Objective—To evaluate 3 neurokinin-2 (NK2) receptor
antagonists on the basis of their ability to block neurokinin
A (NKA)-induced contractile responses in various
regions of the guinea pig respiratory tract.
Animals—48 clinically normal guinea pigs.
Procedure—After euthanasia, the trachea and lungs
were removed en bloc. The spirally cut trachea was
divided into lower, middle, and upper portions. The
main bronchus was spirally cut. A lung strip was cut
from the edge of the lung. Tissue strips were mounted
in organ baths containing Tyrode solution at 37°C
and attached to force transducers interfaced with a
polygraph. Lung strips were set at a tension of 1 g;
other tissue strips were set at 2 g. After 45 minutes
of equilibration, cumulative concentration-response
(CR) relationships to graded concentrations of NKA
were determined. In the treatment groups, tissues
were incubated (30 minutes) with antagonists (MEN
10376, SR 48968, and SR 144190) at 3 concentrations
(10–9, 10–7, and 10–5M) before CR relationships were
determined. Effectiveness of SR 48968 against NKA
was also tested in vivo.
Results—Lung strips failed to contract, but all others
responded in a concentration-dependent manner.
Bronchial spirals were most sensitive. SR 48968 had
the highest pA2 value and effectively blocked NKA.
Conclusions and Clinical Relevance—The bronchial
region where airflow resistance is high was the most
sensitive to NKA, suggesting the importance of NKA
in bronchoconstriction. Nonpeptide antagonists (SR
48968 and SR 144190) were more potent than the
peptide antagonist (MEN 10376), indicating their
greater therapeutic potential as antiasthmatic agents.
( Am J Vet Res 2004;65:984–991)
Objective—To evaluate the in vitro effects of adenosine
tryphosphate (ATP) on vasomotor tone of equine
Sample Population—Arteries and veins from the left
ventral colon of 14 mixed-breed horses euthanatized
for reasons unrelated to cardiovascular or gastrointestinal
Procedures—Endothelium-intact and -denuded arterial
and venous rings were precontracted with 10–7 and
1.8 × 10–8M endothelin-1, respectively. In 1 trial,
endothelium-intact rings were also incubated with
10–4M Nω-nitro-L-arginine methyl ester (L-NAME) to
inhibit nitric oxide (NO) production. Adenosine
triphosphate (10–8 to 10–3M) was added in a noncumulative
manner, and relaxation percentage versus time
curves were generated. Areas under the curves (ie,
percentage of relaxation time) were calculated.
Results—Relaxation response of arterial and venous
rings to ATP was dose-dependent. Percentage of
relaxation time in response to 10–4 and 10–3M ATP was
significantly greater, compared with that for rings not
treated with ATP. Removal of endothelium attenuated
but did not eliminate the relaxation response. Addition
of L-NAME did not attenuate the relaxation response
in arteries. At higher concentrations, the vascular
response to ATP was biphasic.
Conclusions and Clinical Relevance—ATP applied to
equine colonic arterial and venous rings with and without
intact endothelium induced a biphasic response
characterized by transient contraction followed by slow,
substantial, and sustained relaxation. This ATP-induced
response is possibly mediated by a mechanism other
than NO. Adenosine triphosphate may be a useful
treatment to modulate colonic vasomotor tone in horses
with strangulating volvulus of the ascending colon.
(Am J Vet Res 2001;62:1928–1933)
Objective—To compare responses of bronchial rings
obtained from healthy horses and horses affected
with summer pasture-associated obstructive pulmonary
disease (SPAOPD) to selected mediators of
airway hyperreactivity in vitro.
Sample Population—Bronchial rings from 6 healthy
horses and 6 horses affected with SPAOPD.
Procedure—Bronchial rings obtained from each
group of horses were mounted in organ baths and
attached to force transducers interfaced with a polygraph.
After applying 2g of tension, each ring was
allowed to equilibrate for 45 minutes in Tyrode's solution
at 37 C. Cumulative concentration-response relationships
to graded concentrations of selected mediators
(10–8 to 10–4 M ) were determined and analyzed
for significance at each concentration.
Results—Acetylcholine, histamine, 5-hydroxytryptamine,
and leukotriene D4 induced concentrationdependent
contractile responses in bronchial rings.
Prostaglandin F2α induced weak and inconsistent contractile
responses. The other 2 agents, norepinephrine
and substance P, did not induce concentrationdependent
responses. Considering the overall groupdrug
effect, acetylcholine, histamine, 5-hydroxytryptamine,
and leukotriene D4 were effective in inducing
consistent concentration-dependent contractile
responses in both groups. Only 5-hydroxytryptamine
and histamine induced significant responses
in contractility between groups. The response of
bronchial rings from horses with SPAOPD to 5-hydroxytryptamine
was significantly greater than those
from control horses, whereas the response to histamine
was significantly lower. Significant responses
were evident at concentrations ranging from 10–6 to
10–4M for both drugs.
Conclusions and Clinical Relevance—Because the
airways of horses with SPAOPD had increased
responsiveness to 5-hydroxytryptamine in vitro, treatment
modalities using 5-hydroxytryptamine antagonists
should be investigated to address this phenomenon.
(Am J Vet Res 2001;62:259–263).
Objective—To evaluate the effectiveness of 2 potential
endothelin (ET)-1 antagonists in blocking the contractile
responses of equine colonic vessels to
increasing concentrations of ET-1.
Sample Population—Mesenteric vessels from 6
clinically healthy horses.
Procedure—Colonic vessels (arterial and venous
rings) were placed in organ baths with oxygenated
Tyrode solution at 37 C. Each was attached to a force
transducer interfaced with a polygraph, and 2 g of
tension was applied and equilibrated for 45 minutes.
Then, B-1 (PD 142893) and B-2 (PD 145065) ET-1
antagonists were tested. One ring from each vessel
type was used as a control for determining concentration-
response relationships of ET-1 (10–10 to 10–6M).
Three rings of each vessel type were incubated with
3 concentrations of each antagonist (10–7, 10–6, and 10
–5M) for 30 minutes before ET induced contractions
were determined. The maximum contractile
response and pA2 values were determined.
Results—Vessels contracted in a concentrationdependent
manner to ET-1. Arteries responded slowly
but reached greater contractions. Veins responded
immediately with sustained contractions. Both antagonists
inhibited contractions in a concentrationdependent
manner with significant differences at 10–6
and 10–5M for arteries and 10–5M for veins. Complete
blockade of contractions was observed with B-2
(10–5M). The pA2 values for B-1 were 8.26 and 6.82 for
arteries and veins, respectively, whereas they were
8.25 and 7.21 for B-2.
Conclusion and Clinical Relevance—Both antagonists
effectively blocked ET-1-induced contractions of
equine colonic vessels. Because B-2 is water soluble
and caused complete blockade at 10–5M, it appears to
be the preferred antagonist. (Am J Vet Res 2001;62:154–159)