1 Department of Physiology and Medical
Biophysics, The aim of this study was to examine the
integrative response to neurokinin A (NKA) on duodenal mucosal
permeability, bicarbonate secretion, fluid flux, and motility in an in
situ perfusion model in anesthetized rats. Intravenous infusion of NKA
(100, 200, and 400 pmol · kg
duodenum; motility; neurokinin-2 receptor antagonist; tachykinin; cyclooxygenase inhibitor
RECENT STUDIES (8) have shown that the duodenal mucosa
in a variety of mammalian species, including humans, secretes
bicarbonate into the viscoelastic mucus gel adherent to the underlying
epithelium. It has been proposed that the resulting juxtaepithelial
"mucus-bicarbonate barrier" forms the major line of defense
against acid-induced mucosal injury (1). Various physiological
mechanisms influence and regulate duodenal mucosal bicarbonate
secretion (8). For instance, recent experiments (10, 18, 19) strongly
suggest that elevation of intraluminal pressure, either by distension or induction of duodenal motility, increases the secretion of bicarbonate. Our hypothesis is that the elevated intraluminal pressure
activates mechanoreceptors and, via a neural reflex arc, stimulates the
bicarbonate-secreting duodenocytes.
The tachykinin neurokinin A (NKA) is involved in the control of
gastrointestinal motility in several species. It has been suggested to
be the dominant and most potent tachykinin in stimulating rat duodenal
contractions (11, 13, 15, 17), either by acting directly on the smooth
muscle cells or by indirect mechanisms mediated by acetylcholine
release (6). One of the aims of this study was to test whether NKA also
stimulates duodenal alkaline secretion.
Almost all tachykinins in the gut occur in two types of neurons:
intrinsic and extrinsic. The tachykinin-containing intrinsic neurons
form a dense network in the myenteric plexus and project to circular
but not longitudinal muscle (21). At least three different subsets of
tachykinin receptors, denoted NK1,
NK2, and NK3, have been identified (4, 15).
Although NKA binds to all three receptor types, it has by far the
highest affinity for NK2
receptors. NK2 binding sites have
been localized both in the circular muscle layer and, to a lesser
extent, in the longitudinal muscle layer of rat duodenum (3, 5, 9).
Neuropeptides of the tachykinin family, released from afferent sensory
neurons, can induce and sustain neurogenic inflammation (20). The
alterations in the tissues associated with this release might also
affect intestinal mucosal permeability. The second aim of this study
was therefore to determine whether the proinflammatory mediator NKA
influences mucosal permeability in the rat duodenum. To further
characterize the mechanisms involved in the responses to NKA, we used
the nicotinic receptor antagonist hexamethonium, the selective NK-2
receptor antagonist MEN 10,627, and the cyclooxygenase inhibitor
indomethacin. NKA was also infused intermittently to evaluate the
possible influence of adaptation of the response.
Surgical Procedures
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
1 · min
1)
induced duodenal motility. Furthermore, duodenal mucosal bicarbonate secretion, fluid output, and mucosal permeability increased in response
to NKA. Pretreatment with the nicotinic antagonist hexamethonium did
not change the response in any of the parameters investigated, whereas
the NK2-receptor antagonist MEN
10,627 effectively inhibited all responses to NKA. Indomethacin induced
duodenal motility and stimulated bicarbonate secretion. In
indomethacin-treated rats, NKA further increased motility but decreased
indomethacin-stimulated bicarbonate secretion by 70%. The NKA-induced
increase in mucosal permeability was unaltered by indomethacin. It is
concluded that NKA not only induces motility but also increases mucosal
permeability and fluid output. Furthermore, the neuropeptide may have
both stimulative and inhibitory effects on bicarbonate secretion. All responses to NKA are dependent on NK-2 receptor activation but are not
mediated through nicotinic receptors.
