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Anesth Analg 2000;91:440-445
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Sevoflurane Stimulates Inositol 1,4,5-Trisphosphate in Skeletal Muscle

Akira Kudoh, MD, and Akitomo Matsuki, MD

Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan

Address correspondence and reprint requests to Akira Kudoh, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, 5 Zaifucho, Hirosaki 036, Aomori, Japan.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Inositol 1,4,5-triphosphate (IP3) plays an important role in excitation-contraction coupling and malignant hyperthermia in skeletal muscle. We investigated whether sevoflurane affects IP3 formation in L6 skeletal muscle cells and studied the mechanisms that modulate IP3. Sevoflurane stimulated IP3 production from a basal level of 78.4 ± 6.1 to 730.0 ± 53.1 pmol · mg · protein-1 in 2 mM of sevoflurane in a dose-dependent manner. A dose of 10 µM of U73122 (a phospholipase C antagonist) significantly decreased 0.8 mM of sevoflurane-stimulated IP3 production from 387.8 ± 24.7 to 247.8 ± 19.8 pmol · mg · protein-1. A dose of 100 µM of (p-amylcinnamoyl) anthranilic acid (a PLA2 antagonist) also significantly decreased sevoflurane-stimulated IP3 production to 282.0 ± 24.0 pmol · mg · protein-1. Exposure to 1 µM of genistein and tyrphostin A23 (tyrosine kinase inhibitors) significantly decreased sevoflurane-stimulated IP3 production to 241.0 ± 35.3 and 267.4 ± 32.9 pmol · mg · protein-1. Sevoflurane-stimulated IP3 production was significantly decreased by 10 µM of 8-(N,N-diethylamino) octyl-3,4-5-trimathoxybenzoate (an intracellular calcium antagonist) and 100 µM and 1 mM of guanosine 5'-O-(2-thiodiphosphate) (GDPßS), a guanosine 5'triphosphate-binding protein inhibitor. Elevation of IP3 production was significantly higher in halothane than in sevoflurane and isoflurane at the same concentration of 0.8 mM. We conclude that sevoflurane-stimulated IP3 production involves phospholipase C, phospholipase A2, tyrosine kinase, and guanosine 5'triphosphate-binding protein and the stimulation is associated with concentration of intracellular ionized calcium.

Implications: Inhaled anesthetics increase intracellular ionized calcium in the skeletal muscle cell and the ionized calcium increase is partly released from the intracellular store by inositol 1,4,5-triphosphate (IP3) formation. IP3 plays an important role in excitation-contraction coupling and malignant hyperthermia. We studied whether sevoflurane affects IP3 formation and the mechanisms that modulate IP3.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Halothane increases intracellular ionized calcium (Ca2+) in skeletal muscle cells (1). An increase of 50% of the Ca2+ is released from intracellular store by phospholipase C (PLC)-mediated inositol 1,4,5-triphosphate (IP3) formation (1). IP3 is important not only in excitation-contraction coupling of skeletal muscle, but also in anesthetic-induced malignant hyperthermia (2). During malignant hyperthermia, intracellular Ca2+ increases in skeletal muscle. The concentrations of intracellular Ca2+ are regulated by the ryanodine receptor and IP3 receptor. Scholz et al. (3) demonstrated that IP3 is involved in the development of malignant hyperthermia. In skeletal muscle, IP3 plays a role in excitation-contraction coupling and intracellular signaling. IP3 releases Ca2+ through an IP3 receptor of sarcoplasmic reticulum. Increase in IP3 production correlates well with the increase in intracellular Ca2+ concentration. Thus, increase in IP3 concentration produces cell response including muscle contraction and plasma membrane depolarization. IP3 is released through PLC, which is activated by cell-surface receptors, including guanosine 5'triphosphate (GTP)-binding protein (G-protein) (4). This increase leads to stimulation of tyrosine kinase activity (5), phospholipase A2 (PLA2) (5), and protein kinase C (PKC) (6), which have a role in regulating IP3 (6,7).

Sevoflurane has a low blood-gas partition coefficient (0.63) and the lowest pungency of commercially available inhaled anesthetics (8). It also has the potential to trigger malignant hyperthermic reaction and is known to induce Ca2+ release from the intracellular store in skeletal muscle at clinical concentrations (9); however, the effects of sevoflurane on IP3 formation in skeletal muscle remains unclarified. Thus, we investigated whether sevoflurane affects IP3 formation in L6 skeletal muscle cells.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Rat L6 rat skeletal muscle cells were grown in Dulbecco’s modified Eagle’s medium, supplemented with 10% horse serum on 0.1% gelatin-coated plates. The cells were grown in 5% CO2 and 100% humidity atmosphere. After 4 days in culture, the cells were used at confluence for this study.

