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© 2001 International Anesthesia Research Society
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Abstract |
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Prostaglandin E2 receptors, subtype EP1 (PGE2EP1) have been linked to several physiologic responses, such as fever, inflammation, and mechanical hyperalgesia. Local anesthetics modulate these responses, which may be due to direct interaction of local anesthetics with PGE2EP1 receptor signaling. We sought to characterize the local anesthetic effects on PGE2EP1 signaling and elucidate mechanisms of anesthetic action. In Xenopus laevis oocytes, recombinant expressed PGE2EP1 receptors were functional (half maximal effect concentration, 2.09 ± 0.98 x 10-6 M). Bupivacaine, after incubation for 10 min, inhibited concentration-dependent PGE2EP1 receptor functioning (half-maximal inhibitory effect concentration, 3.06 ± 1.26 x 10-6 M). Prolonged incubation in bupivacaine (24 h) inhibited PGE2-induced calcium-dependent chloride currrents (ICl(Ca)) even more. Intracellular pathways were not significantly inhibited after 10 min of incubation in bupivacaine. But ICl(Ca) activated by intracellular injection of GTP
S (a nonhydrolyzable guanosine triphosphate [GTP] analog that activates G proteins, irreversible because it cannot be dephosphorylated by the intrinsic GTPase activity of the 
subunit of the G protein) was reduced after 24 h of incubation in bupivacaine, indicating a G protein-dependent effect. However, inositol 1,4,5-trisphosphate- and CaCl2- induced ICl(Ca) were unaffected by bupivacaine at any time points tested. Therefore, bupivacaine’s effect is at phospholipase C or at the G protein or the PGE2EP1 receptor. All inhibitory effects were reversible. We conclude that bupivacaine inhibited PGE2EP1 receptor signaling at clinically relevant concentrations. These effects could, at least in part, explain how local anesthetics affect physiologic responses such as fever, inflammation, and hyperalgesia during the perioperative period. IMPLICATIONS: Clinically relevant bupivacaine concentrations inhibit prostaglandin E2 EP1 subtype signaling. This may explain the effects of regional anesthesia on physiologic responses such as fever, inflammation, and hyperalgesia during the perioperative period.
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Introduction |
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Prostaglandin E2 (PGE2) mediates dilation or constriction of smooth muscle cells, as well as inflammatory processes, through G protein-coupled membrane receptors (1,2). Prostaglandins modulate nociception as well (3), not only by sensitizing peripheral nociceptors, but also by acting within the central nervous system. Furthermore, the pain-modulatory actions of PGE2 are mediated by different subtypes of PGE2 receptors (3,4), which are pharmacologically classified into EP1, EP2, EP3, and EP4 subtypes.
Mechanical hyperalgesia after intradermal injection of PGE2 is mediated by EP1 receptors. Hyperalgesia, as assessed by the hot-plate test in rats after intracerebroventricular injections of PGE2, is mediated through EP1 and EP3 receptors (3). It is interesting to note that a single dose of local anesthetic produced a prolonged suppression of hyperalgesia, edema, and biochemical indices of inflammation (5), which could be due to direct interaction of the used local anesthetic bupivacaine with PGE2 receptors. No investigation has studied local anesthetic interactions with PGE2EP1 receptor signaling. We used the Xenopus oocyte model to study the effects of bupivacaine on PGE2EP1 receptor signaling, because this model forms a flexible system to study recombinantly expressed G protein-coupled receptors and the influence of anesthetics on their functioning and on intracellular signaling pathways. The aim of the study was to determine whether the effects of bupivacaine are mediated by inhibition of the intracellular signaling pathway or by direct effects at the membrane receptor itself.
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Methods |
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The procedures of Xenopus laevis oocyte isolation, messenger RNA (mRNA) synthesis, and microinjection were published previously (6–10). In brief, after the local animal ethics committee of the City of Münster, Germany, had given consent, female Xenopus laevis toads were housed in a newly established frog colony. Toads were anesthetized, and approximately 200 oocytes were surgically removed. The wound was closed and the frog was allowed to recover from the anesthesia and operation. Afterward the oocytes were defolliculated by collagenase type 1A in calcium-free OR2 solution (containing 82.5 mM NaCl, 2 mM KCl, 1 mM MgCl2, and 5 mM HEPES, pH adjusted to 7.4) for 2 h. Microscopic observation confirmed that the follicle cells had been removed.
