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


METHODS
48 clinically normal guinea pigs.


METHODS
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 degrees 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(-5)M) 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
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.
Venugopal
Changaram S
CS
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
Christopher
Craig L
CL
Wilson
Shawn M
SM
Polikepahad
Sumanth
S
Dequeant
Elizabeth
E
Holmes
Earnestine P
EP
D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008168:Lung / Q000378:metabolism; D008782:Methylurea Compounds / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014132:Trachea / Q000378:metabolism
D001549:Benzamides; D008782:Methylurea Compounds; D009025:Morpholines; D010446:Peptide Fragments; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C110304:SR 144190; C069192:neurokinin A(4-10), Tyr(5)-Trp(6,8,9)-Lys(10)-; C073839:SR 48968; D015288:Neurokinin A