1 Cátedra de Fisiología, Faculta de Odontología, Universidad de Buenos Aires, 1122; 2 Centro de Estudios Farmacológicos y Botánicos Consejo Nacional de Investigaciones Científicas y Técnicas, 1414 Buenos Aires, Argentina; and 3 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808-4124
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ABSTRACT |
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Inducible (calcium-independent) nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are important in the regulation of the function of different organs during infection. A single dose of lipopolysaccharide (LPS; 5 mg/kg ip) within 6 h increased NOS activity (20%) and prostaglandin E (PGE) content (100%) in submandibular glands (SMG) and blocked stimulated salivary secretion in adult male rats. The administration of an iNOS synthesis inhibitor, aminoguanidine (AG), with LPS decreased NOS activity and PGE content. Furthermore, the administration of meloxicam (MLX), an inhibitor of COX-2, blocked the increase in PGE and the production of NO. The incubation of slices of SMG in the presence of 3-morpholinosydnonimine, a donor of NO, increased the release of PGE highly significantly. The incubation of SMG in the presence of a PGE1 analog (alprostadil) increased the production of NO. These results indicate that LPS activates NOS, leading to NO release, which activates COX, generating PGEs that act back to further activate NOS, causing further generation of PGEs by activation of COX. Because the alprostadil administration inhibited stimulated salivation, LPS-induced inhibition of salivation appears to be caused by increased PGE production. Diminished salivary secretion produces poor oral health; thus the use of COX-2 inhibitors to counteract the effects of inhibited salivation should be considered.
nitric oxide synthase; cyclooxygenase; noradrenaline; methacholine; endotoxemia
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INTRODUCTION |
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THE SUBMANDIBULAR GLAND (SMG) is one of the major salivary glands, together with the parotid and sublingual glands. The initial saliva is secreted by acini into the terminal end of the ducts and drains into the intercalated ducts, which are succeeded by granular convoluted tubules (GCT). The cells in GCT are characterized by numerous serous-type secretory granules in their cytoplasm. These granules are the repositories of a variety of bioactive substances, including both nerve growth factor and epidermal growth factor and peptidases kallikrein and renin. In the rat, these GCT are succeeded by striated ducts, the appearance of which is due to vertically oriented mitochondria alternating with highly folded plasma membranes. In the rat, the main cells of these ducts are filled with granules. Finally, the striated ducts empty into the excretory ducts (17).
The secretion of saliva is controlled by the autonomic nervous
system. The parasympathetic nervous system is the main controller of
this secretion via impulses in the chorda tympani nerve that innervate
it and release acetylcholine, which evokes copious salivary secretion
by activating muscarinic receptors. The sympathetic nervous system
controls salivary secretion by also acting on - and
-adrenergic receptors.
Nitric oxide (NO) controls the function of many organs of the body (11, 19). Nitric oxide synthase (NOS) is present in nerve terminals that are widely distributed in various parts of the SMG (8). We (10) demonstrated that NO plays a role in the control of salivary secretion. Indeed, we found that inhibition of NOS activity by NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) injected intravenously in rats before stimulation of salivary secretion with methacholine (MC) significantly inhibited the secretion of saliva. The SMG contains all three isoforms of NOS: calcium-dependent neural (n)NOS, endothelial (e)NOS, and calcium-independent, inducible NOS (iNOS), as visualized by immunohistochemistry (10).
Because saliva is the first barrier to the entry of bacteria and viruses into the body, we wished to evaluate the effects of infection, as mimicked by injection of bacterial lipopolysaccharides (LPS), on salivary secretion and on the activity of NOS in the SMG. It is well known that prostaglandins (PGs) also play a very important role in inflammation (18) and are induced by NO, which activates cyclooxygenase (COX) (13). Therefore, we also evaluated the role of PGs in the response of the gland to LPS. Furthermore, because it has been shown that NO stimulates the release of PGE (14) in the hypothalamus, we decided to study also the possible interaction between NO and PGs in the SMG by the use of specific inhibitors of iNOS and COX-2 in vivo and also by a direct action of a donor of NO on PGE release and of an analog of PGE1 on NO production by SMG incubates in vitro.