At 24 h before the experiments, the culture medium was changed to a serum-free medium. 0, 0.2, 0.4, 0.8, 1.2, and 2.0 mM sevoflurane or 0.8 mM isoflurane and halothane were added directly to the flasks containing L6 rat skeletal muscle cells. The caps of the flasks were immediately closed tightly to minimize vaporization of sevoflurane and the flasks were incubated at 37°C for 10 min. Sevoflurane concentrations at 0.4, 0.8, 1.2, and 2.0 mM correspond to 1.3%, 2.6%, 3.9%, and 5.2% in vapor phase, respectively. The reaction was stopped at 10 min after the exposure of sevoflurane by the addition of 0.5 mL of 100% trichloroacetic acid (TCA) for each 1 mg of cells. The acid extract was homogenized and centrifuged for 10 min at 1000g. TCA was removed from the extracts by adding 2 mL of a mixture of 3 volumes 1,1,2-trichloro-1,2,2-trifluoroethane plus 1 volume of trioctylamine for each 1 mL of TCA extract. IP3 content in the aqueous top layer was determined by using a radioreceptor assay kit (NEN Research Products, Boston, MA). The radioreceptor assay was done by methods of competitive ligand binding, where a radioactive ligand competes with a nonradioactive ligand for a fixed number of receptor binding sites. Unlabeled IP3 and a fixed amount of radiolabeled IP3 ([3H]IP3) are allowed to react with a constant. Decreasing amounts of [3H]IP3 are bound to the IP3 receptor as the amount of unlabeled IP3 was increased.

Furthermore, to evaluate whether PLC, PLA2, tyrosine kinase, PKC, G-protein and alteration of intracellular calcium are involved in IP3 formation in the presence of sevoflurane, we studied their antagonists and agonist: U73122 (a PLC antagonist), (p-amylcinnamoyl) anthranilic acid (ACA) (a PLA2 antagonist), genistein and tyrphostin A23 (tyrosine kinase inhibitors), tyrphostin A1 (the inactive analog of tyrosine kinase), phorbol 12 myristate 13 acetate (PMA) (a PKC agonist), staurosporine (a PKC antagonist), guanosine 5'-O-(2-thiodiphosphate) (GDPßS) (a GTP-binding protein inhibitor), TMB-8 (an intracellular calcium antagonist), and verapamil (a calcium channel blocker). The antagonists and agonist, excepting PMA, were added to the cultures for 30 min before sevoflurane. PMA was exposed for 10 min. Each experiment was carried out in duplicate.

PMA, staurosporine, TMB-8, verapamil, cell culture medium, and supplements were purchased from Sigma Chemical, St. Louis, MO. Genistein, tyrphostin A23, and tyrphostin A1 were purchased from Calbiochem-Novabiochem, La Jolla, CA. U73122 and (p-amylcinnamoyl) anthranilic acid (ACA) was purchased from BIOMOL Research Laboratories (Plymouth Meeting, PA). A radioreceptor assay kit for measurement of IP3 was purchased from NEN Research Products. The L6 rat skeletal muscle myoblast was obtained from the American Type Culture Collection (Rockville, MD).

Genistein and tyrphostin A1 and A23, U73122, and ACA were dissolved in 0.1% DMSO and kept protected from light. Protein concentrations were determined by the Bradford method using bovine serum albumin as standard (10).

Results are expressed as mean ± SEM. Every experiment was repeated eight times with different cell preparations. The significance of differences was determined with ANOVA. When a significant F value was obtained, comparisons of mean were done with the Student’s t-test for paired and unpaired samples, the Bonferroni test and the Student-Newman-Keuls multiple comparison test. Differences in mean values were considered significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Sevoflurane stimulated IP3 formation in a dose-dependent manner. IP3 increased from a basal level of 78.4 ± 6.1 to 730.0 ± 53.1 pmol · mg · protein-1 in the presence of 2 mM of sevoflurane (Figure 1). Sevoflurane (0.8 mM) increased IP3 production to 113.6 ± 9.2 at 30 s after exposure to sevoflurane, 183.7 ± 18.4 at 1 min, 321.9 ± 23.0 at 5 min, 387.8 ± 24.7 at 10 min, 374.5 ± 36.3 pmol · mg · protein-1 at 15 min.



