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Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville, VA 22906-0010
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Summary |
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Summary
Introduction
Materials & Methods
Results
Discussion
References
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Nitric oxide (NO) is an important biological messenger involved in the regulation of blood vessel tone, neurotransmission, inflammatory responses, and host defenses. Inhalational anesthetics have been shown to inhibit the function of the NO signaling pathway in a variety of tissues. In addition, acute inhibition of the NO signaling pathway significantly reduced the required alveolar concentration of halothane or isoflurane for anesthesia, which suggests a role for the NO signaling pathway in mechanisms of anesthesia and consciousness. We now report that inhalational anesthetics affect gene expression of nitric oxide synthases (NOS) (EC 1.14.13.39), the enzymes that synthesize NO from L-arginine. Both halothane and isoflurane, at clinically relevant concentrations, significantly up-regulate the mRNA, protein, and activity level of NOS in lipopolysaccharide-treated macrophages (inducible NOS; type II NOS), and bovine pulmonary endothelial cells (endothelial constitutive NOS; type III NOS). This is a novel interaction between inhalational anesthetics and the NO signaling pathway and has wide-ranging implications for both clinical medicine and experimental biology.
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Introduction |
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Summary
Introduction
Materials & Methods
Results
Discussion
References
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NO
is a novel cell-signaling molecule that has been demonstrated to be
involved in a variety of physiological and pathophysiological processes
(1-6). Two types of enzymes, constitutive and inducible NOS (EC 1 14.13.39), are found to be responsible for the production of NO
in vivo. Two constitutive NOS isoforms are known, one of which was found originally in endothelial cells and the other was found
originally in neurons. Both isoforms require calcium, calmodulin,
-NADPH, FAD, flavin mononucleotide, and tetrahydrobiopterin as
cofactors for activation (7). iNOS (type II NOS) is inducible in many
cell types, such as macrophages and smooth muscle cells in response to
LPS and cytokines, and also requires -NADPH, FAD, flavin
mononucleotide, and tetrahydrobiopterin, but not calcium and calmodulin
as cofactors for activation (7). Therefore, iNOS will produce NO
continuously once it is induced, whereas constitutive NOS activity is
regulated by intracellular Ca2+ level. It is
believed that iNOS has a significant role in immune responses, where it
has been implicated in killing tumor cells and microbes, and the
development of inflammatory responses and septic shock (8). eNOS (type
III NOS) is primarily involved in the regulation of blood vessel tone
and is implicated in mechanisms of a wide range of cardiovascular
diseases (8).
Halothane and isoflurane, two widely used inhalational anesthetics, have been demonstrated to inhibit the function of the NO signaling pathway in blood vessels and brain (9, 10). We have shown that the inhibition of NOS dose-dependently and significantly decreased the required alveolar concentration of halothane or isoflurane for anesthesia, demonstrating a possible role for NO in consciousness (6). Therefore, the inhibitory effect of inhalational anesthetics on the function of the NO signaling pathway may be a mechanism of anesthesia and of the side-effects of these inhalational anesthetics. However, one potential target of anesthetic action, gene expression within cells, has been largely neglected. Indeed, both pentobarbital and halothane have been demonstrated to have selective effects on the gene expression of c-fos, and jun-B, two protooncogene members, in rat brain (11). Our current study, using cultured mouse macrophages and BPAEC, addresses the hypothesis that inhalational anesthetics may alter NOS expression.
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Materials and Methods |
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Summary
Introduction
Materials & Methods
Results
Discussion
References
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All reagents and materials were obtained from Sigma Chemical (St. Louis, MO) unless specified in the text.
Cell culture. Mouse macrophages and BPAEC were cultured in glass roller bottles (850 cm2; Wheaton, Millville, NJ) to provide a model to study the expression of iNOS and eNOS. Glass bottles with Teflon caps were used to avoid the possible absorption or interaction of anesthetics by plastic bottles.
Mouse RAW 264.7 macrophages were obtained from the American Type Culture Collection (Rockville, MD), and cultured in RPMI 1640 (Gibco/BRL, Grand Island, NY) containing 10% fetal bovine serum. BPAEC were isolated, characterized, and cultured as we described previously (12). In summary, endothelial cells were sorted out by fluorescence-activated cell sorting using acetylated low-density lipoprotein as the fluorescent marker. They were then further identified by: 1) typical cobblestone morphology; 2) antibody staining for factor VIII antigen; and 3) demonstrating a single mRNA for endothelial cell-actin by Northern blot and the absence of
immunostaining for 
-actin by immunocytochemistry. The cells were
cultured in medium 199 containing 10% fetal bovine serum, 2.4 µg/ml
thymidine, 100 units/ml penicillin, and 100 µg/ml streptomycin.