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
The abdominal cavity was opened by a midline incision, and a PE-10 catheter was inserted into the common bile duct ~2 mm from its entrance into the duodenum to prevent pancreaticobiliary secretions from entering the duodenal segment. A soft plastic tubing (1 mm ID; Silastic, Dow Corning) was introduced via the mouth and gently pushed through the esophagus into the stomach and then through the pylorus into the duodenum. This tubing was secured by a ligature 2-4 mm distal to the pylorus. Another cannula (PE-320) was inserted into the duodenum through an incision ~3 cm distal to the pylorus and secured by ligatures. The orally introduced tubing was connected to a peristaltic pump (Gilson Miniplus 3, Villiers, Le Bel, France) for perfusion of the duodenal segment at a constant rate. The abdominal cavity was stitched closed, and the body temperature of the animal was maintained at ~37.5°C by means of a heating pad controlled by an intrarectal thermistor. All experiments were approved by the Uppsala Ethics Committee for Animal Experiments.
Bicarbonate Secretion
The rate of luminal alkalinization was determined by titration of the effluent to pH 6 with 50 mM HCl, under continuous gassing with 100% N2, using pH-stat equipment (Autoburette ABU 12, TTT 80 Titrator, and PHM 64 pH meter, Radiometer, Copenhagen, Denmark). The pH electrode was routinely calibrated with standard buffers before titration. The rate of luminal alkalinization was expressed as the net amount of base (micromoles) secreted per centimeter of intestine per hour.Mucosal Permeability
After completion of surgery, we administered the radioactive isotope 51Cr-EDTA intravenously as a bolus of ~75 µCi followed by a continuous infusion at a rate of 50 µCi/h (adapted to obtain a constant plasma level of 51Cr-EDTA). The isotope was diluted in a Ringer-bicarbonate solution, infused at a rate of 1 ml/h (infusion pump from Harvard Apparatus, Edenbridge, UK). One hour was permitted for tissue equilibration of the 51Cr-EDTA and for the animal to recover from surgery. Three to four blood samples (0.2 ml) were collected at regular intervals during the experiment, and the blood volume loss was compensated for by the injection of a 5% Ficoll solution. After centrifugation of the samples, we removed 50 µl of the plasma for measurement of radioactivity. The luminal perfusate and the blood plasma were analyzed for 51Cr activity (gamma counter 1282, Compugamma CS, Pharmacia, Uppsala, Sweden). A linear regression analysis of the plasma samples was made to obtain a corresponding plasma value for each effluent sample. The clearance of 51Cr-EDTA from blood to lumen was calculated according to the following formula
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Fluid Secretion and/or Absorption
Vials were weighed individually, before and after effluent collection, on an electronic precision balance (Sauter AR 1014, Albstadt-Ebingen, Germany). The effluent weight was thus determined as the weight difference for each vial. The mean weight of effluent collected during the control period (the first 30 min or, in some of the protocols, the first 20 min of each experiment) was subtracted from the weight of each subsequent effluent. The difference was expressed as grams of fluid per gram of wet tissue weight per hour. The technique used provides information about relative changes of fluid flux across the duodenal mucosa, and a positive fluid flux value indicates increased secretion or decreased absorption.Motility
Duodenal contractions (motility) were monitored as changes in intraluminal pressure. A pressure transducer (Gould P23 ID) was connected to the inlet cannula of the perfusion system via a T-tube. Changes in intraluminal pressure were recorded on the Grass polyrecorder (see above). Duodenal motility was assessed by calculating the fraction of time (in percent) occupied by contractions, i.e, the fractional contraction time (FCT).Experimental Protocols
In all groups, the duodenal segment under study was perfused with saline at a constant rate of 0.4 ml/min both during the hour of recovery and subsequently throughout the experiment. During the experiment, the effluent was collected in 10-min samples. All experiments began with a control period to assess basal conditions.Infusion of 100, 200, or 400 pmol · kg1 · min
1
NKA.
After a 30-min control period, NKA was infused for 60 min in a volume
of 1 ml/h. The experiments continued an additional 30 min after the
infusion was stopped. NKA was administered in three different doses:
100 pmol · kg
1 · min
1
(n = 5), 200 pmol · kg
1 · min
1
(n = 5), and 400 pmol · kg
1 · min
1
(n = 6).
Infusion of 400 pmol · kg1 · min
1
NKA in animals treated with hexamethonium.