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  		Figure 1. Effect of sevoflurane on inositol 1,4,5-trisphosphate (IP3) production. Sevoflurane was incubated at 37°C for 10 min (n = 8) for each data point. *P < 0.05, **P < 0.01, and ***P < 0.001 vs Basal. #P < 0.05, ##P < 0.01, and ###P < 0.001 vs 0.2 mM sevoflurane-stimulated IP3 production.

 
We assessed the involvement of PLC and PLA2 in sevoflurane-stimulated IP3 formation by examining the effect of U73122 (a PLC antagonist) and ACA (a PLA2 antagonist). At 0.8 mM, sevoflurane-stimulated IP3 production was decreased from 387.8 ± 24.7 pmol · mg · protein-1 to 291.8 ± 43.1 and 247.8 ± 19.8 pmol · mg · protein-1 by 1 and 10 µM of U73122. 10 and 100 µM of ACA also decreased sevoflurane-stimulated IP3 production to 331.1 ± 37.7 and 282.0 ± 24.0 pmol · mg · protein-1. Sevoflurane-stimulated IP3 production was blocked to 165.8 ± 16.1 pmol · mg · protein-1 by the mixture of 10 µM U73122 and 100 µM of ACA. (Figure 2).



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  		Figure 2. Effect of U73122 (a PLC inhibitor) and (p-amylcinnamoyl) anthranilic acid (ACA) (a PLA2 inhibitor) on sevoflurane-stimulated inositol 1,4,5-trisphosphate (IP3) production. Cardiomyocytes were incubated for 30 min at 37°C in the presence of 1 and 10 µM of U73122 and 10 and 100 µM of (p-amylcinnamoyl) anthranilic acid (ACA) before exposure of 0.8 mM of sevoflurane for 10 min (n = 8) for each bar. Data are mean ± SEM *P < 0.05, **P < 0.01, and ***P < 0.001 vs 0.8 mM of sevoflurane-stimulated IP3 production. ##P < 0.01 vs 0.8 mM of sevoflurane-stimulated IP3 production in the presence of 10 µM of U73122 and 100 µM of ACA.

 
Figure 3 shows the effect of tyrosine kinase on sevoflurane-stimulated IP3 production. When the cultures were exposed to 100 nM and 1 µM of genistein, sevoflurane-stimulated IP3 attenuated significantly from 387.8 ± 24.7 to 281.9 ± 30.4 and 241.0 ± 35.3 pmol · mg · protein-1 in a dose-dependent manner. 1 µM tyrphostin A23 decreased sevoflurane-stimulated IP3 significantly to 267.4±32.9 pmol · mg · protein-1. When the culture was exposed to 1 µM tyrphostin A1, which is the inactive analog, the sevoflurane-stimulated IP3 formation was 391.4 ± 17.2 with no significant difference.



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  		Figure 3. Effect of genistein and tyrphostin A23 (tyrosine kinase antagonists) on sevoflurane-stimulated IP3 production. Cardiomyocytes were incubated with 100 nM and 1 µM of genistein and tyrphostin A23 for 30 min at 37°C. Sevoflurane was incubated at 37°C for 10 min (n = 8) for each bar. Data are mean ± SEM *P < 0.05 and **P < 0.01 vs 0.8 mM of sevoflurane-stimulated IP3 production.

 
To determine whether sevoflurane-stimulated IP3 production is dependent on alteration of intracellular calcium, we treated the cultures with 1 and 10 µM TMB-8 (an intracellular calcium antagonist) and 1 and 10 µM verapamil (a calcium channel blocker). Sevoflurane-stimulated IP3 was decreased by 1 and 10 µM TMB-8 from 387.8 ±24.7 to 324.9 ±38.7 and 291.5 ± 26.5 pmol · mg · protein-1, respectively. Exposure to 1 and 10 µM verapamil also decreased sevoflurane-stimulated IP3 production to 322.1 ± 44.4 and 264.9 ± 27.5 pmol · mg · protein-1 in a dose-dependent manner (Figure 4).



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  		Figure 4. Effect of TMB-8 (an intracellular calcium antagonist) and verapamil (a calcium channel blocker) on sevoflurane-stimulated IP3 production. The cultures were incubated for 30 min at 37°C in the presence of 1 and 10 µM of TMB-8 and verapamil before exposure of 0.8 mM of sevoflurane for 10 min (n = 8) for each bar. Data are mean ± SEM *P < 0.05 and **P < 0.01 vs 0.8 mM of sevoflurane-stimulated IP3 production.