Incubation. Only confluent mouse RAW 264.7 macrophages (passage 20 to 36) or BPAEC (passage 9 to 12) were used in the experiments. Macrophages were incubated with LPS (100 ng/ml) in the presence or absence of 2% isoflurane (Ohmeda Caribe, Liberty Corner, NJ) for 0.5, 1, 3, 7, 15, and 24 hr at 37° in RPMI 1640 containing 1% fetal bovine serum. Endothelial cells were incubated with or without 2% isoflurane for 0.5, 1, 3, 7, 15, and 24 hr at 37° in the endothelial cell culture medium. In another set of experiments, BPAEC or LPS-activated macrophages were incubated with 2% halothane (Halocarbon Laboratories, Hackensack, NJ) for 7 hr at 37° in the respective incubation medium as used in isoflurane experiments.
Northern analysis. Total RNA from both macrophages, and endothelial cells was purified using TRIREAGENT (MRC, Cincinnati, OH), and the method of Chomczynski (13). Twenty micrograms of total RNA per sample was analyzed using standard Northern blot and hybridization techniques with cDNA probes (14). The eNOS cDNA clone was from Dr. Sessa (Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT) (15). The iNOS cDNA clone was from Drs. Xie and Nathan (Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, NY) (16). cDNA probes were labeled with 32P using a random primed labeling kit (Boehringer Mannheim, Indianapolis, IN) (17). The blot was also hybridized with an 18S rRNA oligonucleotide probe labeled with 32P using a terminal transferase system (Boehringer Mannheim) (18) to normalize the iNOS and eNOS mRNA data for RNA loading and transfer. Bands were quantified using a PhosphorImager and IMAGEQUANT software (Molecular Dynamics, Sunnyvale, CA).
Western analysis. Western blot of cell homogenates was performed as detailed by North et al. (19). Cell homogenates were prepared by homogenizing the cells in 25 mM Tris·HCl, pH 7.4, containing 1 mM EDTA, 1 mM EGTA, 0.1% (v/v) 2-mercaptoethanol, 1 mM phenylmethylsulfonyl fluoride, 2 µM leupeptin, and 1 µM pepstatin A, and then centrifuging the crude homogenates at 1000 × g for 10 min at 4°. Fifteen or thirty micrograms of total protein per lane was used for iNOS or eNOS studies, respectively. Mouse anti-iNOS IgG2a monoclonal antibody and mouse anti-eNOS IgG1 monoclonal antibody were from Transduction Laboratories (Lexington, KY). The intensity of the autoradiographic bands was quantitated by densitometry (Personal Densitometer/IMAGEQUANT; Molecular Dynamics).
Nitrite analysis. The culture media were collected from the glass roller bottles of the cultured cells used to produce the Northern and Western blots of Figs. 1 and 4. The nitrite level in the medium was measured by a fluorometric assay detailed by Misko et al. (20). The samples were read with excitation at 365 nm and emission at 450 nm. To confirm that the accumulation of nitrite in the roller bottles reflected the NOS activity of the cells, LPS-activated macrophages or BPAEC were incubated with various combinations of agents including 2% isoflurane, L-NAME, 1.0 mM L-arginine, and 1.0 mM D-arginine for 7 hr at 37°. The culture media were then collected for measurements of nitrite accumulation.
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Statistical analysis. Results are presented as mean ± standard error in the bar graphs. Statistical analysis was performed by Student t test. p < 0.05 was accepted as significant (21).
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Results |
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Summary
Introduction
Materials & Methods
Results
Discussion
References
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The level of mRNA and protein for NOS in the LPS-activated
macrophages and BPAEC were detected by Northern and Western blot analysis, respectively. Northern analysis detected a single iNOS band
at 4.2 kilobase pairs in activated macrophages, and a single eNOS band
at 4.5 kilobase pairs in BPAEC. Western blot analysis found a 130-kDa
iNOS protein in activated macrophages and a 140-kDa eNOS protein in
BPAEC. No eNOS mRNA or protein band was detected in activated
macrophages, and no iNOS mRNA or protein band was detected in BPAEC.
