1 Department of Internal Medicine and Public Health, University of L'Aquila, 67100 L'Aquila; and 2 Department of Internal Medicine and Therapeutics, Division of Clinical and Experimental Pharmacology, University of Pavia, 27100 Pavia, Italy
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ABSTRACT |
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The
role of the tachykinin neurokinin (NK)2 receptors on rabbit
distal colon propulsion was investigated by using two selective NK2-receptor antagonists, MEN-10627 and SR-48968.
Experiments on colonic circular muscle strips showed that contractile
responses to [-Ala8]NKA-(4
10) (1 nM-1
µM), a selective NK2-receptor agonist, were competitively antagonized by MEN-10627 (1-100 nM), whereas
SR-48968 (0.1-10 nM) caused an insurmountable antagonism, thus
confirming the difference in the mode of action of the two compounds.
Colonic propulsion was elicited by distending a mobile rubber balloon with 0.3 ml (submaximal stimulus) or 1.0 ml (maximal stimulus) of
water. The velocity of anal displacement of the balloon (mm/s) was
considered the main propulsion parameter. At low concentrations (1.0-100 nM and 0.1-10 nM, respectively), MEN-10627 and
SR-48968 facilitated the velocity of propulsion, whereas at high
concentrations (100 nM and 1 µM, respectively) they decelerated
propulsion. The excitatory and inhibitory effects of both antagonists
were observed only with submaximal stimulus. We focused on the
hypothesis that the facilitatory effect on propulsion may result from
blockade of neuronal NK2 receptors and the inhibitory
effect from suppression of the excitatory transmission mediated by
NK2 receptors on smooth muscle cells. In the presence of
NG-nitro-L-arginine (300 µM), a
nitric oxide synthase inhibitor, MEN-10627, at a concentration (10 nM)
that was found to accelerate propulsion in control experiments
inhibited the velocity of propulsion. In the presence of threshold
(1-10 nM) or full (1 µM) concentration of atropine, which
inhibited to a great extent the velocity of propulsion, the inhibitory
effect of MEN-10627 (1 µM) was markedly increased. In conclusion, in
the rabbit distal colon NK2 receptors may decelerate
propulsion by activating a nitric oxide-dependent neuronal mechanism
and may accelerate it by a postjunctional synergistic interaction with
cholinergic muscarinic receptors.
rabbit distal colon propulsion; MEN-10627; SR-48968; tachykinin neurokinin 2 receptor; nitrergic transmission
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INTRODUCTION |
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IN MAMMALIAN GASTROINTESTINAL tract, the tachykinins (TKs) substance P (SP) and neurokinin (NK) A are cotransmitters in several functional classes of myenteric neurons and are concomitantly released in response to depolarizing stimuli (31). They are implicated in both neuroneuronal and neuromuscular transmission. In the guinea pig ileum, tachykinergic neurons have adequate projections and chemical coding to be considered excitatory motor neurons to both longitudinal and circular muscle layers, ascending interneurons, and intrinsic sensory neurons in the enteric circuits subserving peristaltic reflexes and intestinal propulsion (7). The vast majority of TK-containing neurons also costore and corelease acetylcholine (8).
The best-documented actions of both TKs in the enteric nervous system are consistent with their status as noncholinergic neuromuscular excitatory transmitters (for review, see Ref. 20). The TK postjunctional receptors are identified as NK2 (NKA preferring) and NK1 (SP preferring) receptors located on smooth muscle cells (3, 38, 45, 48, 52). NK1 receptors are also located on enteric neurons and interstitial cells of Cajal. Thus NK1 receptors may directly or indirectly participate in the activation of intestinal circular muscle (26, 51). Recently, a subset of NK2 receptors has been identified using immunohistochemical procedures on terminals of descending interneurons in the guinea pig myenteric plexus expressing nitric oxide (NO) or bombesin (44). Similarly, neuronal NK2 receptors are located on nerve terminal varicosities in the rat gastrointestinal tract (16). There is also pharmacological evidence that NK2 receptors are implicated in the activation of inhibitory motorneurons in the guinea pig colon circular muscle, mainly releasing NO, which is one of the most important inhibitory transmitters at the neuromuscular level and an important neuromodulatory agent of sensory and excitatory enteric neurons (47, 54, 55, 56).