An additional group of animals
(n = 5) was treated with the nicotinic
receptor antagonist hexamethonium intravenously; 20 mg/kg was given as
a bolus 15 min before the start of effluent collection and immediately
followed by 10 mg · kg
1 · h
1
as a continuous infusion throughout the experiment. This group received
NKA (400 pmol · kg
1 · min
1)
for 60 min, and the experiments were terminated after an additional 30-min period, as described above.
Intermittent infusion of NKA.
In this group of rats (n = 5), NKA was
administered as an intravenous infusion at a rate of 400 pmol · kg1 · min
1
for 5 min. The infusion pump was then turned off for 5 min. This procedure was repeated throughout the 60-min infusion period. Following
an additional 30 min after the end of the intermittent infusion, the
experiments were terminated.
Pretreatment with MEN 10,627.
Thirty minutes before the start of effluent collection, an intravenous
infusion of the NK-2 receptor antagonist MEN 10,627 was started. The
infusion began with a bolus of 0.5 µmol/kg MEN 10,627 infused for 10 min, immediately followed by 0.5 µmol · kg1 · h
1
MEN 10,627 throughout the experiment
(n = 6). MEN 10,627 was dissolved in dimethyl sulfoxide (DMSO), and the infused volume was kept
very low (total infused volume <150 µl/kg). A 100-µl Hamilton
glass syringe (Hamilton Bonaduz, Bonaduz, Switzerland) was used. After
a 30-min control period, NKA (400 pmol · kg
1 · min
1)
was infused intravenously for 60 min.
Vehicle controls. This group of animals (n = 4) first received the same volume of the vehicle (DMSO) instead of MEN 10,627 and subsequently received NKA as described above.
Pretreatment with indomethacin.
Twenty minutes after the start of effluent collection, the animals
(n = 7) were given an intravenous
bolus of indomethacin (5 mg/kg). After an additional 40-min period, NKA
(400 pmol · kg1 · min
1)
was infused intravenously for 30 min. The experiments were continued an
additional 30 min after cessation of the NKA infusion.
Indomethacin controls. This group of animals (n = 6) received indomethacin (5 mg/kg) in the same manner as described above, i.e., after a 20-min control period, and served as controls to the indomethacin-NKA group.
Controls. One group of rats (n = 6) served as time controls (120 min) and did not receive any of the tested drugs.
Chemicals
Inactin was obtained from Research Biochemicals (Natick, MA). NKA was purchased from Peninsula Laboratories (Merseyside, UK). MEN 10,627 was a kind gift from Dr. C. A. Maggi (Menarini Pharmaceuticals, Florence, Italy). Indomethacin (Confortid for injection) was obtained from Dumex (Copenhagen, Denmark). Ficoll, hexamethonium chloride, and NaCl were all purchased from Sigma Chemical (St. Louis, MO). Heparin was from Pharmacia and 51EDTA from NEN-Du Pont (Boston, MA).Statistics
Values are expressed as means ± SE. The statistical significance of data was tested by analysis of variance with contrast (Fisher protected least-significant difference test) by comparing results before and after drug treatment (repeated measures) and by comparing differences between groups of animals (nonrepeated measures). Student's t-test was also used where appropriate. The values given in RESULTS are pooled from all the measurements taken during the basal or infusion period. All statistical analyses were done on a Macintosh computer using Statview software (Abacus Concepts, Berkeley, CA). P < 0.05 was considered significant (two-tailed test). ![]() |
RESULTS |
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Effects of NKA
All doses of NKA significantly increased bicarbonate secretion (Fig. 1). The mean increase in bicarbonate output did not differ among the three doses tested (3.7 ± 0.6, 2.9 ± 0.6, and 2.4 ± 0.6 µmol · cm
|
All doses of NKA increased fluid output (Fig. 1), and there was no
difference in mean fluid output between the groups ( 2.2 ± 0.2, 2.6 ± 0.2, and 1.8 ± 0.3 g · g1 · h
1
for 100, 200, and 400 pmol · kg
1 · min
1
NKA, respectively). After cessation of the NKA
infusion, fluid output was similar to that under control conditions or,
in the case of the highest dose of NKA, slightly negative during the first 10 min immediately after the infusion
(P < 0.05).
