Departments of Large Animal Clinical Sciences and Physiology, Michigan State University, East Lansing, Michigan 48824-1314
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ABSTRACT |
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The effects of
capsaicin and neuropeptides were examined in equine tracheal smooth
muscle (TSM). Neither capsaicin nor substance P (SP) contracted TSM.
Capsaicin (100 µM) elicited relaxation in TSM contracted with
methacholine. This relaxation was not mimicked by SP or calcitonin
gene-related peptide (CGRP). Relaxation was not attenuated by removal
of the epithelium or by pretreatment of tissue with meclofenamate or
the nitric oxide (NO) synthase inhibitor
NG-nitro-L-arginine. Previous
exposure of TSM to capsaicin did not eliminate the relaxation responses
to subsequent capsaicin. Although vasoactive intestinal peptide (VIP)
elicited marked relaxation that was attenuated by -chymotrypsin,
-chymotrypsin did not affect the capsaicin-induced relaxation.
Capsaicin-induced relaxation was abolished by charybdotoxin, a blocker
of large-conductance Ca2+-activated
K+ channels. These results
indicate that capsaicin-induced equine TSM relaxation is not mediated
either by neuropeptides such as SP or CGRP released from
capsaicin-sensitive sensory nerves or by prostanoids, NO, or VIP.
Relaxation is due to the effect of capsaicin on large-conductance
Ca2+-activated
K+ channels. The peptidergic
nerves play no important role in the regulation of TSM tone in horse
airways.
calcium-activated potassium channels; neuropeptides; horse
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INTRODUCTION |
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THE NEURAL CONTROL of airways is complex. Together with the cholinergic and adrenergic mechanisms, there are sensory nerve fibers that are thought to play an important role by release of neuropeptides (20). Capsaicin is used widely to activate sensory nerve fibers and cause release of sensory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) from these nerve endings. These neuropeptides are thought to play a role in the pathogenesis of asthma (14) by contracting airway smooth muscle (10), modulating epithelial cell function (1, 8), causing vasodilation (17), and increasing vascular permeability (18). In addition to these excitatory and proinflammatory effects of neuropeptides, a few studies have revealed apparent inhibitory effects of sensory nerves in airways. These inhibitory effects of capsaicin have been observed in human lung (11, 12) and in isolated human (3), rat (23), and mouse (16) airways. In rat and mouse airways, the relaxation response to capsaicin seems to be due to the release of sensory neuropeptides from capsaicin-sensitive sensory nerves. These neuropeptides activate neurokinin type 1 (NK1) receptors on epithelium and subsequently release the inhibitory prostaglandins that cause relaxation (16, 23). In human airways, Chitano et al. (3) reported that the inhibitory effect of capsaicin may also involve the NK1 receptor, but the mechanism was not clear. However, in a whole cell patch-clamp study on human bronchial smooth muscle cells, Ellis et al. (7) recently demonstrated that capsaicin can enhance outward K+ currents due to activation of large-conductance Ca2+-activated K+ channels. This study indicates that there are tachykinin-independent effects of capsaicin on human smooth muscle cells. We have previously demonstrated that SP does not contract equine tracheal smooth muscle (TSM). In the present studies, we discovered an inhibitory effect of capsaicin on equine TSM precontracted with methacholine (MCh) and investigated both the mechanism of capsaicin-induced relaxation and the role of peptidergic nerves in TSM regulation in the horse.
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MATERIALS AND METHODS |
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Animals. Horses (body wt, 863-997 lb; age, 6-15 yr) were used in this study, which was approved by the All-University Committee on Animal Use and Care of Michigan State University. Horses that had no clinical signs of respiratory disease for several weeks were killed by injection of an overdose of pentobarbital sodium through the jugular vein. Other investigators also used tissues from the same animals for a variety of studies. Postmortem examination revealed that the lungs and airways were normal in gross appearance. A segment of trachea between the 6th and 15th cartilaginous ring above the carina was quickly collected, immersed in Krebs-Henseleit (KH) solution (in mM: 118.4 NaCl, 25.0 NaHCO3, 11.7 dextrose, 4.7 KCl, 2.6 CaCl2 · 2H2O, 1.19 MgSO4 · 7H2O, and 1.16 KH2PO4), and gassed with 95% O2-5% CO2 during the whole experiment.
