmaStat for Windows Version 2.0 (Jandel Corporation, San Rafael, CA). Statistical significance was inferred for P < 0.05. One-way analysis of variance (ANOVA) with the Tukey test was used if normality and equal variance tests were passed. If not, one-way ANOVA on ranks was used. The specific test used is indicated in the Results section.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Propofol did not inhibit Ca²⁺-dependent release of ß-endorphin from permeabilized cells (Fig. 1) at propofol concentrations that almost totally inhibited secretion of ß-endorphin from intact cells (1). Propofol did not significantly alter ß-endorphin secretion from permeabilized cells, analyzed by ANOVA on ranks (Dunnett method, pair-wise multiple comparison versus no propofol).

View larger version (14K): [in this window] [in a new window]   Figure 1. Effect of 10 µM of Ca2+ on secretion of ß-endorphin from digitonin-permeabilized AtT-20 cells. The control represents ß-endorphin release from digitonin-treated cells in the absence of Ca2+. Other points represent Ca2+-induced ß-endorphin secretion from digitonin-permeabilized cells (mean ± SD of three separate experiments). The presence of 0–100 µM of propofol did not alter Ca2+-induced release. There were no statistically significant differences among the propofol-exposed groups.

Cells loaded with Fura-2 were stimulated with KCl to increase the external potassium concentration by 20, 30, 40, 50, 60, 70, 80, or 100 mM (Fig. 2). The magnitude of the Ca²⁺ peak increased with increasing potassium concentration up to 60 mM of KCl. One-way ANOVA (Dunnett Method) comparing all conditions to 60 mM indicated P < 0.05 for 60 mM versus 20, 30, or 40 mM of KCl. The addition of potassium to cells studied in the absence of extracellular Ca²⁺ did not generate a Ca²⁺ transient (data not shown).

View larger version (12K): [in this window] [in a new window]   Figure 2. Effect of varying KCl concentration on the magnitude of intracellular Ca2+ transients. Each point represents the mean ± SD of potassium-induced Ca2+ peaks from three separate experiments.

View larger version (13K): [in this window] [in a new window]   Figure 3. Effect of propofol on the magnitude of intracellular Ca2+ transients induced by depolarization with 60 mM of KCL. Each point represents the mean ± SD of Ca2+ peaks from three separate experiments. *P < 0.05 versus control.

View larger version (11K): [in this window] [in a new window]   Figure 4. Effect of 15 µM of propofol on magnitude of intracellular Ca2+ transients induced by 20–100 mM of KCl. Data (mean ± SD) from three experiments were combined by calculating the ratio (Ca2+ peak height in the presence of propofol)/(Ca2+ peak height in the absence of propofol). There were no statistically significant differences.

View larger version (12K): [in this window] [in a new window]   Figure 5. Effect of propofol on the magnitude of intracellular Ca2+ transients induced by thapsigargin. Each point represents the mean ± SD of thapsigargin-induced Ca2+ peaks from three experiments. *P < 0.05 versus 0 propofol.

View larger version (12K): [in this window] [in a new window]   Figure 6. Effect of nitrendipine on the magnitude of Ca2+ transients. (A) Nitrendipine inhibited KCl-induced Ca2+ transients. Each point represents the mean ± SD of three experiments. *P < 0.05 versus 0 nitrendipine. (B) Nitrendipine did not decrease the magnitude of thapsigargin-induced Ca2+ transients. Each point represents the mean ± SD of three experiments.

	Discussion

Top Abstract Introduction Methods Results Discussion References

Propofol inhibited the generation of intracellular Ca²⁺ transients by depolarization. Propofol could inhibit depolarization-induced Ca²⁺ transients by decreasing Ca²⁺ entry through L-type channels in the plasma membrane, as has been suggested in other systems (16). Nitrendipine (a Ca²⁺ channel blocker) inhibited the potassium-induced Ca²⁺ peak (Fig. 3). Based on this experiment, one could conclude that propofol inhibits potassium-induced Ca²⁺ transients via blockade of Ca²⁺ channels. For example, the inhibition by propofol of secretion of arginine vasopressin from supraoptic nucleus slices was attributed to inhibition of voltage-gated Ca²⁺ currents (17). Further support for this interpretation comes from the knowledge that AtT-20 cells express genes encoding L-type channels and have Ca²⁺ currents characteristic of L-type channels (18). Verapamil and nifedipine (L-type channel blockers) block neuropeptide secretion stimulated by a phorbol ester from AtT-20 cells (19) and also inhibit generation of Ca²⁺ transients (15). However, the demonstration that both nitrendipine and propofol inhibit potassium-induced Ca²⁺ peaks does not prove that propofol and nitrendipine have the same mechanism of action.

