Biology Reference
In-Depth Information
The role of tachykinins in the regulation of airway function has been under even
more intense investigation since the demonstration that the atropine-resistant contrac-
tion (about 60% of the contractions that can be induced by electrical field stimulation
[EFS]) in guinea pig airways was ascribable to transmitters released from substance
P-containing afferent neurons
[50]
. Such a noncholinergic bronchoconstriction has
not been consistently demonstrated in human airways. Human bronchi respond to
EFS with a fast, cholinergic contraction followed by a slow relaxation. However, in a
few bronchial preparations, a small, noncholinergic contraction was seen upon EFS
[51]
. The fact that capsaicin, which mediates tachykinin release, contracts human
bronchi has led to the hypothesis that similar noncholinergic excitatory nerves exist
in human airways
[52]
. This was further supported by the observation that up to 45%
of isolated human bronchi contracted spontaneously when peptidase inhibitors were
added to the organ bath
[53]
. Moreover, tachykinin receptor antagonists blocked the
capsaicin-induced contraction
[54]
. However, other studies did not confirm the latter
finding
[55]
. Inhalation of capsaicin-induced bronchoconstriction in normal volun-
teers, but this response was considered a vagally mediated cholinergic reflex
[56]
. At
present, it is unclear whether excitatory noncholinergic, nonadrenergic mechanisms
exist in human airways.
In guinea pig airways, tachykinin NK
2
receptors (and to a lesser extent tachykinin
NK
1
receptors) have been shown to be involved in the bronchoconstrictor response
to exogenous tachykinins, capsaicin, and EFS
[57-59]
. Strain differences were
observed in rats: more particularly, in BDE rats, contraction is mediated via tachyki-
nin NK
2
receptors, whereas in Fisher 344 rats, contraction is mediated via tachykinin
NK
1
receptors
[60,61]
. In humans, it has long been thought that only tachykinin NK
2
receptors were involved in the direct contraction of isolated bronchi
[62]
. However,
in small-diameter bronchi, tachykinins also cause contraction via stimulation of
tachykinin NK
1
receptors
[63]
. In medium-sized bronchi, tachykininergic contraction
is partially mediated through tachykinin NK
1
receptors
[64]
.
Tachykinin-induced contractions of guinea pig airways and isolated human bron-
chi are direct effects, as antihistamines and muscarinic receptor antagonists do not
influence them
[51]
. In human medium-sized bronchi, activation of the tachykinin
NK
1
receptor on the smooth muscle caused inositoltriphosphate formation and rise
of intracellular calcium levels and subsequent contraction of the smooth muscle
cells
[64]
. However, in small-diameter bronchi, contraction appears to be mediated
through the formation of prostanoids, which represents an indirect mechanism
[63]
.
Another possible indirect mechanism by which tachykinins could mediate con-
traction is the facilitation of cholinergic contraction. Substance P facilitated release
of acetylcholine from postganglionic cholinergic nerves in guinea pig
[65]
, rabbit
[66]
, and human airways
[67,68]
, probably through the tachykinin NK
1
receptor. In
guinea pig trachea, tachykinin NK
2
receptors were also found to be involved in the
facilitation of acetylcholine release
[69]
. Substance P is also known to induce degran-
ulation of human and rat mast cells, with subsequent release of histamine and sero-
tonin, which in turn could cause contraction
[70,71]
. Both a receptor-dependent and a
receptor-independent mechanism have been reported for mast-cell activation induced
by substance P. Higher (micromolar) concentrations caused a direct activation