Mouse PGE2EP1 receptor was obtained from Dr. K. R. Lynch (Department of Pharmacology, University of Virginia, Charlottesville, VA) as a complementary DNA encoding a 402-amino-acid protein in pcDNA3 vector. This construct was linearized by the nuclease BamHI and transcribed in the presence of capping analog by bacteriophage RNA polymerase T7, by using a commercial RNA preparation kit (mMESSAGE mMACHINETM T7 Kit; Ambion Inc., Austin, TX). The oocytes were injected with 10 ng of mRNA in 50.6 nL sterile water, by using an automated microinjector (Nanoject; Drummond Scientific, Broomall, PA) and incubated in modified Barth solution (containing 88 mM NaCl, 2.4 mM NaHCO3, 0.41 mM CaCl2, 0.82 mM MgSO4, 0.3 mM Ca2NO3, 0.1 mM gentamycin, and 15 mM HEPES, pH adjusted to 7.4) for 72 h.
A single defolliculated cell was positioned in a continuous-flow chamber with 0.5 mL volume perfused (5 mL/min) by Tyrode’s solution (containing 150 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgSO4, 10 mM dextrose, and 10 mM HEPES, pH adjusted to 7.4). Microelectrodes were pulled in one stage from capillary glass on a vertical computer-controlled electrode puller (Model 773; Campden Instruments Ltd., Bad Homburg, Germany). Electrode tips were broken to a diameter of approximately 10 µm, providing a resistance of 1–3 M
, and filled with 3 M KCl. The oocytes were voltage clamped with a two-electrode voltage clamp amplifier (OC725C; Warner Instruments Corp., New Haven, CT) connected to a personal computer for data acquisition and analysis (software programmed by J. Kardeous, PhD, University of Münster, Germany). All measurements were performed at a steady potential of -70 mV and recorded for 5 s before and 85 s after drug administration. The different concentrations of PGE2 were delivered as a 30-µL aliquot (Tyrode’s solution containing 0.1% fatty acid-free bovine serum albumin; Sigma Aldrich Chemie GmbH, Steinheim, Germany) during a period of 5 s. Intracellular injections were established as described previously (6,8) by a third electrode inserted into the oocyte. This electrode was connected to an automated microinjector (Nanoject).
For the different experiments, oocytes were exposed to bupivacaine solutions (dissolved in Tyrode’s solution) at different concentrations for 10 min. For the prolonged anesthetic administration, bupivacaine was dissolved in modified Barth solution for 24 h.
If not stated otherwise, all results are reported as mean ± SEM with n = 7. Differences among treatment groups were analyzed with Student’s t-test or the Mann-Whitney U-test. If multiple comparisons were made, analysis of variance was conducted, followed by a t-test corrected for multiple comparisons (Bonferroni). P < 0.05 was considered significant. Concentration-response curves were fit to the following logistic function, derived from the Hill equation: y = ymin + (ymax - ymin) x [1- xn/(x50n + xn)], where ymax and ymin are the maximum and minimum response obtained, n is the Hill coefficient, and x50 is the half-maximal effect concentration (EC50)/half-maximal inhibitory effect (IC50) (EC50 for agonist/IC50 for antagonist).
PGE2 was obtained from Sigma Aldrich Chemie GmbH and diluted in 0.1% fatty acid-free bovine serum albumin in Tyrode’s solution to appropriate concentrations. Collagenase A was acquired from Boehringer Mannheim GmbH (Mannheim, Germany). Inositol 1,4,5-trisphosphate (IP3), GTPS (a nonhydrolyzable guanosine triphosphate [GTP] analog that activates G proteins, irreversible because it cannot be dephosphorylated by the intrinsic GTPase activity of the subunit of the G protein), heparin, EDTA, and bupivacaine were obtained from Sigma Aldrich Chemie GmbH as well.
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Results |
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Although application of PGE2 to uninjected oocytes was without effect, its application to oocytes injected with 10 ng PGE2EP1 mRNA resulted in a transient inward Cl- current. Currents developed 1–3 s after agonist application, resulting in a peak current within 18–20 s, followed by relaxation over several seconds, which was superimposed by small fluctuations. Such responses were previously described as a typical response pattern for Cl- inward flux (ICl(Ca)) induced by G protein-coupled receptors in Xenopus oocytes (11). The responses to 1 µM PGE2 were 3.48 ± 0.43 µC (n = 26). The effect of PGE2 was concentration dependent. Curve fitting with the Hill equation revealed an EC50 of 2.09 ± 0.98 x 10-6 M and a Hill coefficient of 0.67 ± 0.15 (r2 = 0.97, Fig. 1).
