Pharmacologic evaluation of neurokinin-2 receptor antagonists in the guinea pig respiratory tract

Changaram S. Venugopal Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

Search for other papers by Changaram S. Venugopal in
Current site
Google Scholar
PubMed
Close
 BVSc, PhD
,
Craig L. Christopher Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

Search for other papers by Craig L. Christopher in
Current site
Google Scholar
PubMed
Close
 MS
,
Shawn M. Wilson Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

Search for other papers by Shawn M. Wilson in
Current site
Google Scholar
PubMed
Close
 BS
,
Sumanth Polikepahad Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

Search for other papers by Sumanth Polikepahad in
Current site
Google Scholar
PubMed
Close
 BVSc
,
Elizabeth Dequeant Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

Search for other papers by Elizabeth Dequeant in
Current site
Google Scholar
PubMed
Close
 BA
, and
Earnestine P. Holmes Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

Search for other papers by Earnestine P. Holmes in
Current site
Google Scholar
PubMed
Close
 BS

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)

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)

Advertisement