Preparation of trachealis strips. The trachea was opened longitudinally by dissection of cartilage in its anterior aspect and was pegged flat on a paraffin block submerged by KH solution. TSM strips with epithelium intact were cut with a template along the fiber direction. Strips (2 × 10 mm), tied with 3-0 surgical silk thread on both ends, were suspended between platinum ring electrodes in 15-ml tissue baths that contained KH solution bubbled with 95% O2-5% CO2 and were maintained at 38°C. The lower thread was attached to a hook on the electrode unit, whereas the upper thread was connected to a force transducer (Grass model FTO3) that was mounted on a manipulator to adjust tissue length. Tension produced by the tissue was measured by the transducer and was recorded on a polygraph (Grass model 7E). Tissues were equilibrated for ~100 min with a passive tension (optimal resting tension for trachealis strips) of 2 g applied and maintained. During the equilibration, tissues were repeatedly stimulated by electrical field stimulation (16 Hz, 20 V, 0.5 ms) for 2-3 min at 8- to 10-min intervals until the baseline was stable and the magnitude of the response to this stimulus was consistent. The bath solution was changed every 15 min. After equilibration, the maximal response to 127 mM KCl-substituted KH solution (KClmax) was recorded, and this response was used to normalize the forces developed by the muscle. The tissues were then repeatedly rinsed with KH solution until the muscle tension returned to baseline.
Study design. Isolated horse trachealis does not exhibit intrinsic tone; thus the trachealis strips were contracted with MCh to 50-75% of KClmax to observe the relaxation responses.
Protocol 1: Effects of capsaicin and neuropeptides on TSM
contracted with MCh.
Trachealis was contracted with MCh to ~50-75% of
KClmax, and, after the tension was
stable, except for time-matched MCh control, the tissues were treated
with 104 M capsaicin,
10
8-10
4
M SP, or 10
6 M CGRP. If
CGRP elicited relaxation, the effect of the CGRP antagonist human CGRP
fragment 8-37 (10
6 M)
on CGRP-induced relaxation was also examined.
Protocol 2: Role of epithelium and endogenous prostanoids on
capsaicin-induced relaxation.
Epithelium-denuded trachealis strips were prepared by carefully rubbing
their luminal side with a cotton-tipped applicator. In some strips, the
epithelium was peeled away by grasping the epithelium and lamina
propria with Allis tissue forceps and gently easing the mucosa from the
underlying tissues. These preparations were used to study the effect of
epithelium on capsaicin-induced relaxation. To examine the effect of
endogenous prostanoids, tissues were incubated for 60 min with
106 M meclofenamate, a
cyclooxygenase inhibitor, before the administration of MCh. This
concentration of meclofenamate was chosen because it dramatically
inhibits the TSM endogenous prostanoid synthesis (24).
Protocol 3: Effects of sensory neuropeptide depletion on
capsaicin-induced relaxation.
It previously was demonstrated that
106-10
5
M capsaicin treatment causes neuropeptide depletion from sensory
nerves, rendering them insensitive to further exposure of capsaicin (2,
23). Therefore, to examine the effects of sensory nerve desensitization on inhibitory responses evoked by capsaicin or neuropeptides, the
trachealis strips were incubated for 30 min with
10
5 M capsaicin before
being contracted with MCh. Then
10
4 M capsaicin-induced
relaxation was elicited.
Protocol 4: Role of endogenous nitric oxide and vasoactive
intestinal peptide on capsaicin-induced relaxation.