Endogenous TKs serve as neuromuscular transmitters of the ascending reflex contraction of the circular muscle and contribute to the propulsive motility both in ileal and colonic preparations through activation of NK2 receptors (11, 14, 25). However, only when cholinergic neuromuscular transmission is blocked by atropine/hyoscine is it possible to demonstrate a significant contribution of endogenous TKs in both the ascending reflex contraction and propulsive activity. Furthermore, at least in the guinea pig ileum, a comparison of the effects of atropine and NK2-receptor antagonists suggests that acetylcholine and TKs act synergistically to contract the circular muscle in response to gut distension and to subserve peristalsis (22, 23). This is consistent with the coexistence and corelease of acetylcholine and TKs from the enteric motor neurons (5, 35).
Recently, it has been shown that blockade of the NK2 receptor increases peristaltic activity in the guinea pig colon in vivo, even though only one class of NK2-receptor antagonist (i.e., the MEN compounds) induced a significant prokinetic action. This action has been tentatively interpreted as due to the preferential blockade of a subset of NK2 receptors activating inhibitory neuronal pathways, probably located on descending interneurons (29).
In the present study, we investigated the possible role of NK2 receptors on propulsion of an intraluminally distended balloon in isolated rabbit distal colon segments. Two selective NK2-receptor antagonists, structurally different and endowed with different mechanisms of blocking NK2 receptors, MEN-10627 and SR-48968 (10, 33, 41), were used. Previous studies, in which peristalsis was induced by intraluminal fluid distension, reported that rabbit distal colon propulsion was markedly resistant to muscarinic receptor blockade. This suggests that noncholinergic excitatory transmitters play an important role in the neuromuscular transmission subserving the propulsive activity (30, 32). Furthermore, there is evidence that, in circular muscle strips of rabbit distal colon, electrical field stimulation induced a contractile response that was partially cholinergic and that the atropine-resistant response was abolished by SP-receptor desensitization and by spantide, a nonselective TK-receptor antagonist (50). Together, these findings suggest that TKs play a substantial role in the excitatory neuromuscular transmission subserving peristalsis in this intestinal preparation.
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MATERIALS AND METHODS |
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Male New Zealand White rabbits weighing 2,000-2,400 g were killed by stunning and bleeding, in agreement with the National Research Council's criteria for the care and use of animals. A 10-cm segment of distal colon was excised, with the aboral end cut nearly 1 cm above the pubis symphysis, and transferred to a petri dish containing prewarmed Tyrode solution to remove the intraluminal content. From each specimen two kinds of preparation were obtained. All preparations were equilibrated for at least 60 min before experiments were started.
Circular Muscle Strips
Segments (3 mm long) of distal colon were cut open at the mesenteric border to obtain rectangular circular muscle strips. After removal of mucosa, strips were mounted isometrically (load 0.5 g) in a 20-ml organ bath containing Tyrode solution maintained at 37°C and continuously bubbled with 95% O2 and 5% CO2. This preparation was used to investigate the effect of MEN-10627 and SR-48968 as antagonists of contractile responses mediated by the selective NK2-receptor agonist [At least two cumulative concentration-response curves to the agonists were performed at intervals of 45-60 min, with repeated washing after each curve and before testing the effect of the antagonists. In each preparation, a single concentration of antagonist was used and left in contact with the tissue for 15 min.
In a separate set of experiments, the concentration of hexamethonium able to inhibit the response of the nicotinic-receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) was determined.
Measurement and Pharmacological Characterization of Peristalsis
The method for peristalsis induction has been described previously (12). Briefly, whole segments of distal colon, 8 cm long, were transferred to an organ bath containing 100 ml of Tyrode solution. Each segment was set up horizontally, with the aboral end tied to a fixed Perspex holder and the free aboral end connected to an isotonic transducer (2-g load) via a pulley.Propulsion was elicited using a thin rubber balloon that was inserted intraluminally 1 cm below the oral end of the colon and distended with either 0.3 or 1.0 ml of water (external balloon diameters of 6 and 13 mm, respectively). In each experiment, the velocity of balloon propulsion was considered the main parameter of peristaltic activity and was evaluated by recording the time (s) required for the balloon to travel the entire length (mm) of the preparation. Stimuli were elicited every 10 min by alternating 0.3- and 1.0-ml balloon distension, which caused submaximal and maximal velocity of propulsion. The mean velocity of propulsion was calculated by considering two consecutive propulsions.