Calculations of the amount of base (bicarbonate) in the net fluid
secreted showed that the concentration of bicarbonate was significantly
lower (P < 0.05) than in
interstitial fluid (assumed to be 24 mM in calculations) at 200 and 400 pmol · kg1 · min
1
(13 ± 3 and 14 ± 3 mM, respectively) but not significantly
different at 100 pmol · kg
1 · min
1
(17 ± 4 mM).
During basal conditions, as well as in control animals, spontaneous
contractions were very rare. Infusion of NKA induced duodenal motility
in a dose-dependent manner (Fig. 1). The mean FCT was 21.2 ± 1.5%,
46.9 ± 9.2%, and 72.4 ± 4.3% for 100, 200, and 400 pmol · kg1 · min
1,
respectively, and there were significant differences among the effects
of all doses. As depicted in Fig. 2, the
NKA-induced motility was very intense, especially at the two higher
doses, and disappeared only minutes after termination of the
infusion.
|
All doses of NKA increased mucosal permeability (Fig.
3). However, the increase was more profound
and sustained at the highest dose. The mean increases during NKA
infusion were 0.18 ± 0.04, 0.23 ± 0.04, and 0.45 ± 0.08 ml · min1 · 100 g
1 for 100, 200, and 400 pmol · kg
1 · min
1,
respectively (Fig. 3). The mean increase at 400 pmol · kg
1 · min
1
was significantly higher than in the groups infused with 100 or 200 pmol · kg
1 · min
1
(P < 0.05).
|
Infusion of NKA did not have any sustained effect on mean arterial blood pressure (in some animals a transient dip was observed) compared with controls (data not shown).
Effects of NKA in Animals Treated with Hexamethonium
After hexamethonium, NKA (400 pmol · kg
|
|
Intermittent Infusion of NKA
To investigate the possible involvement of adaptation in the response to NKA, an intermittent infusion of NKA (400 pmol · kg
|
Because of the rapid offset of the effect of NKA on duodenal motility,
duodenal contractions disappeared for some time between NKA infusion
periods (Fig. 2). The motility pattern was similar to that obtained in
response to indomethacin (see below). FCT was approximately one-half
(33.6 ± 5.4%) of that in animals receiving 400 pmol · kg1 · min
1
NKA as a continuous infusion (Fig. 6). There was no
significant difference in mean FCT, calculated from the entire 60-min
infusion period, between intermittent infusion and continuous infusion of 200 pmol · kg
1 · min
1
NKA. However, at steady state, which was considered to be the last 30 min of the infusion, there were differences in mean FCT between all
three groups.
Finally, intermittent infusion of NKA also increased mucosal
permeability (Fig. 7). The mean increase
(0.27 ± 0.03 ml · min1 · 100 g
1) was similar to that
of 200 pmol · kg
1 · min
1
NKA infused continuously but differed significantly from that of 400 pmol · kg
1 · min
1
NKA (P < 0.01).
|
Effects of NKA in Animals Treated with MEN 10,627
Neither the NK-2 receptor antagonist MEN 10,627 (n = 6; data not shown) nor the vehicle DMSO (n = 4; data not shown) had any effect on basal conditions. However, MEN 10,627 efficiently inhibited the responses to NKA (400 pmol · kgIn some experiments, motility, although sparse and with low amplitude, occurred toward the end of the NKA infusion. Thus the mean FCT was slightly but significantly increased (4 ± 2%). However, compared with the motility observed in animals receiving NKA alone (72 ± 4%), the motility was still very low (Fig. 4).
Animals infused with the vehicle (DMSO) responded to NKA in a manner similar to that described for NKA given alone (n = 4; data not shown).