 
To study the effect of PKC on sevoflurane-stimulated IP3 production, we studied the effect of 10 µM PMA (a PKC agonist) and staurosporine (a PKC antagonist). PMA decreased significantly to 217.5 ± 29.1 and staurosporine increased significantly to 547.6 ± 52.1 IP3 production. We studied whether sevoflurane-stimulated IP3 production can be altered by GDPßS (a GTP-binding protein inhibitor). GDPßS (100 µM and 1 mM) significantly decreased sevoflurane-stimulated IP3 production to 302.8 ± 32.3 and 275.5 ± 34.0 pmol · mg · protein-1 (Figure 5).



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  		Figure 5. Effect of 10 µM of phorbol 12 myristate 13 acetate (PMA) (a PKC agonist) and staurosporine (a PKC antagonist), and 100 µM and 1 mM of GDPßS (a GTP-binding protein inhibitor) on sevoflurane-stimulated IP3 production. Cardiomyocytes were incubated for 10 min in PMA (a PKC agonist) and for 30 min in staurosporine and GDPßS. Cells were then exposed by sevoflurane for 10 min (n = 8) for each bar. Data are mean ± SEM *P < 0.05 and ***P < 0.001 vs 0.8 mM of sevoflurane-stimulated IP3 production.

 
We compared the effect of 0.8 mM of sevoflurane, of isoflurane, and of halothane on IP3 production. Sevoflurane, isoflurane, and halothane stimulated IP3 formation to 387.8 ± 24.7, 351.6 ± 34.9, and 480.3 ± 44.2 pmol · mg · protein-1, respectively. Elevation of IP3 production was significantly higher in halothane than in sevoflurane and isoflurane.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We demonstrated that sevoflurane stimulates IP3 production in skeletal muscle cells in a dose-dependent manner. The effects of sevoflurane were inhibited by antagonists of PLC and PLA2. PLC is activated through G-protein, resulting in the hydrolysis of phosphatidylinositol 4,5-bisphosphate and stimulation of the rapid formation of IP3, which mobilizes Ca2+ from sarcoplasmic reticulum (SR) (11). PLA2, which is a key protein in the production for arachidonic acid and prostaglandins (12), is related to positive regulation of PLC (6). The interaction between PLC and PLA2 may occur through activation of G-protein (5). We showed that sevoflurane-stimulated IP3 production was decreased by tyrosine kinase inhibitors. Sevoflurane-stimulated IP3 production also involves activation of tyrosine kinase, which has a role in the regulation of inositol phosphorylation and intracellular Ca2+ (7,13). Tyrosine kinase can stimulate inositol phosphate formation through G-protein (7). Halothane and isoflurane stimulate PLC in presence of G-protein, but not in the absence of G-protein (14). We observed an inhibition of sevoflurane-stimulated IP3 production by a G-protein inhibitor. Therefore, sevoflurane-stimulated IP3 production appears to act via PLA2 and PLC and tyrosine kinase linked to G-protein. IP3 is phosphorylated to IP2 and IP4. IP2 is phosphorylated to IP1 or inositol, and IP4 is phosphorylated to IP5 or IP6. Anesthetics have not been reported to affect the pathway including IP2, IP1, inositol, IP4, IP5, and IP6. Thus, increase in IP3 is unlikely caused by depressed degradation of IP3.

