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  • Author or Editor: Earnestine P. Holmes x
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Abstract

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)

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in American Journal of Veterinary Research

Abstract

Objective—To evaluate the in vitro effects of adenosine tryphosphate (ATP) on vasomotor tone of equine colonic vasculature.

Sample Population—Arteries and veins from the left ventral colon of 14 mixed-breed horses euthanatized for reasons unrelated to cardiovascular or gastrointestinal tract disease.

Procedures—Endothelium-intact and -denuded arterial and venous rings were precontracted with 10–7 and 1.8 × 10–8 M endothelin-1, respectively. In 1 trial, endothelium-intact rings were also incubated with 10–4 M Nω-nitro-L-arginine methyl ester (L-NAME) to inhibit nitric oxide (NO) production. Adenosine triphosphate (10–8 to 10–3 M) 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 10–3 M 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)

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in American Journal of Veterinary Research

Abstract

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 F 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 10–4 M 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).

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in American Journal of Veterinary Research

Abstract

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 10–6 M). Three rings of each vessel type were incubated with 3 concentrations of each antagonist (10–7, 10–6, and 10 –5 M) 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 10–5 M for arteries and 10–5 M for veins. Complete blockade of contractions was observed with B-2 (10–5 M). 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 10–5 M, it appears to be the preferred antagonist. (Am J Vet Res 2001;62:154–159)

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in American Journal of Veterinary Research