Effects of Indomethacin
We have previously shown that the cyclooxygenase inhibitor indomethacin induces duodenal motility and increases alkaline secretion (19). The purpose of the following experiments was to compare the response to NKA to that induced by indomethacin. The rate of alkalinization was stimulated by indomethacin (Fig. 8). The mean increase, calculated from the first 60 min after administration, was 6.2 ± 0.7 µmol · cm
|
|
Effects of NKA in Animals Treated with Indomethacin
The following experiments were performed to evaluate whether NKA affects duodenal mucosal alkaline secretion in animals subjected to prostaglandin synthesis blockade and thus with ongoing motility. In indomethacin-treated animals, NKA decreased the rate of alkalinization and during the last 20 min of infusion the bicarbonate secretion did not differ from basal secretion (Fig. 8). The net rate of secretion during steady state, i.e., the 20 min immediately before the start of NKA infusion and the last 20 min of NKA infusion, was 3.6 ± 0.3 and 1.0 ± 0.4 µmol · cmIn indomethacin-treated rats, infusion of NKA increased FCT from 33.0 ± 3.9% to 72.6 ± 4.2% (P < 0.001; Fig. 8). Thus NKA induced motility of the same
magnitude whether or not the rats were treated with the cyclooxygenase
inhibitor. NKA infusion increased mucosal permeability in
indomethacin-treated animals (0.47 ± 0.10 ml · min1 · 100 g
1) to a similar extent
as in rats receiving NKA alone (0.52 ± 0.1 ml · min
1 · 100 g
1; Fig. 9).
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DISCUSSION |
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The present study demonstrates that the tachykinin NKA, apart from being a potent stimulant of duodenal motility, also increases bicarbonate secretion, mucosal permeability, and fluid output in the duodenum. Pretreatment with MEN 10,627, a potent and highly selective antagonist to NK-2 receptors (14), did not influence basal parameters but inhibited all effects otherwise induced by NKA treatment. The involvement of NK-2 receptors in all observed responses is thus indicated.
We have previously suggested a relationship between duodenal motility
and mucosal secretion of bicarbonate. The hypothesis is based on the
following findings: 1) elevation of
intraluminal hydrostatic pressure by distension increases duodenal
mucosal bicarbonate secretion (19);
2) basal duodenal mucosal alkaline secretion is twice as high in the few rats exhibiting spontaneous duodenal contractions compared with those that do not (18); 3) cyclooxygenase inhibitors, such
as indomethacin, as well as the nitric oxide (NO) synthase inhibitor
N -nitro-L-arginine
methyl ester
(L-NAME), induce duodenal
motility and increase bicarbonate secretion concomitantly (10,
19). It has also been shown (10, 19) that distension-,
indomethacin-, and
L-NAME-induced increases in
duodenal mucosal bicarbonate secretion are abolished by hexamethonium.
In contrast, the present study demonstrates that both the NKA-induced
motility and the increase in duodenal mucosal bicarbonate are
independent of nicotinic transmission and thus differ from the
responses obtained in indomethacin- or L-NAME-treated rats.
It has recently been shown that indomethacin, despite an additional increase in duodenal motility, does not further increase L-NAME-induced bicarbonate secretion. This implies that the assumed reflex arc is already maximally activated (18). In theory, if NKA affected bicarbonate secretion solely by activation of the postulated reflex arc, the neuropeptide would not further increase indomethacin-stimulated alkaline secretion. In fact, NKA actually decreased indomethacin-stimulated bicarbonate secretion by more than 70%. This finding strongly suggests the existence of an inhibitory mechanism triggered by the neuropeptide. Two additional findings further substantiate the involvement of an inhibitory component in the response to NKA. First, despite the profound duodenal motility induced by NKA, the increase in alkalinization was considerably smaller than that obtained in indomethacin-treated rats. Second, bicarbonate secretion declined with time, especially at the highest dose of NKA.
The time-related decrease in alkaline secretion may be analogous to the adaptation of the secretory response to prolonged distension reported by Sababi and Nylander (19). To investigate adaptation as a possible inhibitory mechanism, we infused NKA in an intermittent manner. The motility pattern in intermittently infused animals resembled that obtained in indomethacin-treated rats, with complexes of motility occurring at regular intervals and interrupted by periods of quiescence. Nevertheless, the response to the intermittent infusion was analogous to that in rats receiving NKA continuously. Hence, adaptation is probably of minor significance to our results.