To examine the effects of endogenous nitric oxide (NO) and
106 M vasoactive intestinal
peptide (VIP) on capsaicin-induced relaxation, we pretreated trachealis
strips with either the NO synthase inhibitor NG-nitro-L-arginine
(L-NNA; 3 × 10
5 M; see Ref. 27) or 2 U/ml
-chymotrypsin. Yu et al. (27) from our laboratory have
demonstrated that 3 × 10
5 M
L-NNA abolishes nitroxidergic
inhibitory nonadrenergic noncholinergic (iNANC)-mediated relaxation of
equine TSM.
Protocol 5: Effect of charybdotoxin on capsaicin-induced
relaxation.
We investigated the role of large-conductance
Ca2+-activated
K+ channels in capsaicin-induced
relaxation. Trachealis strips were incubated for 20 min with 5 × 107 M charybdotoxin before
an attempt to elicit the capsaicin-induced relaxation was made.
Drugs.
Acetyl--methacholine chloride, SP, CGRP, CGRP-(8
37), VIP,
-chymotrypsin, charybdotoxin,
L-NNA, and meclofenamate sodium monohydrate (Sigma Chemical, St. Louis, MO) were dissolved in distilled
water and were diluted in KH solution. Stock solutions of capsaicin
(Sigma Chemical) were prepared in ethanol and were diluted with KH as
appropriate. All the drugs were prepared on the day of the experiment.
Drug solution was pipetted into the tissue bath at 1% of the bath
volume. The final concentration of the drugs was expressed as their
bath molar concentration.
Data analysis. In vitro relaxation responses are represented as percentage of relaxation from the level of contraction induced by MCh. All values are expressed as means ± SE. The effect of treatments was evaluated by an unpaired Student's t-test by Statview II (Abacus Concepts, Calabasas, CA) for the Macintosh computer. P < 0.05 was considered significant; n represents the number of horses studied.
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RESULTS |
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Protocol 1: Effects of capsaicin and neuropeptides on TSM contracted
with MCh.
Capsaicin at a concentration of 100 µM evoked marked relaxation in
equine TSM (Figs. 1 and
2; n = 10). At concentrations <100 µM, capsaicin neither contracted nor
relaxed smooth muscle (data not shown). SP at concentrations up to 100 µM did not elicit relaxation (Fig. 2;
n = 5). In trachealis strips from a
total of five horses, CGRP caused relaxation in only one horse (20%
inhibition). This relaxation was inhibited by the CGRP antagonist human
CGRP fragment 8-37
(106 M; data not shown).
However, the capsaicin-induced relaxation (31.6 ± 2.5% inhibition)
was not affected by pretreatment of tissues with the CGRP antagonist
(29.1 ± 3.9% inhibition; n = 6).
In parallel time-matched control preparations, the spontaneous decline
in MCh-induced tone was only 1.7 ± 1.1% (Fig. 2;
n = 5) over 30 min, the total
observation period of the capsaicin-induced relaxation. The capsaicin
vehicle ethanol had no effect on precontracted TSM (25).
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Protocol 2: Role of epithelium and endogenous prostanoids on
capsaicin-induced relaxation.
Neither denuding nor peeling off of epithelium affected
capsaicin-induced relaxation. Capsaicin-induced inhibitions were 32.9 ± 6.0 and 30.9 ± 5.0% before and after denuding the
epithelium, respectively, and 33.7 ± 6.0 and 31.1 ± 6.0% before and after peeling off of the epithelium, respectively.
Treatment of the tissues with the cyclooxygenase inhibitor
meclofenamate (106 M) had
no effect on relaxation responses to capsaicin. Capsaicin-induced inhibitions were 32.9 ± 6.4 and 33.0 ± 7.4% before and after
meclofenamate, respectively (n = 4).
Protocol 3: Effects of sensory neuropeptide depletion on
capsaicin-induced relaxation.
Depletion of sensory neuropeptides with
105 M capsaicin did not
eliminate relaxation responses upon subsequent addition of 10
4 M capsaicin.
Capsaicin (10
4 M)-induced
inhibition was 39.5 ± 4.9 and 34.1 ± 1.9% with or without
10
5 M capsaicin
pretreatment, respectively (n = 6). In
addition, after 10
4 M
capsaicin-induced relaxation, the second administration of 10
4 M capsaicin to the same
trachealis strip still elicited the same magnitude of relaxation (Fig.