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MATERIAL AND METHODS |
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Chemicals. Norepinephrine (NE)-HCl, bacterial LPS (Escherichia coli serotype 055:B5), HEPES, L-valine, CaCl2, aminoguanidine (AG), antiserum anti-PGE, standard prostanoids, and 3-morpholinosydnonimine (SIN-1) were purchased from Sigma Chemicals (St. Louis, MO). Chloralose and methacholine (MC) were obtained from FLUKA (Laborchemikalien, Berlin, Germany). [3H]PGE and [14C]arachidonic acid were purchased from New England Life Science (Boston, MA). [14C]arginine was purchased from Amersham Pharmacia Biotech (Piscataway, NJ). AG-50W-X8 resin was obtained from Bio-Rad Laboratories (Hercules, CA). Alprostadil was obtained from Upjohn (Puurs, Belgium). Nitroglycerine was purchased from FADA (Buenos Aires, Argentina). Meloxicam (MLX) was obtained from Boehringer Ingelheim (Buenos Aires, Argentina). All solvents were of analytical grade.
Salivary secretion studies. Male Wistar rats (250-300 g) from our own colony were housed under standard conditions (12:12-h light-dark cycle at 22-25°C) and with free access to rat chow and tap water. Food was removed 14 h before experimental procedures to decrease variation in salivary secretion.
Salivary responses were determined in anesthetized rats [chloralose 100 mg · kgEffect of LPS and MLX on salivary secretion.
To study the effect of LPS on salivary secretion, the rats were
injected with LPS (5 mg · kg1 · 0.5 ml
1 ip) or NaCl 0.9% (saline) 6 h before
cannulation of the duct and measurement of salivary secretion with
increasing doses of the different sialogogues such as NA or MC (1, 3, 10, and 30 µg/kg in saline). In another series of experiments, the
rats were injected with LPS and MLX (0.5 mg · kg
1 · 50 µl
1 im in
saline solution) or MLX alone to evaluate the participation of
increased PGs due to induction of COX-2 by LPS on salivary secretion.
Effect of nitroglycerine or alprostadil on salivary secretion. To investigate the role of NO or PGE on salivary secretion, rats were injected intravenously with different sialogogues at the same dose every 5 min. MC or NA were injected at a dose of 10 µg/kg every 5 min. Nitroglycerine (100 mg/kg iv) or alprostadil (a PGE analog, 2.5 µg/kg iv) was injected just before injection of the second pulse of MC or NA. All of the results are expressed as mean weight of saliva secreted per rat (± SE).
Determination of NOS activity. A modification (2) of the method of Bredt and Snyder, which measures the conversion of [!4C]arginine into [14C]citrulline, was used. The method indirectly measures NO production, an index of NOS activity. Because the SMG has an active urea cycle in the tissue, arginine will also be converted to citrulline by this cycle, thereby giving false high values for NOS activity. This problem was obviated by addition of L-valine (25 mM) to the HEPES buffer for homogenization and incubation to block the arginase of the urea cycle. The details of the method used were published previously (10).
Measurements of PGE content in SMG. PGE content of the SMG was measured by specific RIA as a determinant of COX activity as described elsewhere (3).
Measurements of radioconversion of [14C]arachidonic acid to prostanoids in SMG. These measurements were performed by chromatography of ethyl acetate extracts and counting of the labeled prostanoids as previously reported (4). The area of each of the radioactive peaks corresponding to authentic prostanoids was calculated and expressed as a percentage of the total radioactivity of the plates.
In vitro studies. The animals were killed by cervical dislocation, and the salivary glands were removed. One-millimeter-thick sliced SMG were preincubated in Krebs-Ringer-bicarbonate buffer medium (pH 7.4) containing 0.1% glucose for 15 min before replacement with fresh medium containing the compounds to be tested. The incubation was continued for 30 min, after which the media were extracted for PGE determination, or the SMG were homogenized for NOS determination.
PGE extraction from incubation media.
Incubation media were acidified to pH 3 with 1 N HCl and extracted
three times with one volume of ethyl acetate. The extracts were dried
in a centrivap at room temperature. These residues were stored at
70°C until RIA was performed.
Statistics.
The statistical evaluation of the salivary secretion studies was
performed by calculating the differences in salivation before and after
the administration of nitroglycerine or alprostadil to each animal.
Each point was evaluated by paired t-test, and P
values 0.05 were considered statistically significant. For the
statistical evaluation for in vitro studies when two groups were
compared, Student's t-test was used and P values
0.05 were considered statistically significant. In all other studies,
comparisons between groups were performed by ANOVA and
Student-Newman-Keuls tests, with P values
0.05 considered
statistically significant.
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RESULTS |
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Effect of LPS on salivary secretion.
Injection of LPS (5 mg/kg ip) to induce endotoxemia produced a highly
significant inhibition of salivary secretion stimulated by NE or MC
(Fig. 1, A and B).
At a dose of 10 µg/kg of NE or MC, LPS reduced salivation 62 and
59%, respectively. At a dose of 30 µg/kg, this reduction was 82 and
72%, respectively.