Halothane increases intracellular Ca2+ and approximately 50% of this increase is released from SR in skeletal muscle cells (1). The elevation of intracellular Ca2+ may be caused by stimulation of PLC-mediated IP3 formation (9,15). Halothane concentrations used in these studies were 5.7 and 3.5 mM, which are approximately 10- to 20-fold larger than 1 minimum alveolar concentration (MAC). However, we found sevoflurane-stimulated IP3 production in more relevant concentrations of sevoflurane. Kress et al. (16) suggest that halothane and isoflurane increase intracellular Ca2+ concentration by negative feedback on Ca2+ influx through a receptor-operated Ca2+ channel that is activated by an increase in intracellular Ca2+ by IP3 and IP4, which is a phosphorylated product of IP3 and G-protein. Thus, the release of IP3 induced Ca2+ from SR plays an important role in the elevation of intracellular Ca2+ in skeletal muscle. Our data shows that sevoflurane-stimulated IP3 production was blocked by intracellular Ca2+ antagonist and Ca2+ channel blocker, indicating that the sevoflurane-stimulated IP3 production may be associated with intracellular Ca2+ concentration. TMB-8 inhibits the release of Ca2+ from SR. A major effect of TMB-8 on cellular calcium metabolism is to prevent intracellular Ca2+ mobilization by inhibiting the IP3-induced Ca2+ release (17). The link between IP3 and voltage-dependent Ca2+ channel remains unclear in skeletal muscle. IP3 elicits a rapid release of calcium from intracellular store. On the contrary, the L-type voltage-gated channel is the main channel for slow and sustained Ca2+ entry across the plasma membrane. These two phases of Ca2+ release from intracellular Ca2+ stores and Ca2+ entry across the plasma membrane are dependent on receptor-stimulated phosphatidylinositol 4,5-bisphosphate as the same substrate as IP3 (18). The voltage-dependent Ca2+ channel is stimulated by an increase in IP3 (18). Activation of PLC, PLA2, and tyrosine kinase required elevation of intracellular Ca2+ in various cell types (5). That is to say, sevoflurane stimulated PLC, PLA2, and tyrosine kinase receptors through G-protein and increased IP3, which leads to an increase in intracellular Ca2+. The elevation of intracellular Ca2+ stimulated PLC, PLA2, and tyrosine kinase receptors. Activation of PLC, PLA2, and tyrosine kinase receptors further increases in IP3 production (Figure 6).



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  		Figure 6. Mechanism of sevoflurane-stimulated IP3 formation in skeletal muscle cells. Sevoflurane stimulates PLC, PLA2, and tyrosine kinase receptor through G-protein, which increase IP3 production. IP3 increases intracellular Ca2+ from sarcoplasmic reticulum (SR). The elevation of intracellular Ca2+ activates PLC, PLA2, tyrosine kinase receptor, and PKC. The activation of PLC, PLA2, and tyrosine kinase receptor further stimulates IP3 production and PKC produces feedback inhibition of PLC and regulates intracellular Ca2+.

 
The regulation of IP3-mediated Ca2+ release involves PKC, which produces feedback inhibition of PLC and decreased IP3 formation (19). As PKC activation is associated with several cellular responses, PMA-mediated inhibition of IP3 formation might occur at one or more different sites. One proposed mechanism by which PMA-attenuated IP3 production is caused by its increasing degradation mediated by activation of phosphomonoesterase specific for IP3 (20). Others have proposed that PKC phosphorylates the IP3 receptor of SR (21) and produces feedback inhibition of PLC (6), resulting in diminished IP3 in releasing Ca2+. In addition, PKC plays a role in returning intracellular Ca2+ to baseline and stimulating the movement of Ca2+ from the intracellular to extracellular compartment. Thus, PKC regulates the IP3-Ca2+ sequence and appears to act as a buffer for intracellular Ca2+. An association between inhaled anesthetics and PKC activity is suggested. The potency of inhaled anesthetics to inhibit PKC correlates with the lipid solubility (22). However, the effect of inhaled anesthetics on PKC has not been adequately evaluated. In this study, PMA inhibited and staurosporine stimulated sevoflurane-stimulated IP3 production. PKC appears to partly regulate sevoflurane-stimulated IP3 production.

Elevation of IP3 production was significantly higher in halothane than in sevoflurane and isoflurane. Kunst et al. (9) showed that an increase in Ca2+ from SR induced by halothane was higher than that induced by sevoflurane and isoflurane. These results indicate that elevation of intracellular Ca2+ by inhaled anesthetics appears to be closely related to IP3 formation. In addition, caffeine-induced muscle contractures induced by halothane are greater than those by either sevoflurane or isoflurane. Thus, IP3 is probably involved in the development of malignant hyperthermia. In this study, we compared the effect of halothane, sevoflurane, and isoflurane on IP3 production at the same concentration. However, the concentration was not at an equal MAC. In this study, because the MAC of halothane was larger than that of sevoflurane and isoflurane, differences of MAC might affect the elevation of IP3 production.

We conclude that sevoflurane-stimulated IP3 production involves activation of phospholipase C, phospholipase A2, and tyrosine kinase linked to G-protein. The stimulation is associated with protein kinase C and intracellular Ca2+.


   Acknowledgments
 
The authors thank Professor Dr. E. G. Erdos of the Department of Pharmacology, University of Illinois College of Medicine at Chicago, and Dr. S. F. Rabito of the Department of Anesthesiology and Pain Management, Cook County Hospital, Chicago, Illinois, for their support for this research and her critical comments.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 21, 2000.




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Lippincott, Williams & Wilkins 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 HighWire Press