Isoflurane caused a significant increase in the level of mRNA and
protein of both iNOS and eNOS. Activated macrophages incubated with 2%
isoflurane for longer than 3 hr expressed significantly more iNOS mRNA
than the corresponding control cells (Fig.
1A). However, if macrophages are not
activated, inhalational anesthetics alone did not induce iNOS
expression (data not shown). The BPAEC incubated with 2% isoflurane
for longer than 7 hr expressed significantly more eNOS mRNA than their
respective control cells (Fig. 1C). This up-regulation of mRNA was the
same regardless of whether 18S rRNA (as presented here) or -actin or
glyceraldehyde-3-phosphate dehydrogenase (data not shown) was used as
the loading control. Consistent with this up-regulation of mRNA, 2%
isoflurane greatly increased the level of iNOS protein in activated
macrophages after 3 hr of incubation and slightly but significantly
increased the level of eNOS protein in BPAEC after 7 hr of incubation
(Fig. 1, B and D).
To confirm that this up-regulation of NOS mRNA and protein led to functional NO production, NO synthesis by iNOS or eNOS in activated macrophages or BPAEC was quantified by measuring the accumulation of nitrite (the NO oxidation product) in the conditioned culture medium (22). Consistent with the temporal pattern of the up-regulation of NOS mRNA, and protein, macrophages, and BPAEC incubated with 2% isoflurane for longer than 7 hr produced significantly more nitrite than the corresponding control cells (Fig. 2). This increased nitrite production is caused by NOS because 0.1 mM L-NAME, a specific NOS inhibitor, abolished this increase and 1 mM L-arginine but not D-arginine reversed this inhibition by L-NAME (Fig. 3). These results suggest that the up-regulation of NOS mRNA and protein caused by isoflurane leads to enhanced NO production.
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The effect of halothane on NOS expression has also been investigated. Similar to the effect of isoflurane, 2% halothane, after incubating with the cells for 7 hr, significantly increased the level of mRNA and protein for iNOS in activated macrophages and for eNOS in BPAEC (Fig. 4). This up-regulation of mRNA and protein level by halothane was also functionally expressed by the increase of nitrite accumulation in the conditioned culture medium of both activated macrophages and endothelial cells (Fig. 5).
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Discussion |
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Summary
Introduction
Materials & Methods
Results
Discussion
References
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NO has been implicated in the function of macrophages to kill tumor cells and microbes (8). We now show that inhalational anesthetics increased iNOS expression and NO production in activated macrophages. These results suggest that inhalational anesthetics may have a significant effect on the NO-related functions of the immune system. Consistently, both in vivo and in vitro studies have demonstrated that inhalational anesthetics significantly affect humoral and cell-mediated immunity (23, 24). The fact that anesthetics potentiate the induction of iNOS by LPS is of great clinical significance because inhalational anesthetics are commonly administered to patients with sepsis and patients with acute inflammatory lesions (e.g., adult respiratory distress syndrome, pneumonia, and inflammatory bowel disease) when iNOS is likely to be up-regulated.
Inhalational anesthetics have been demonstrated to significantly inhibit the function of the eNOS signaling pathway (9, 25), although there is some controversy; under some circumstances, inhalational anesthetics may enhance endothelium-dependent vasodilation (26). Our current study showed a novel interaction between inhalational anesthetics and the eNOS signaling pathway. This may be one of the mechanisms by which inhalational anesthetics cause vessel relaxation in the clinical setting.
Apart from their roles in the immune and cardiovascular systems, iNOS and eNOS have been suggested to have other functions. For example, iNOS can be induced in vascular smooth muscle cells, fibroblasts, and myocytes of the cardiovascular system and astrocytes and other glial cells in the central nervous system (7, 27). iNOS has also been implicated in mechanisms of hyperalgesia in the spinal cord (28). eNOS has been implicated in the pathogenesis of several disease states such as diabetes, ischemic heart disease, hypertension, and myocardial ischemia-reperfusion injury (27, 29). Therefore, our novel observations may have multiple important physiological and pathophysiological implications. Furthermore, as many studies of the NO signaling pathway are performed in animals anesthetized with inhalational anesthetics, this novel action of anesthetics may significantly alter the outcome of those studies.