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Comparing the original traces, integrals corresponding to a baseline on the one hand and peak currents on the other hand revealed only small differences between the calculated EC50 values. Integrals yielded an EC50 of 2.09 ± 0.98 x 10-6 M and a Hill coefficient of 0.67 ± 0.15 (r2 = 0.97), whereas peak currents showed an EC50 of 1.26 ± 1.30 x 10-7 M and a Hill coefficient of 0.48 ± 0.21 (r2 = 0.88). Thus, both values are useful for interpretation of our experiments. For these reasons and because the area under the curve tends to have smaller variance and better fitting values, we decided to use integrals (given in µC) in this investigation.
Low-molecular-weight heparin, despite its effect on phosphorylation and some second messenger systems, selectively blocks IP3 receptors. To determine whether the expressed PGE2EP1 receptors signaled through IP3 release, we injected 25 ng heparin into oocytes injected with mRNA encoding the EP1 receptor. PGE2 applied 10 min later induced only minute currents in these cells. Responses to 1 µM PGE2 were suppressed to 12% of control (0.49 ± 0.29 µC). In contrast, control injections with 150 mM KCl did not affect PGE2EP1 signaling (4.42 ± 1.49 µC). Thus, intracellular Ca2+ release induced by PGE2 application must be mediated mainly via IP3 (Fig. 2).
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To prove that Ca2+ mediates the PGE2EP1 signal, we injected EDTA (50.6 nL, 10 mM in KCl). Currents induced by PGE2 application reached <10% of control (0.26 ± 0.18 µC, control; injection of 150 mM KCl, 5.02 ± 1.45 µC; Fig. 2). Because EDTA has a high affinity for Mg as well, we tested the effect of intracellular injected BAPTA on PGE2EP1 signaling as well. BAPTA reduced the currents induced by PGE2 application to a similar degree as EDTA. The resting intracellular oocyte Ca2+ concentration was 10-7 M (12,13). The injection of 50.6 nL of 10-4 M CaCl2 enabled us to create a Ca2+ concentration of 10-5 M in the cytoplasm, which is regarded as the Ca2+ level reached by G protein-coupled receptors (9). The currents induced by intracellular injection of CaCl2 had the same size as the currents induced by application of the agonist at EC50 concentrations. The intracellular signaling pathway of PGE2EP1 receptors recombinantly expressed in Xenopus oocytes is shown in Figure 2C.
After confirming that the recombinant PGE2 receptors were working immaculately and that the intracellular cascade operated as described in the literature, we tested the effect of bupivacaine on PGE2EP1 receptor signaling. Bupivacaine at a concentration of 10-4 M reduced ICl(Ca) induced by PGE2 10-6 M to 30% of that measured on the same day in control cells (1.65 ± 0.56 µC, control 5.64 ± 1.32 µC). The inhibition by bupivacaine was concentration dependent. Curve fitting by using the Hill equation revealed an IC50 of 3.06 ± 1.26 x 10-6 M and a Hill coefficient of 0.48 ± 0.08 (Fig. 3). It is interesting to note that the IC50 concentration corresponds to concentrations measured in arterial blood samples during epidural anesthesia and analgesia as found during cesarean delivery and major orthopedic, cardiac, or abdominal surgery (14).
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To explore whether inhibition caused by bupivacaine is reversible, we exposed oocytes to bupivacaine’s IC50 for 10 min. The 10-min exposure led to reduced currents (1.94 ± 0.46 µC compared with control, 6.43 ± 0.82 µC). A complete recovery could be observed after 24 h in Barth solution with 7.32 ± 1.42 µC (Fig. 4A).
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Next, we determined whether prolonged exposure (24 h) of bupivacaine (1 µM) had a more pronounced inhibitory effect on PGE2EP1 receptor signaling than an exposure of 10 min. Control groups, not exposed to bupivacaine but cultured for a similar duration (4.43 ± 1.03 µC), were studied at the same time. Prolonged 24-h incubation in bupivacaine suppressed ICl(Ca) in response to PGE2 more (bupivacaine for 24 h, 0.95 ± 0.23 µC) than after 10 min incubation (bupivacaine for 10 min, 1.88 ± 0.62 µC) (P < 0.05).
If the inhibition by bupivacaine on PGE2EP1 receptors resulted from hydrophobic interactions at the ligand-binding pocket, we would expect a competitive interaction, which means that the concentration-response curve in the presence of bupivacaine would be parallel and shifted to the right. Additionally, the effect could be reversed by large agonist concentrations, so that Emax is not reduced. A noncompetitive inhibition would point to the interaction of bupivacaine with proteins somewhere else. Emax would be reduced and the gradient of the curve, corresponding to the calculated Hill coefficient, would be lowered.