A priori, propofol could have inhibited potassium-induced Ca²⁺ release by shifting the dose-response curve to the right. If this were the case, larger concentrations of potassium would have overcome the inhibitory effects of propofol. Instead, 15 µM of propofol inhibited potassium-induced Ca²⁺ transients by approximately 50% at all concentrations of potassium studied. This result strengthens the proposition that propofol affected the biochemical processes that link depolarization to increased Ca²⁺ concentration. These steps include opening of voltage-dependent Ca²⁺ channels in the plasma membrane and Ca²⁺-induced Ca²⁺ release from intracellular stores (20).

Cytoplasmic Ca²⁺ levels reflect the balance of Ca²⁺ entry and Ca²⁺ removal. Depolarization of cells leads to Ca²⁺ entry through voltage-dependent Ca²⁺ channels. In response to Ca²⁺ entry, additional Ca²⁺ is released from intracellular stores (Ca²⁺-induced Ca²⁺ release). The magnitude of the depolarization-induced Ca²⁺ peak depends on the rate of Ca²⁺ release from cytoplasmic stores and on the rate of removal of Ca²⁺ from the cytoplasm. Thapsigargin inhibits an endoplasmic reticulum Ca²⁺ adenosine triphosphatase, thereby blocking Ca²⁺ uptake into the endoplasmic reticulum (9). At steady state, Ca²⁺ levels are constant because the rate of Ca²⁺ entry equals the rate of Ca²⁺ removal. Thapsigargin generates a Ca²⁺ transient only if there are thapsigargin-sensitive pumps that play a major role in intracellular Ca²⁺ turnover. Propofol inhibited thapsigargin-induced Ca²⁺ transients (Fig. 5), but the Ca²⁺-channel blocker nitrendipine did not inhibit thapsigargin-induced Ca²⁺ transients. The thapsigargin data prove that propofol has actions that cannot be explained by blockade of L-type Ca²⁺ channels. Propofol may inhibit Ca²⁺ release from intracellular stores, promote Ca²⁺ uptake from the cytoplasm into intracellular stores, or inhibit loading of intracellular stores.

Based on the calculation of IC₅₀s, propofol has 2 actions on AtT-20 cells. Propofol inhibits Ca²⁺ entry via L-type channels (depolarization-induced Ca²⁺ peaks were inhibited by propofol with an IC₅₀ of 15 µM), and propofol alters intracellular Ca²⁺ homeostasis, perhaps by inhibiting release from intracellular stores (thapsigargin-induced Ca²⁺ peaks were inhibited by propofol with an IC₅₀ near 50 µM). Based on these data, 10–20 µM of propofol inhibited L-type channels, but propofol at concentrations larger than 50 µM inhibited intracellular Ca²⁺ release.

The Cp₅₀i, the arterial concentration of propofol required to block response to skin incision in 50% of unpremedicated patients receiving no other anesthetic drugs, is 85 µM, and the Cp₉₅i is 153 µM (21). The concentration of propofol in rat brains is 7.8 times the plasma-propofol concentration (22), suggesting that the effect site concentration of propofol is many times that of the plasma concentration. It has been asserted that relevant concentrations of propofol are very small (0.4 µM) (23). However, these calculations were based on many assumptions, including an assumption that free-plasma propofol was the relevant concentration. Pharmaco-kinetic studies of propofol transfer from the blood to the brain in rats indicate that all propofol molecules in the blood can transfer to the brain (24), which indicates that the total propofol concentration in the blood determines the clinically relevant concentration. If this is true, then the concentrations of propofol used in these experiments were clinically relevant. Nonetheless, the actual effect site propofol concentration obtained clinically remains uncertain. The concentration range studied here (5–100 µM, with 50% effective concentrations of approximately 15 and 50 µM) is similar to that reported in some in vitro studies (1,3,4,10,16,17) but exceeds the range used in others (25,26).