Although the presence of an inhibitory component in the NKA-induced response is clear, the net effect of NKA was that of increased bicarbonate secretion. The mechanism involved is probably not related to the induction of motility for the following reasons: 1) the time courses of motility and secretion differ; 2) there is a dose-response relationship in the effect of NKA on motility, whereas bicarbonate secretion is unaltered with increasing dose; 3) as mentioned above, the mechanism is insensitive to hexamethonium and thereby differs from that of L-NAME-, indomethacin-, and distension-induced secretion (10, 19). Should the hypothesis of a causal relationship between duodenal motility and mucosal bicarbonate secretion be rejected based on the presented data? To reject the hypothesis, it has to be assumed that NKA, when given systemically, has only one mode of action, i.e., induction of duodenal motility. This assumption is contradicted by the fact that NKA diminished indomethacin-stimulated alkalinization. Therefore, we speculate that NKA activates the reflex arc by virtue of its stimulative effect on duodenal motility and concomitantly inhibits signal transmission to the enterocytes (see Fig. 10).
|
An alternate explanation for the increase in alkaline secretion in response to NKA must be sought. Based on the effect of NKA in indomethacin-treated rats, the stimulative action of the neuropeptide may be attributed to the release of endogenous prostaglandins. Prostaglandin E2, which is a well-known stimulant of duodenal mucosal bicarbonate secretion (8), is released in response to NK-2 receptor activation (7).
Because NKA also increases paracellular permeability, the possibility of a parallel increase in diffusion of bicarbonate ions has to be considered. However, whereas the increase in 51Cr-EDTA clearance in response to NKA was further augmented by the highest dose of NKA, the net secretion of bicarbonate tended to decrease with increasing dose of the tachykinin. Furthermore, the net secretion during NKA infusion was lower in indomethacin-treated animals, despite the maintained increase in mucosal permeability, than in rats receiving NKA alone. Thus an increased paracellular transport of bicarbonate ions does not fully explain the increased rate of alkalinization in response to NKA. The exact mechanism by which NKA increases duodenal bicarbonate secretion remains unclear.
Infusion of NKA increased the blood-to-lumen clearance of 51Cr-EDTA, suggesting an increased paracellular permeability across the duodenal epithelium. Interestingly, the permeability of the tight junctions can be altered by pressure and/or volume changes in the intercellular space (2). Moreover, NKA increases the permeation of Evans blue, indicative of an increased vascular permeability to macromolecules, in the duodenum (12). We speculate that an increased filtration of vascular fluid and plasma proteins in response to NKA elevates interstitial fluid pressure. Subsequently, the high interstitial pressure affects the size and shape of the epithelial paracellular pathways and thereby increases the pore area for diffusion of 51Cr-EDTA across the mucosa.
NKA increased the secretion (or decreased the absorption) of fluid in the duodenum. Furthermore, the concentration of bicarbonate in the net fluid output was lower than in the interstitial fluid, suggesting that NKA stimulates the secretion of another ion, possibly chloride (22). The NKA-induced increase in fluid flux is not dependent on nicotinic transmission but may involve endogenous prostaglandins since indomethacin diminished this response.
It is concluded that NKA, apart from being a potent stimulant of duodenal motility, also increases duodenal epithelial permeability to 51Cr-EDTA and the output of fluid. NKA also increases duodenal mucosal bicarbonate secretion. However, since the indomethacin-induced increase in bicarbonate secretion was attenuated by NKA, dual effects of the neuropeptide are suggested; a dominant stimulative action and a weaker inhibitory action. The stimulative action is probably not related to the induction of motility but could be due to the release of endogenous prostaglandins. Nicotinic receptors are not involved in mediating any of the investigated effects, whereas the activation of NK-2 receptors is essential to all the responses obtained in response to NKA.
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ACKNOWLEDGEMENTS |
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We thank Dr. C. A. Maggi, Menarini Pharmaceuticals, Florence, Italy, for kindly supplying the antagonist MEN 10,627.
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FOOTNOTES |
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This study was supported by Swedish Medical Research Council Grant 04X-03515 and grants from the Swedish National Board of Health and Welfare and the Swedish Society for Medical Research.
Address for reprint requests: A. Hällgren, Dept. of Physiology and Medical Biophysics, Biomedical Center, Uppsala Univ., PO Box 572, S-751 23 Uppsala, Sweden.
Received 18 February 1997; accepted in final form 1 August 1997.
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