The mechanisms for the up-regulation of NOS expression by inhalational
anesthetics are not known; they may be mediated through alterations in
the rate of transcription and/or stability of the mRNA. The cloning and
analysis of the promoter regions for iNOS and eNOS have revealed the
potential for a complex array of transcription factor interactions with
these promoters (30-33). Both iNOS and eNOS promoters have AP-1 and
p53 sites. Other PKC responsive cis-elements, including the
serum response element of the c-fos gene, the nuclear factor-
B binding site, and the AP-2 binding site are present in the
promoters of NOS isoforms (30-33). Because inhalational anesthetics
have been shown to activate PKC, and PKC up-regulates NOS (34, 35),
this would be one potential mechanism of NOS up-regulation by
anesthetics. Inhalational anesthetics have also been shown to increase
the level of interleukin-1 in the culture medium of human lung
macrophages (36). Interleukin-1 induces iNOS expression in
macrophages (37). Thus, this may be a mechanism by which inhalational
anesthetics up-regulate iNOS expression. In addition, NO has been
demonstrated to down-regulate NOS gene expression (38). Because
inhalational anesthetics clearly inhibit NO production and the NO
signaling pathway (9), this may therefore prevent the inhibitory effect
of NO on NOS gene expression, accounting for the up-regulation of NOS
expression induced by anesthetics. The mechanism of NOS gene regulation
by inhalational anesthetics, however, awaits further investigation, and
detailed analysis of anesthetic interactions with the 5
-flanking
regions of the NOS isoforms.
Intravenous anesthetics, such as pentobarbital, have been demonstrated to alter the expression of many genes (39). There has been lack of systematic investigation, however, of the effects of inhalational anesthetics on gene expression. Perhaps it has been overshadowed by the concept that changes in gene expression occurred slowly and, therefore, could not be important for a highly dynamic phenomenon such as neuronal information processing or cardiovascular hemodynamics and the changes anesthesia produces in them. However, evidence suggests that anesthetics can regulate gene expression in rats, which, after inhaling halothane for 2 hr, express significantly lower levels of jun-B mRNA in their cerebral tissue compared with the controls (11). It is notable from our study that the effect of up-regulation of eNOS, and LPS-induced inducible NOS is apparent after three or more hours of exposure to isoflurane. This is consistent with the typical time course of changes in gene expression. Three hours may be a long exposure time for many surgeries. However, anesthetics are very frequently administered in excess of 3 hr for numerous surgical procedures including major vascular surgery, hepatic surgery, major brain surgery, organ transplantation, etc. Knowledge of the multiple physiologic actions of NO suggests that NOS up-regulation could have many highly significant effects on the postoperative state including wound healing, inflammatory responses, metabolism, vascular responsiveness, renal function, and reperfusion following vascular clamp release, and organ transplantation.
In summary, we demonstrated that halothane and isoflurane, two inhalational anesthetics very commonly used in clinical medicine and in laboratory animal experimentation, increased the mRNA, protein, and activity level of iNOS and eNOS in cultured cells at clinically relevant concentrations. This represents a novel site of interaction between inhalational anesthetics, and the highly important NO signaling pathway and may contribute significantly to the physiological and pathophysiological changes after exposure to inhalational anesthetics.
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Acknowledgments |
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We are grateful to Ms. A. Tichotsky, and N. Zhou for technical assistance, Dr. T. Le Cras for advice with Northern blotting procedures, and Dr. L. V. Ravichandran for helpful discussion.
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Footnotes |
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Received December 20, 1996; Accepted June 20, 1997
This study was supported by National Institutes of Health Grants R01-GM49111, and R01-HL39706
Send reprint requests to: Dr. Roger A. Johns, Department of Anesthesiology, P.O. Box 10010, University of Virginia Health Sciences Center, Charlottesville, VA 22906-0010. E-mail: raj2d{at}virginia.edu
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Abbreviations |
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NO, nitric oxide;
NOS, nitric oxide
synthase;
BPAEC, bovine pulmonary artery endothelial cells;
eNOS, endothelial constitutive nitric oxide synthase;
iNOS, inducible nitric
oxide synthase;
L-NAME, nitroG-L-arginine-methyl-ester;
LPS, lipopolysaccharide;
PKC, protein kinase C;
EGTA, ethylene glycol
bis(-aminoethyl
ether)-N,N,N,N-tetraacetic
acid.
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References |
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Summary
Introduction
Materials & Methods
Results
Discussion
References
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