To study the role of NK2 receptors in the rabbit distal colon propulsion, the NK2-receptor antagonists MEN-10627 and SR-48968 were used. Propulsion was elicited 20 min after antagonist administration, a time span sufficient to obtain the maximum effect of the concentration tested, which remained stable for at least 60 min. A concentration-dependent effect of both antagonists on velocity of propulsion was evaluated (MEN-10267, 1 nM-1 µM; SR-48968, 0.1 nM-0.1 µM). In each preparation, a single concentration of antagonist was used.
In a separate series of experiments, MEN-10627 at a concentration (1 µM) that caused a slight but significant antipropulsive effect was tested in the presence of 1 µM atropine according to a procedure used to either unmask or enhance the inhibitory effect of NK2-receptor blockade in both ileal and colonic peristaltic motor activity (14, 29). Finally, to further evaluate the nature of interaction between cholinergic-muscarinic receptors and NK2 receptors, we tested the effect of MEN-10627 in the presence of threshold concentrations of atropine (10-20 nM) able to inhibit propulsion.
The effects of a low concentration of MEN-10627 (10 nM), which induced a significant enhancement of the velocity of propulsion, were assessed in the presence of L-NNA (200 µM), an inhibitor of NO synthase (28), left in contact for at least 20 min. In addition, the effects of 10 nM MEN-10627 were evaluated in the presence of the nicotinic receptor blocker hexamethonium (200 µM) (incubation time 10 min).
Calculations and Statistical Analysis
Antagonist pA2 value of MEN-10627 (10 and 100 nM) and SR-48968 (1 and 10 nM) was calculated following Schild regression analysis (2), using [Values are expressed as percentage of control value and were calculated
as means ± SE, with n indicating the number of preparations. Statistical significance of mean differences was assessed by applying Student's t-test for paired or unpaired data. For multiple
mean comparisons, one-way ANOVA plus Bonferroni post hoc analysis was used. P values 0.05 were regarded as significant; P > 0.05 was referred to as not significant.
Solutions and Drugs
Tyrode solution (pH 7.3) contained the following (in mM): 136.9 NaCl, 2.7 KCl, 1.8 CaCl2, 1.04 MgCl2, 11.9 NaHCO3, 0.4 NaH2PO4, and 5.5 glucose. Drugs and substances included SR-48968 (Sanofi Recherche, Montpellier, France; by courtesy of Dr. X. Edmond-Alt), MEN-10627 (Menarini, Florence, Italy, by courtesy of Dr. C. A. Maggi), [Stock solutions (1-10 mM) of MEN-10627, SP-methyl ester, and
[-Ala8]NKA-(4
10) were prepared in DMSO and
diluted in distilled water. The control experiments showed that DMSO
alone (0.1-0.3% final concentration) had no effect on colonic
motor activity.
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RESULTS |
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Colonic Circular Muscle Strips
Effects of NK2-receptor antagonists on
[-Ala8]NKA-(4
10)-induced
contractions.
Circular muscle strips usually displayed low basal tone, which was
rhythmically interrupted by phasic contractions. This activity persisted unchanged for up to 60 min.
[
-Ala8]NKA-(4
10) (1 nM-1 µM)
induced a concentration-dependent contractile effect. This effect was
not modified by tissue pretreatment with atropine (1 µM) (n = 3) or L-NNA (200 µM) plus apamin (100 nM) (n = 3), even though atropine induced a slight inhibition and L-NNA plus apamin induced a sustained increase in muscular
tone. These findings suggest that, in this preparation, functional
NK2 receptors are largely located at a postjunctional
level. In preparations displaying a higher basal tone, MEN-10627 and
SR-48968 induced a concentration-dependent smooth muscle relaxation,
which was slow in onset and peaked within 15 min. After this period,
the tone remained stable for at least 40 min, indicating that
NK2 receptors modulate resting tone in isolated circular
muscle (34). MEN-10627 (10 or 100 nM) and SR-48968 (1 or 10 nM)
produced concentration-dependent rightward shifts of the curve to
[
-Ala8]NKA-(4
10) (1 nM-1 µM) (Figs.