3).
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Protocol 4: Role of endogenous NO and VIP on capsaicin-induced
relaxation.
VIP (106 M) elicited a
rapid and large-magnitude relaxation that was inhibited by pretreatment
of the tissues with the peptidase enzyme
-chymotrypsin (2 U/ml; Fig.
4; n = 5).
However, the capsaicin-induced relaxation was not affected by 2 U/ml
-chymotrypsin (Fig. 4; n = 5).
Pretreatment of tissues with the NO synthase inhibitor L-NNA (3 × 10
5 M) also did not
alter capsaicin-induced relaxation. The capsaicin-induced relaxations
were 32.8 ± 6.3 and 33.3 ± 6.0% before and after
L-NNA pretreatment, respectively
(n = 4).
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Protocol 5: Effect of charybdotoxin on capsaicin-induced relaxation.
Pretreatment of tissue with 5 × 107 M charybdotoxin, the
blocker of the large-conductance
Ca2+-activated
K+ channels, almost totally
abolished the capsaicin-induced relaxation (Fig.
5; n = 5).
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DISCUSSION |
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Neuropeptide-containing sensory nerves have been described in
airways of many species, including the horse. Activation of these
sensory nerve fibers results in the release of NKs such as SP and CGRP.
These peptides induce a number of biological effects within the lungs,
such as airway smooth muscle contraction, mucus secretion, and enhanced
vascular permeability. However, in airways of some species, such as the
Sprague-Dawley rat, mouse, and human, an inhibitory effect of these
neuropeptides has also been reported. Therefore, it seems likely that
the peptidergic nerves may play different physiological and
pathophysiological roles in airway regulation in different species. In
horse TSM, our present study demonstrated that SP, CGRP, and capsaicin
(<104 M) do not produce
either contraction or relaxation. These results indicate that
neuropeptides released from capsaicin-sensitive nerves play no direct
role in the regulation of horse TSM tone. This functional observation
agrees with the patterns of distribution of SP- and CGRP-like
immunoreactive nerves in horse airway. Nerve fibers immunoreactive for
SP or CGRP are most prominently associated with the epithelium and the
vasculature of the airways, where they may play an important role in
the modulation of epithelial and bronchial vascular function (21). Only
a small number of immunoreactive nerve fibers are closely associated
with smooth muscle, suggesting that these neuropeptides have no direct
effect on equine airway smooth muscle. It remains possible that
tachykinins or CGRP may regulate TSM tone indirectly, either by causing
the release of inflammatory mediators from mast cells (22) or by modulation of cholinergic neurotransmission at nerve terminals (4) or
at parasympathetic ganglia (19, 21).
The interesting observation of this study is that capsaicin at a
concentration of 104 M
caused a significant relaxation of horse trachealis TSM. This concentration of capsaicin induced a relaxation of similar magnitude in
human bronchi (7). It is widely accepted that capsaicin selectively
stimulates sensory nerves leading to a local release of sensory
neuropeptides such as tachykinins and CGRP (9, 15). However, in our
present study, direct application of SP or CGRP did not mimic the
capsaicin-induced relaxation. Furthermore, the CGRP antagonist
did not attenuate the capsaicin-induced relaxation. These results
indicated that capsaicin-induced relaxation is not mediated via SP or
CGRP.
In rat and mouse airways, capsaicin induces relaxation through release of prostanoids from the epithelium (16, 23). In equine airway, both epithelium and prostanoids, such as prostaglandin E2, have an inhibitory effect on smooth muscle contraction (26). Therefore, it was possible that capsaicin-induced relaxation in equine TSM may be due to release of prostanoids or another epithelium-derived factor. However, this is unlikely because removal of epithelium and inhibition of endogenous prostanoids by use of the cyclooxygenase inhibitor meclofenamate did not affect the relaxation of TSM to capsaicin.