Therefore, we determined the concentration-response relationship for ICl(Ca) induced by PGE2 in the presence of the IC50 of bupivacaine (3 x 10-6 M). Figure 4B demonstrates that the effect of bupivacaine is neither competitive nor noncompetitive. Emax is reduced by 23% of control, indicating a noncompetitive interaction. But the EC50 is parallel and shifted by one order of magnitude to the right, speaking for a competitive effect as well. Fitting variables are given in Table 1.
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Therefore, we wanted to identify the site of action of bupivacaine within the intracellular PGE2 signaling pathway. We activated segments of the intracellular pathway by injection of second messengers in the presence and absence of the anesthetic and after different incubation times (10 min and 24 h incubation).
IP3 releases Ca2+ from the endoplasmic reticulum, stimulating its specific receptor. We injected 50.6 nL of 2 mM IP3. This concentration induces currents of a magnitude corresponding to responses induced by receptor activation (6,9). Bupivacaine had no effect on currents induced by intracellularly injected IP3. Average responses in control cells were 8.24 ± 2.73 µC after 10 min and 24 h (7.13 ± 0.64 µC) in Barth’s solution. IP3-induced responses in cells exposed to bupivacaine for 10 min (9.27 ± 2.47 µC) and for 24 h (7.84 ± 1.24 µC) were not significantly different.
As control and to exclude that bupivacaine interferes with the Ca2+-dependent Cl- channels, we injected 50.6 nL of 100 µM CaCl2. After 24 h exposure to bupivacaine, mean currents (4.89 ± 1.60 µC) did not differ significantly from those of control cells (4.40 ± 0.54 µC). Both results indicate that bupivacaine most likely does not interfere with the intracellular signaling pathway downstream from IP3.
To investigate the signaling pathway upstream of the IP3 generation, we activated G proteins by intracellular injection of GTPS (6). We exposed oocytes to bupivacaine (IC50) for 10 min and for 24 h and compared them with cells that had been stored for the same time in Barth’s solution (control). After a 10-min incubation injection of 50.6 nL of 100 mM, GTPS induced ICl(Ca) in bupivacaine-exposed cells with 6.37 ± 1.40 µC. This was 76% of the mean current of the control cells (8.36 ± 1.52 µC). After 24 h, the current was significantly lowered to 37% of control (24 h bupivacaine, 2.80 ± 0.39 µC; control, 7.57 ± 0.18 µC; Fig. 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this investigation, we have shown that bupivacaine, at clinically relevant concentrations, inhibited the function of PGE2EP1 receptors. Bupivacaine affects the membrane receptor itself and also the intracellular pathway.
The PGE2EP1 receptor used in this investigation was cloned first in 1995 by Batshake et al. (15). It exhibits 83.8% identity to human PGE2EP1 receptors (15,16). In mice, the EP1 subtype is restricted to kidneys—resulting in natriuresis and diuresis accompanied by renin secretion (1,17)—and hypothalamus, whereas in humans its distribution and effects are more widespread (18). Macrophages and eosinophile and neutrophile granulocytes release PGE2 in inflammation-enhancing, edema-producing properties of bradykinin and histamine (18). This effect is mediated by the EP1 subtype tested in this study, which plays a key role in modulation of the immune response. PGE2 seems to have a dual excitatory/inhibitory effect on B cells, natural killer cells, macrophages, and T cells (18–20). PGE2EP1 is thought to be responsible for PGE2-induced fever and for its hyperalgesic effect by sensitizing pain receptors (4,19–22).
The PGE2EP1 receptor is a Gq protein-coupled receptor. Shibuya et al. (23), however, stated in 1999 that the Ca2+ release induced by stimulation of PGE2EP1 receptors in bovine adrenal medullary cells was due to ryanodine/caffeine-sensitive stores. In their model, Ca2+ release was unaffected by the IP3 blocker cinnarizine and the phospholipase-C inhibitor U-73122. In contrast to this finding (20,24), we were able to induce currents by IP3 injection and to suppress them by the IP3 blocker heparin (25).
We were able to inhibit 90% of the response by blockade of IP3 receptors with low-molecular-weight heparin. We confirm that the observed currents are dependent on Ca2+, because answers to PGE2 administration were suppressed by injection of EDTA, a substance that forms complexes with Ca2+ and thereby keeps it from activating the Cl- channel.