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Effect of LPS on SMG NOS activity.
Administration of LPS (5 mg/kg) 6 h before the animals were killed
induced a 20% increase (P < 0.05) of NOS activity in
the SMG (Fig. 2).
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Effect of LPS on PGE content in SMG.
Because we previously found that NO played a stimulatory role in
salivary secretion (10), we proposed that there must be another molecule mediating salivary inhibition by LPS; therefore, we
focused on a possible role of PGs in salivary secretion. Indeed, LPS
injection produced an increase in SMG PGE content detectable at 1 h, and values remained elevated for 6 h postinjection
(P < 0.001; Fig. 3).
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Effect of LPS plus AG or MLX on NOS activity in SMG. Because AG has been shown to be a specific inhibitor of iNOS in vitro (6) and in vivo (21), we injected AG (20 mg/kg ip) 2 min before injection of LPS and measured the activity of NOS in the SMG at the same time (6 h) as for LPS alone (Fig. 2). In another series of experiments, animals were injected with MLX (0.5 mg/kg im), a known COX-2 inhibitor, or with MLX followed by LPS, as described in Effect of LPS and MLX on salivary secretion. The administration of AG together with LPS prevented the increase of NOS activity (P < 0.05) compared with the LPS group. MLX unexpectedly also inhibited LPS-stimulated NOS activity.
Effect of LPS and LPS plus AG or MLX on radioimmunoassayable PGE
content in SMG.
Injection of LPS dramatically increased PGE content at 6 h by
100% (P < 0.001; Fig.
4). The injection of AG or MLX just
before LPS prevented this increase induced by LPS on SMG PGE content.
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Effect of LPS and LPS plus AG or MLX on COX as measured by
radioconversion of [14C]arachidonic acid to prostanoids
by SMG.
The radioconversion assay of [14C]arachidonic acid that
indirectly measures COX activity by measuring arachidonate metabolites such as 6-keto-PGF1, PGF2
, and
PGE2 gave similar results to those observed when PGE
content of the SMG was measured by RIA. The results were expressed as a
percentage of total counts per minute of a particular prostanoid on
plate per 100 milligrams wet weight of the SMG. The increase in PGE
induced by LPS was significantly greater (P < 0.05)
compared with the other groups (Fig. 5).
Similar results were obtained for 6-keto-PGF2
and PGF1
.
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Effect of NO on salivary secretion.
To determine whether NO itself stimulates salivary secretion, we
injected an NO donor, nitroglycerin (100 mg/kg iv). The injection of
nitroglycerin alone had no significant effect on salivary secretion; therefore, we used NE or MC as sialogogues. NE or MC was injected at a
dose of 10 µg/kg every 5 min during 20 min. Nitroglycerin (100 mg/kg)
was injected just before the second injection of NE or MC. There was a
significant potentiation of salivary outflow by nitroglycerine after
administration of NE or MC that was of very short duration and was not
significant in the next stimulation (Fig.
6, A and B).
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Effect of a PGE1 analog on salivary secretion.
Because we have found (9) that NO augments
stimulated salivary secretion and that the administration of LPS,
which increases NOS activity with higher production of NO,
paradoxically produced an almost total abolition of stimulated salivary
secretion, we hypothesized that this inhibition could be caused by an
inhibitory effect of PGs. Therefore, we stimulated salivary secretion
by NE or MC, as previously described (10) and
injected the PGE1 analog (alprostadil 2.5 µg/kg). The
injection of the analog dramatically (P < 0.01) and
irreversibly inhibited the NA- and MC-stimulated salivary secretion
(Fig. 7, A and B).
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Cross talk between NO and PGE in SMG.
To clarify the possible interaction between NO and PGE, in vitro
experiments were performed by incubating sliced SMG in the presence of
SIN-1 (a well-known donor of NO), and PGE release was measured. The
addition of SIN-1 (300 µM) to the incubation media for 30 min
increased the release of PGE (Fig.
8A). On the other hand, the
addition of alprostadil, a PGE1 analog, significantly increased the activity of NOS (P < 0.001; Fig.
8B).
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Effect of LPS ± MLX on salivary secretion.
After injection of LPS, NE and MC were unable to stimulate salivary
secretion, as shown in Fig. 1, A and B.
LPS augmented PG production in the SMG, and intravenously injected PGE
decreased salivary secretion. In view of these results, we tried to
reverse the inhibitory effect of LPS on salivary secretion by
coinjecting MLX at the same time. LPS inhibition of salivary secretion
could be partially reversed by MLX (Fig.