Study of the effects of propofol, thapsigargin, and Ca²⁺-channel blockers on intracellular Ca²⁺ in guinea pig hearts indicated that propofol impaired sarcoplasmic reticulum Ca²⁺ handling (25). Direct comparisons of different systems are problematic, but we also found that propofol inhibited Ca²⁺ transients and that the inhibition may be caused by alteration of intracellular Ca²⁺ dynamics.

In summary, propofol inhibited release of Ca²⁺ from intracellular stores of AtT-20 cells and also inhibited entry of Ca²⁺ through L-type Ca²⁺ channels. Propofol did not block the effects of increased intracellular Ca²⁺. These findings are consistent with the hypothesis that propofol inhibited ß-endorphin secretion by inhibiting the required increase in intracellular Ca²⁺. Additional investigation would be required to prove this hypothesis. Such experiments could include studies of the effects of propofol on calcium-independent secretion. Further work on this topic could also involve measurement of effects of propofol on Ca²⁺ release from vesicles derived from the endoplasmic reticulum of neuropeptide-secreting cells.

	Acknowledgments

 
Supported, in part, by an Anesthesiology Young Investigator Award from the Foundation for Anesthesia Education and Research and by the Research Fund of the Anesthesiology Division of the Hospital for Special Surgery.

The authors thank Thomas J.J. Blanck, MD, PhD, Fang Xu, PhD, and the other members of the Excitable Tissues Laboratory for their advice and support.