Bupivacaine inhibits PGE2EP1 signaling significantly with a half-maximal effect at 3.06 x 10-6 M. This is a concentration that is clinically relevant and observed during epidural anesthesia (14). The concentration-response curve of PGE2 under the influence of bupivacaine is parallel and shifted to the right; this most likely can be regarded as a result of hydrophobic competitive interactions between bupivacaine and PGE2 at the ligand-binding pocket. Emax is reduced to 77% of control, indicating a noncompetitive interaction as well. Thus, it is most likely that bupivacaine acts at the hydrophobic ligand-binding pocket and at another site within the intracellular signaling pathway.
For this reason, we injected Ca2+ and IP3 to explore whether induced currents are influenced by bupivacaine. However, the data did not reveal significant differences. It is interesting to note that ICl(Ca) caused by GTPS injection was not statistically significantly decreased after 10 minutes of incubation in the 3 µM bupivacaine solution. In contrast, ICl(Ca) induced by injection of GTPS was statistically significantly reduced after prolonged incubation in 1 µM bupivacaine (24 hours). The mechanism behind the acute inhibition (10 minutes of incubation) of PGE2EP1 receptor signaling is definitely different from the mechanism behind the prolonged effect of bupivacaine on the GTPS-induced Cl- currents. This indicates several possible mechanisms.
- Bupivacaine may hinder the subunit, irreversibly activated by GTPS, from stimulating phospholipase C. The release of second messengers would be inhibited.
- Bupivacaine may affect the G protein itself, e.g., by preventing the exchange from guanine diphosphate (GDP) by GTP, resulting in an indivisible G protein.
- Bupivacaine may affect the receptor not only at the ligand-binding pocket but also at its intracellular loops or the C-terminal end. Inhibition of its guaninnucleotid-releasing-protein function, which is responsible for the detachment of GDP from the G protein, could, as a result, cause stabilization of the GDP/G protein complex. If GDP is still present, GTP will not be able to activate the G protein.
Additional effects might be responsible for the time dependency of the effect of bupivacaine on GTPS-induced Cl- currents, e.g., changes in phosphorylation, effects at the gene level, or protein expression.
In summary, our data clearly show significant inhibition of PGE2 receptor functioning by bupivacaine at clinically relevant concentrations. There are at least two different mechanisms involved: an interaction at the ligand-binding pocket and another site of action within the intracellular signaling pathway. The effect is most likely due to modulation of G protein or phospholipase C function.
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Acknowledgments |
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Supported by the Ben Covino Award 1998 of the International Anaesthesia Research Society, sponsored by Astra Pain Control, Inc. (CWH) and by Innovative Medizinische Forschung (IMF I-6-II/97-27), Münster, Germany. Parts of the study have been supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany.
The authors thank F. Volkery for technical assistance, Dr. K. R. Lynch, PhD, for providing the PGE2EP1 receptor, and Joachim Kardaeus for programming the analyzing software. Special thanks to Marcel Durieux, MD, PhD, for the time he spent for my training during my stay in his lab at the University of Virginia.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Breyer MD, Zhang Y, Guan YF, et al. Regulation of renal function by prostaglandin E receptors. Kidney Int Suppl 1998; 67: S88–94.[Medline]
- Caggiano AO, Kraig RP. Prostaglandin E receptor subtypes in cultured rat microglia and their role in reducing lipopolysaccharide-induced interleukin-1beta production. J Neurochem 1999; 72: 565–75.[Web of Science][Medline]
- Oka T, Hori T, Hosoi M, et al. Biphasic modulation in the trigeminal nociceptive neuronal responses by the intracerebroventricular prostaglandin E2 may be mediated through different EP receptors subtypes in rats. Brain Res 1997; 771: 278–84.[Web of Science][Medline]
- Hosoi M, Oka T, Hori T. Prostaglandin E receptor EP3 subtype is involved in thermal hyperalgesia through its actions in the preoptic hypothalamus and the diagonal band of Broca in rats. Pain 1997; 71: 303–11.[Web of Science][Medline]
- Garry MG, Jackson DL, Geier HE, et al. Evaluation of the efficacy of a bioerodible bupivacaine polymer system on antinociception and inflammatory mediator release. Pain 1999; 82: 49–55.[Web of Science][Medline]
-
Sullivan LM, Honemann CW, Arledge JA, Durieux ME. Synergistic inhibition of lysophosphatidic acid signaling by charged and uncharged local anesthetics. Anesth Analg 1999; 88: 1117–24.