1A and 2A). Low antagonist
concentrations (1 nM MEN-10627 and 0.1 nM SR-48968) were ineffective.
The antagonism of MEN-10627 was competitive, as indicated by the
parallel rightward shift of concentration-response curves to the
agonist, without depression of the maximal agonist effect
(Emax), by the slope of the Schild plot not
significantly different from unity (Fig. 1A), with a
pA2 value of 9.1. These results are consistent with what is
found in human ileum and colon, where MEN-10627 featured a similar
nanomolar affinity for NK2 receptors (42). The antagonistic effect of MEN-10627 was not completely reversed by washout up to 1 h.
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Effects of MEN-10627 and SR-48968 on the velocity of propulsion.
The mean velocity of propulsion was 2.2 ± 0.2 mm/s (n = 6)
and 2.8 ± 0.4 mm/s (n = 6) at 0.3- and 1.0-ml balloon
distension, respectively. In preparations in which peristalsis was
elicited by 0.3-ml distension, MEN-10627 caused an acceleration of the velocity of propulsion at concentrations from 0.1 nM to 100 nM (Fig.
3). MEN-10627, at 100 nM, was less
effective than 1 nM and 10 nM in enhancing the velocity of propulsion,
whereas at 1 µM it caused a slight but significant antipropulsive
effect (Fig. 3). Higher concentration (3 µM) did not further inhibit
the velocity of propulsion (data not shown). At 1.0-ml distension,
MEN-10627 did not significantly affect the velocity of propulsion at
any concentration (Fig. 3). Similarly, SR-48968 (0.01-10 nM)
accelerated the velocity of propulsion induced by submaximal (0.3-ml)
distension (Fig. 4). The maximal effect was
observed at 0.1 nM. A concentration of 100 nM was ineffective, whereas
the highest concentration administered (1 µM) induced a slight but
significant inhibitory effect on the velocity of propulsion. At 1.0-ml
distension, SR-48968 did not affect the velocity of propulsion at any
concentration (Fig. 4).
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DISCUSSION |
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The results of the present study suggest that endogenous TKs contribute to the propulsive activity of the isolated rabbit distal colon through the activation of NK2 receptors located on neuronal pathways and muscular structures subserving peristalsis. The role of NK2 receptors has been investigated using two structurally different selective antagonists, MEN-10627 and SR-48968 (10, 33). MEN-10627 is a polycyclic peptide antagonist, whereas SR-48968 is a nonpeptide compound possessing high affinity for rabbit smooth muscle NK2 receptors (1) and considered to act through a different mechanism than MEN-10627, at least in the guinea pig gallbladder and colon (41). The antagonism of SR-48968 at NK2 receptors may be allosteric (9, 13). The different mechanisms of NK2-receptor blockade by SR-48968 and MEN-10627 were also observed in the present study, in which we showed that SR-48968 induced an insurmountable (noncompetitive) antagonism of NK2 receptor-mediated contraction in colonic circular muscle strips, whereas MEN-10627 produced a competitive antagonism. Both types of antagonism were time independent (no change in the antagonistic effect was observed by prolonging the incubation from 15 min to 120 min). The affinity of SR-48968 at NK2 receptors was ~3 times higher than that of MEN-10627.