	Footnotes

 
Presented, in part, at the following meetings of the International Anesthesia Research Society: the 72nd, Orlando, FL, March 7–11, 1998; the 73rd, Los Angeles, CA, March 12–16, 1999; and the 74th, Honolulu, HI, March 10–14, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Ya Deau JT. Inhibition of regulated neuropeptide secretion from mouse pituitary cells by propofol. Anesth Analg 1996; 83: 611–7.[Abstract]
2. Zucker RS. Exocytosis: a molecular and physiological perspective. Neuron 1996; 17: 1049–55.[Web of Science][Medline]
3. Lambert DG, Willets JM, Atcheson R, et al. Effects of propofol and thiopentone on potassium- and carbachol-evoked [³H]noradrenaline release and increased [Ca²⁺] from SH-SY5Y human neuroblastoma cells. Biochem Pharmacol 1996; 51: 1613–21.[Web of Science][Medline]
4. Tsutsumi S, Tomioka A, Sudo M, et al. Propofol activates vanilloid receptor channels expressed in human embryonic kidney 293 cells. Neurosci Lett 2001; 312: 45–9.[Web of Science][Medline]
5. Holz RW, Bittner MA, Senter RA. Regulated exocytotic fusion. I. chromaffin cells and PC12 cells. Methods Enzymol 1992; 219: 165–78.[Web of Science][Medline]
6. Luini A, De Matteis MA. Evidence that receptor-lined G protein inhibits exocytosis by a post-second-messenger mechanism in AtT-20 Cells. J Neurochem 1990; 54: 30–8.[Web of Science][Medline]
7. Adler M, Sabol AL, Busis N, Pant H. Intracellular calcium and hormone secretion in clonal AtT-20/D16–16 anterior pituitary cells. Cell Calcium 1989; 10: 467–76.[Web of Science][Medline]
8. Lesh RE, Lynch C. Intracellular Ca²⁺ regulation. In: Yaksh TL, Lynch C, Zapol WM, et al, eds. Anesthesia: biologic foundations. Philadelphia: Lippincott-Raven Publishers, 1998: 105–30.
9. Treiman M, Caspersen C, Christensen SB. A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca²⁺-ATPases. Trends Pharmacol Sci 1998; 19: 131–5.[Medline]
10. Xuan YT, Glass PS. Propofol regulation of calcium entry pathways in cultured A10 and rat aortic smooth muscle cells. Br J Pharmacol 1996; 117: 5–12.[Web of Science][Medline]
11. Feany MB. Neuropeptide modulation of learning and memory processes. Rev Neurosci 1996; 7: 151–64.[Web of Science][Medline]
12. Portzehl H, Caldwell PC, Ruegg JC. The dependence of contraction and relaxation of muscle fibres from the crab Maia squinado on the internal concentration of free calcium ions. Biochim Biophys Acta 1964; 79: 581–91.[Medline]
13. Dunn LA, Holz RW. Catecholamine secretion from digitonin-treated adrenal medullary chromaffin cells. J Biol Chem 1983; 258: 4989–93.[Abstract/Free Full Text]
14. Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca²⁺ indicators with greatly improved fluorescence properties. J Biol Chem 1985; 260: 3440–50.[Abstract/Free Full Text]
15. Luini A, Lewis D, Guild S, et al. Hormone secretagogues increase cytosolic calcium by increasing cAMP in corticotropin-secreting cells. Proc Natl Acad Sci USA 1985; 82: 8034–8.[Abstract/Free Full Text]
16. Olcese R, Usai C, Maestrone E, Nobile M. The general anesthetic propofol inhibits transmembrane calcium current in chick sensory neurons. Anesth Analg 1994; 78: 955–60.[Abstract/Free Full Text]
17. Inoue Y, Shibuya I, Kabashima N, et al. The mechanism of inhibitory actions of propofol on rat supraoptic neurons. Anesthesiology 1999; 91: 167–78.[Web of Science][Medline]
18. Lievano A, Bolden A, Horn R. Calcium channels in excitable cells: divergent genotypic and phenotypic expression of 1-subunits. Am J Physiol Cell Physiol 1994; 267: C411–24.[Abstract/Free Full Text]
19. Reisine T, Guild S. Activators of protein kinase C and cyclic AMP-dependent protein kinase regulate intracellular calcium levels through distinct mechanisms in mouse anterior pituitary tumor cells. Mol Pharmacol 1987; 32: 488–96.[Abstract]
20. Berridge MJ. Neuronal calcium signaling. Neuron 1998; 21: 13–26.[Web of Science][Medline]
21. Smith C, McEwan AI, Jhaveri R, et al. The interaction of fentanyl on the Cp₅₀ of propofol for loss of consciousness and skin incision. Anesthesiology 1994; 81: 820–8.[Web of Science][Medline]
22. Shyr M-H, Tsai T-H, Tan PPC, et al. Concentration and regional distribution of propofol in brain and spinal cord during propofol anesthesia in the rat. Neurosci Lett 1995; 184: 212–5.[Web of Science][Medline]
23. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367: 607–14.[Medline]
24. Dutta S, Matsumoto Y, Muramatsu A, et al. Steady-state propofol brain: plasma and brain:blood partition coefficients and the effect-site equilibration paradox. Br J Anaesth 1998; 81: 422–4.[Abstract/Free Full Text]
25. Nakae Y, Fujita S, Namiki A. Propofol inhibits Ca²⁺ transients but not contraction in intact beating guinea pig hearts. Anesth Analg 2000; 90: 1286–92.[Abstract/Free Full Text]
26. Furuya R, Oka K, Watanabe I, et al. The effects of ketamine and propofol on neuronal nicotinic acetylcholine receptors and PT2x purinoceptors in PC12 cells. Anesth Analg 1999; 88: 174–80.[Abstract/Free Full Text]

This article has been cited by other articles:

				H.-R. Kim, G.-H. Lee, K.-C. Ha, T. Ahn, J.-Y. Moon, B.-J. Lee, S.-G. Cho, S. Kim, Y.-R. Seo, Y.-J. Shin, et al. Bax Inhibitor-1 Is a pH-dependent Regulator of Ca2+ Channel Activity in the Endoplasmic Reticulum J. Biol. Chem., June 6, 2008; 283(23): 15946 - 15955. [Abstract] [Full Text] [PDF]

				S.-W. Ying and P. A. Goldstein Propofol-Block of SK Channels in Reticular Thalamic Neurons Enhances GABAergic Inhibition in Relay Neurons J Neurophysiol, April 1, 2005; 93(4): 1935 - 1948. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ya Deau, J. T. Articles by Desravines, S. Search for Related Content PubMed PubMed Citation Articles by Ya Deau, J. T. Articles by Desravines, S. Related Collections Mechanisms Pharmacology

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999