[Abstract/Free Full Text] - Nietgen GW, Honemann CW, Durieux ME. Influence of anesthetics on endogenous and recombinantly expressed G protein-coupled receptors in the Xenopus oocyte. Toxicol Lett 1998; 100–1:319–27.
- Honemann CW, Wong A, Arledge JA, Durieux ME. Chronic ethanol exposure enhances signaling through muscarinic receptors expressed by cRNA injection in Xenopus oocytes: implications for mechanism of action. Alcohol Clin Exp Res 1999; 23: 791–8.[Web of Science][Medline]
- Honemann CW, Nietgen GW, Podranski T, et al. Influence of volatile anesthetics on thromboxane A2 signaling. Anesthesiology 1998; 88: 440–51.[Web of Science][Medline]
- Honemann CW, Arledge JA, Podranski T, et al. Volatile and local anesthetics interfere with thromboxane A2 receptors recombinantly expressed in Xenopus oocytes. Adv Exp Med Biol 1999; 469: 277–83.[Web of Science][Medline]
- Durieux ME. Halothane inhibits signaling through m1 muscarinic receptors expressed in Xenopus oocytes. Anesthesiology 1995; 82: 174–82.[Web of Science][Medline]
- Lechleiter JD, Clapham DE. Molecular mechanisms of intracellular calcium excitability in X. laevis oocytes. Cell 1992; 69: 283–94.[Web of Science][Medline]
-
Takahashi A, Camacho P, Lechleiter JD, Herman B. Measurement of intracellular calcium. Physiol Rev 1999; 79: 1089–125.
[Abstract/Free Full Text] - Downing JW, Johnson HV, Gonzalez HF, et al. The pharmacokinetics of epidural lidocaine and bupivacaine during cesarean section. Anesth Analg 1997; 84: 527–32.[Abstract]
- Batshake B, Nilsson C, Sundelin J. Molecular characterization of the mouse prostanoid EP1 receptor gene. Eur J Biochem 1995; 231: 809–14.[Web of Science][Medline]
-
Funk CD, Furci L, FitzGerald GA, et al. Cloning and expression of a cDNA for the human prostaglandin E receptor EP1 subtype. J Biol Chem 1993; 268: 26767–72.
[Abstract/Free Full Text] -
Breyer MD, Davis L, Jacobson HR, Breyer RM. Differential localization of prostaglandin E receptor subtypes in human kidney. Am J Physiol 1996; 270: F912–8.
[Abstract/Free Full Text] - Coleman RA, Smith WL, Narumiya S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 1994; 46: 205–29.[Web of Science][Medline]
- Baxter GS, Clayton JK, Coleman RA, et al. Characterization of the prostanoid receptors mediating constriction and relaxation of human isolated uterine artery. Br J Pharmacol 1995; 116: 1692–6.[Web of Science][Medline]
- Coleman RA, Eglen RM, Jones RL, et al. Prostanoid and leukotriene receptors: a progress report from the IUPHAR working parties on classification and nomenclature. Adv Prostaglandin Thromboxane Leukot Res 1995; 23: 283–5.[Web of Science][Medline]
- Safieh-Garabedian B, Dardenne M, Kanaan SA, et al. The role of cytokines and prostaglandin-E(2) in thymulin induced hyperalgesia. Neuropharmacology 2000; 39: 1653–61.[Web of Science][Medline]
- Hamilton SG, Wade A, McMahon SB. The effects of inflammation and inflammatory mediators on nociceptive behaviour induced by ATP analogues in the rat. Br J Pharmacol 1999; 126: 326–32.[Web of Science][Medline]
- Shibuya I, Tanaka K, Uezono Y, et al. Prostaglandin E2 induces Ca2+ release from ryanodine/caffeine-sensitive stores in bovine adrenal medullary cells via EP1-like receptors. J Neurochem 1999; 73: 2167–74.[Web of Science][Medline]
- Asboth G, Phaneuf S, Europe-Finner GN, et al. Prostaglandin E2 activates phospholipase C and elevates intracellular calcium in cultured myometrial cells: involvement of EP1 and EP3 receptor subtypes. Endocrinology 1996; 137: 2572–9.[Abstract]
-
Parys JB, Sernett SW, DeLisle S, et al. Isolation, characterization, and localization of the inositol 1,4,5-trisphosphate receptor protein in Xenopus laevis oocytes. J Biol Chem 1992; 267: 18776–82.
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