9, A and B), but
MLX alone had no effect on stimulated salivary secretion. The
inhibitory effect of LPS on both NE- and MC-stimulated salivary
secretion was reversed only by MLX.
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DISCUSSION |
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The results of our previous research (10) and those
reported here establish a role of NO and PGE in salivary secretion in both physiological and pathological conditions. Our previous results showed that inhibitors of NOS such as L-NAME or
L-NMMA inhibit salivary secretion induced by muscarinic
cholinergic agonists, substance P, NA, and the -adrenergic agonist
isoproterenol. These were confirmed by others (12) in
another experimental paradigm. Furthermore, in the present study, we
found that a donor of NO, nitroglycerine, increases the stimulatory
action of sialogogues. NO has a relatively small role, at least in the
anesthetized rat, because the effect of nitroglycerine is relatively
small and NOS inhibitors only partially reduced the effects of
secretagogues. In the pancreas, an organ structurally and functionally
similar to the SMG, NO also plays a stimulatory role in the
stimulated exocrine secretion (7).
Because saliva contains many compounds important to combating invading organisms, it was important to study the effect of LPS on salivary secretion. The same dose of LPS shown previously to produce a massive increase in iNOS mRNA and iNOS content in the anterior pituitary and pineal glands (19) increased the number of iNOS-containing macrophages in the SMG and increased total NOS activity (15). In the present study, although there was an increase in NOS activity in SMG by LPS, the salivary secretion, instead of being increased as we expected, was completely blocked. We found that LPS dramatically increased PGs in SMG as measured by RIA and radioconversion, which showed that there was an increased activity of COX. Because an inhibitor of COX-2 such as MLX blocked this increase by LPS, we suppose that LPS induced COX-2 in the SMG. Furthermore, AG also was able to block the increase in the arachidonate metabolites by LPS. These results are in agreement with many other studies that demonstrated that LPS induces COX-2 (9).
On the other hand, the increase in NOS activity by LPS was accompanied by a complete block of salivation in response to different secretagogues. Furthermore, the PGE1 analog tested (alprostadil) inhibited salivation induced by NA or MC, confirming previous results (22). These results are in agreement with others that showed an inhibitory effect of PGs on exocrine pancreatic secretion (16). There is a similar response of mesenteric vessels to LPS to those of the SMG (VE Mendizabal, A Lomniczi, C Mohn, V Rettori, and E Adler-Graschinsky, unpublished data). Because the mesenteric vessels release NO and PGs into the circulation, a contribution of peripheral production of PGs or NO that reaches the SMG via the circulation should also be considered; however, the concentrations reaching the SMG via the circulation would probably be too low to have an effect.
Finally, we could reduce the inhibitory effect of LPS on NE- or MC-stimulated salivary secretion with a specific inhibitor of COX-2, MLX. Furthermore, AG, a highly selective inhibitor of iNOS synthesis, decreased NOS activity in the gland and reduced the increase in plasma NO2/NO3 induced by LPS (data not shown).
The present results are consistent with the following sequence of
events (Fig. 10). LPS acts on toll-like
receptors, as described in the myocardium of rats, mice, and humans
(5), on the salivary cells to induce iNOS mRNA synthesis,
which increases iNOS. The liberated NO activates COX-2 synthesis,
resulting in synthesis and release of PGs, which act back on
iNOS-containing cells to augment further iNOS synthesis, which by NO
further augments COX-2 synthesis and PG production. Because NO is a
weak stimulator of salivary secretion at best, the secreted PGs nearly
completely block salivary secretion, leading to the dry mouth that
characterizes infection.
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There are no previous reports indicating the effect of acute endotoxemia on salivary responses in humans or animals. Here, we report for the first time the effect of LPS and the participation of PGs on salivary responses during systemic inflammation in an animal model. If a dose of AG or MLX can be found to increase salivation during infection, it might be therapeutically useful by decreasing the hyposialosis induced by infection.
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ACKNOWLEDGEMENTS |
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This work was supported by Grants TO 04, Facultad Odontología, Universidad de Buenos Aires, BID 802-OC-AR-PICT 00353, Consejo Nacional de Investigaciones Científicas y Técnicas, and MH 51853-83. We also thank Ana Inés Casella for administrative assistance.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Lomniczi, Cátedra de Fisiología, Facultad de Odontología, Univ. de Buenos Aires, M. T. de Alvear 2142 (1122), 3er Piso A, Buenos Aires, Argentina (E-mail: lomniczi{at}yahoo.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10 October 2000; accepted in final form 26 March 2001.
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