Capsaicin administration causes a chemical desensitization of sensory
nerves and renders them insensitive to further exposure of capsaicin
(2). In our present studies, pretreatment of the horse trachealis with
capsaicin to deplete sensory neuropeptides did not change the
relaxation responses to subsequent capsaicin. Furthermore, repeated
application of 104 M
capsaicin to the same tissue strips elicited the similar magnitude of
relaxation. These results further confirmed that capsaicin-induced relaxation does not involve the sensory neuropeptides.
Yu et al. (27) have previously reported that the iNANC system is a
major inhibitory nervous system in equine airway and that
neurotransmission involves NO. Because NO synthase and VIP have been
colocalized with SP in the same nerve fibers and cell bodies of cat and
ferret airways (5, 6), we hypothesized that the capsaicin-induced
relaxation response may be due to activation of NO synthase or release
of VIP. This, however, does not appear to be the case. The NO synthase
inhibitor L-NNA was without
effect on the relaxant responses to capsaicin. VIP is a very potent
relaxant of airway smooth muscle of many species, and capsaicin can
induce release of VIP-like immunoreactivity from guinea pig airways
(13). Therefore, we further investigated the effect of VIP on horse trachealis and the role of VIP on capsaicin-induced relaxation response. VIP elicited a marked relaxation in horse
trachealis. The relaxation to VIP was different from that of capsaicin,
being more rapid and of greater magnitude. Even though the peptidase enzyme -chymotrypsin eliminated the VIP-induced relaxation
response, capsaicin-induced relaxation was not affected by
-chymotrypsin. These results indicate that VIP has a strong
inhibitory effect in equine TSM but does not mediate the relaxation to
capsaicin.
The results discussed so far indicate that the capsaicin-induced
relaxation does not involve either sensory neuropeptides released from
capsaicin-sensitive nerves or endogenous prostanoids, epithelium, NO,
or VIP. It is therefore plausible to hypothesize that
104 M capsaicin may have a
direct effect on smooth muscle cells, possibly acting via an inhibitory
ion channel. In whole cell patch-clamp studies on human isolated
bronchial smooth muscle cells, Ellis et al. (7) have recently reported
that capsaicin can activate charybdotoxin-sensitive large-conductance
Ca2+-activated
K+ channels. Activation of these
channels tends to hyperpolarize the membrane and leads to relaxation.
We tested this possibility by examining the effect of charybdotoxin, a
potent blocker of large-conductance
Ca2+-activated
K+ channels, on capsaicin-induced
relaxation in equine TSM. In our experimental conditions, pretreatment
of the tissue with charybdotoxin virtually abolished the
capsaicin-induced relaxation. This observation indicates that
relaxation is due to the activation of these large-conductance Ca2+-activated
K+ channels. Capsaicin therefore
appears to have two mechanisms of action in the airways. First, it
stimulates sensory nerves, causing release of neuropeptides; and
second, at a high concentration, it activates the
charybdotoxin-sensitive large-conductance
Ca2+-activated
K+ channels of the smooth muscle.
When capsaicin is used in pharmacological studies, both effects need to
be considered in data interpretation.
In summary, our present study has demonstrated that in equine TSM 1) sensory neuropeptides released from capsaicin-sensitive nerves have no direct effect on smooth muscle tone, 2) VIP is a potent relaxant, and 3) capsaicin at high concentrations can activate charybdotoxin-sensitive large-conductance Ca2+-activated K+ channels and cause relaxation of TSM.
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ACKNOWLEDGEMENTS |
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We thank Cathy Berney for technical assistance and Victoria Hoelzer-Maddox and MaryEllen Shea for manuscript preparation.
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FOOTNOTES |
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Address for reprint requests: F.-X. Zhu, Dept. of Large Animal Clinical Sciences, Michigan State Univ., East Lansing, MI 48824-1314.
Received 21 April 1997; accepted in final form 30 July 1997.
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