MEN-10627 (1-100 nM) and SR-48968 (0.1-10 nM) induced a
significant increase in the velocity of propulsion. The effects of both
antagonists tended to fade at higher concentrations. By contrast, MEN-10627 (1 µM) and SR-48968 (0.1 µM) induced a slight but
significant inhibitory effect on the velocity of propulsion. Both
excitatory and inhibitory effects induced by the two antagonists were
shown only on propulsion induced by submaximal stimulus. The prokinetic action caused by NK2-receptor blockade was rather
unexpected on the basis of previous observations obtained in both ileal
(25) and colonic (11) preparations of guinea pig, which indicated an
inhibitory effect on peristaltic activity evaluated in the absence and
presence of atropine (23). We speculated that the facilitatory effect
induced by low concentrations of both antagonists on rabbit distal
colon propulsion may arise from blockade of inhibitory mechanisms
activated by NK2 receptors. It is likely that this effect
is mediated by NK2 receptors located in myenteric plexus since the prokinetic concentrations of MEN-10627 (1 nM) and SR-48968 (0.1 nM) did not affect the direct contraction of circular muscle strips induced by the selective NK2-receptor agonist
[-Ala8]NKA-(4
10). This is consistent with
the presence of NK2 receptors on a subset of descending
myenteric interneurons expressing bombesin and NO (44) and with the
evidence that NK2-receptor activation induces NO release,
thus leading to depression of circular muscle activity (56). Indeed,
L-NNA induced a significant enhancement of the velocity of
propulsion (at both 0.3-ml and 1-ml distension), thus confirming the
involvement of NO in mediating the inhibition of the velocity of
colonic propulsion in the rabbit (6). The inhibition of NO synthase
activity was also found to induce a facilitatory effect on peristalsis
in the guinea pig ileum (53). More recently, dual excitatory and
inhibitory effects of NO on peristalsis have been reported in the
guinea pig intestine. The excitatory effect involved cholinergic
motorneurons, whereas the inhibitory effect reflected relaxation of
intestinal muscle (21).
In contrast to what we observed in the rabbit colon, the inhibition of NO synthase induced an inhibitory effect in the guinea pig colonic propulsion (11). In this preparation, recent evidence suggests that NO facilitates and depresses the release of acetylcholine from interneurons in ascending and descending pathways, respectively, in addition to directly inhibiting smooth muscle (49). Whatever the mechanism by which endogenous NO negatively modulates the rabbit distal colon propulsion, low concentrations of MEN-10627 and SR-48968 inhibited the propulsion evoked at submaximal stimulus once NO synthase activity was suppressed by L-NNA. This suggests that the facilitatory effect of MEN-10627 recorded in the absence of L-NNA may be due to the blockade of a subset of NK2 receptors activating NO-dependent inhibitory mechanisms on propulsive activity. Similar results were obtained using low concentrations of SR-48968 (not shown).
To further assess the putative prejunctional action of MEN-10627 in enhancing the velocity of propulsion, we investigated the effect of this compound in the presence of hexamethonium, a blocker of cholinergic-nicotinic transmission. Hexamethonium induced a slight transient decelerating effect on the velocity of propulsion that may be due to the occurrence of adaptive responses, since it was not modified by a second administration of hexamethonium. This is in agreement with previous observations in the same preparations in which peristalsis was induced by fluid supply (30, 32). In the presence of hexamethonium, low concentrations of MEN-10627 still induced a significant enhancing effect on the velocity of propulsion, although to a lesser degree than that obtained in the absence of nicotinic-receptor blockade. Partial inhibition of the prokinetic effect of MEN-10627 in the presence of hexamethonium may suggest that descending interneurons activated by endogenous TKs through NK2 receptors can be cholinergic. However, this is not supported by the immunohistochemical localization of NK2 receptors, at least in the guinea pig ileal myenteric plexus (44). Hexamethonium may also inhibit the MEN-10627 effect through other mechanisms, including antagonism of nicotinic receptors distributed along the ascending pathways subserving peristalsis (27). The impairment of such nicotinic transmission may mask, at least in part, the prokinetic effect of NK2 antagonists through inhibition of NO-production/release.
At the highest concentration (1 µM), MEN-10627 significantly inhibited the velocity of propulsion elicited at low distension. It is reasonable to assume that this inhibitory effect is due to the blockade of postjunctional NK2 receptors, which comediate with muscarinic receptors (and to a minor extent with postjunctional NK1 receptors) the activation of muscular effectors subserving peristalsis (22, 25). Thus the antiperistaltic effect of MEN-10627 was evaluated in the presence of atropine. This procedure has been commonly applied to unmask or to enhance the contribution of excitatory noncholinergic transmitters mainly at a postjunctional level in sustaining neuromediated muscle contractions, such as those underlying ascending circular muscle reflexes and peristalsis (14, 23). Atropine induced a reduction of the velocity of propulsion and sometimes a transient blockade when peristalsis was evoked by submaximal stimulus. In the presence of atropine, the velocity of propulsion underwent a time-dependent partial recovery, which was significantly more pronounced when the propulsion was evoked by maximal stimulus. These findings suggest the existence of adaptive mechanisms, probably consisting of activation/enhancement of noncholinergic excitatory transmission, leading to a partial substitution of the cholinergic drive. Apparently, this noncholinergic excitatory mechanism plays a major role when the propulsion is evoked by maximum degree of stimulus. These results are in agreement with previous observations suggesting that the atropine-resistant ascending reflex contraction of the circular muscle in both ileal and colonic preparations is more pronounced with maximal or supramaximal stimuli (18, 23).
