Tachykinin-induced bronchoconstriction in sheep is NK-1 receptor mediated and exhibits tachyphylaxis.
OBJECTIVE
Tachykinins are mediators of airway hyper-reactivity and inflammation. There is in vitro evidence that ovine responses to tachykinins correlate closely to human responses. This study was designed to characterize the effect of intravenously administered tachykinins on sheep lung resistance in vivo to determine the effect of dose timing on reproducibility of responses and the induction of tachyphylaxis. We then used this information to help further characterize the response with several pharmacological agents.


METHODS
Substance P (SP) was administered by infusion to conscious merino ewes and lung resistance (RL) was measured. Infusions were given at 30, 60, 120 min and 24 h intervals. The effect of various agents on the response to SP was then assessed.


RESULTS
Substance P led to a transient increase in RL, mean (+/- SEM) 754.8 (+/- 139)% of baseline, with marked tachyphylaxis at 30, 60 and 120 min. Phosphoramidon increased the peak response to 1151.5 +/- 196%. Atropine and CP 96 345 abolished the response to SP, while indomethacin, sodium cromoglycate and pyrilamine had no significant effect. Substance P had a greater effect on RL than did neurokinin A.


CONCLUSIONS
Substance P increases RL in sheep via a cholinergic mechanism which is mediated by NK-1 receptors, and is subject to tachyphylaxis. These findings have implications for the design of studies using the ovine model in the evaluation of tachykinin antagonists as potential therapeutic agents.
Rice
A J
AJ
Department of Preventive Medicine, University of Wisconsin-Madison,Wisconsin, USA. tonyrice@mail.com
Reynolds
P N
PN
Reynolds
A M
AM
Holmes
M D
MD
Scicchitano
R
R
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D001993:Bronchodilator Agents / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D015203:Reproducibility of Results; D012756:Sheep; D013373:Substance P / Q000502:physiology*; D013618:Tachyphylaxis
D001993:Bronchodilator Agents; D006634:Histamine H1 Antagonists; D018040:Receptors, Neurokinin-1; D013373:Substance P; D001285:Atropine