In the presence of muscarinic receptor blockade, MEN-10627 (1 µM) produced a marked and persistent inhibition and often a blockade of propulsion evoked by submaximal distension. Similarly, in the presence of threshold concentrations of atropine (10-20 nM), able to consistently reduce the velocity of propulsion, the inhibitory effect of MEN-10627 was significantly increased. These findings suggest a synergistic interaction between muscarinic and NK2 receptors. A similar interaction between muscarinic and NK2 receptors has been previously described in guinea pig ileal peristalsis (23).
The apparent lack of participation of NK2 receptors in the atropine-resistant propulsion evoked by maximum stimulus is more difficult to explain. There is evidence that tachykinergic contribution, via NK2 and NK1 receptors, to atropine-resistant ascending reflex contraction of the circular muscle is directly related to the extent of stimulation (14, 17, 19). These findings indicate the presence of a low-threshold cholinergic transmission and a high-threshold tachykinergic transmission mediated by NK1 and NK2 receptors. However, it was recently demonstrated that the contribution of acetylcholine and TKs in circular muscle contraction to electrical field in the guinea pig colon is relatively independent of the intensity of the stimulus and/or the mechanism of transmitter release. Therefore, postjunctional factors seem predominant in determining the contribution in producing excitation of the circular muscle (35). This observation may be consistent with the important role exerted by NK2 receptors on atropine-resistant propulsion evoked by the submaximal stimulus. Nevertheless, the atropine-resistant, non-NK2-receptor component of propulsion evoked by maximal stimulation may be mediated by different TK receptors (mainly NK1) or by other noncholinergic excitatory transmitters. Our previous findings indicate that the atropine-resistant component of peristalsis evoked by maximal distension was sensitive to a concomitant blockade of NK1 and NK2 receptors by SR-140333 and MEN-10627, respectively (39). Under this condition, an ~65% inhibition of the velocity of propulsion was obtained. However, it is interesting to point out that the administration of SR-140333 alone failed to significantly affect peristalsis. This indicates that TKs contribute to the atropine-resistant component of peristalsis to high stimulation and that a synergistic interaction between the two TK receptor systems may intervene. The atropine- and TK-resistant component may be mediated by excitatory transmitters such as bombesin, which was found to be released by electrical field stimulation in the rabbit distal colon and to induce circular muscle contraction (4, 50). Therefore, in the present study, a noncholinergic transmitter(s) other than TKs may contribute to the atropine-resistant peristalsis induced by maximal gut wall distension.
Finally, the large difference in concentration range (100- to 1000-fold) at which the NK2-receptor antagonists exert their dual effect on colonic propulsion suggests the existence of different subtypes of NK2 receptors in the rabbit distal colon, which are probably located on distinct structures, such as nerves and smooth muscle cells. Recently, the existence of two distinct NK2-receptor subtypes on human colonic muscle strips has been proposed (37, 52). In addition, a high degree of pharmacological homology has been described between human colon and rabbit NK2 receptors (36, 43). However, our data did not allow us to establish clear-cut evidence for the existence of NK2-receptor heterogeneity in the rabbit colon.
In conclusion, our findings provide evidence that NK2-receptor antagonists accelerate or inhibit the velocity of propulsion in the rabbit isolated distal colon according to concentration. These effects are probably mediated by indirect neuronal (leading to acceleration) and direct postjunctional (leading to deceleration) mechanisms, due to inhibition of NO production and blockade of muscular NK2 receptors, respectively.
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ACKNOWLEDGEMENTS |
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Preliminary results of this study were presented at Digestive Disease Week 1999, Orlando, FL (40).
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: L. Onori, Dept. of Internal Medicine and Public Health, Univ. of L'Aquila, 22E, via San Sisto, 67100-L'Aquila, Italy (E-mail: taddei{at}tin.it)
Received 21 July 1999; accepted in final form 8 September 1999.
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