Conscious guinea-pig aerosol model for evaluation of peptide leukotriene antagonists.
A new conscious animal model for evaluating leukotriene antagonists is described. The model consists of monitoring the change in the respiratory pattern induced by aerosol administration of various airway constrictors in six guinea pigs secured in a plexiglass chamber by a neck yoke. The animals are pretreated with indomethacin (10 mg/kg, i.p.) and propranolol (5 mg/kg, i.p.) 30 min prior to the challenge. After a 30-min stabilization period, the animals are challenged by various agonists delivered via a Monaghan ultrasonic nebulizer at a flow rate of 2.0 L/min for 5 min. The end point is defined as the onset of slow, labored abdominal breathing (dyspnea) measured in seconds. Peptide leukotrienes (LTs) (30 nM-60 microM) produced concentration-related decreases in time to dyspnea with a rank order of potency of LTD4 greater than LTC4 greater than LTE4. LTD4 was 1,000-fold more potent than histamine or carbachol. Pretreatment of the animals with either FPL55712 or LY171883 delayed the time to reach dyspnea induced by LTD4. In contrast, pyrilamine, cyproheptadine, and phenoxybenzamine failed to alter LTD4-induced dyspnea. The results indicate that this model is useful in assessing the efficacy of LT receptor antagonists in vivo.
Snyder
D W
DW
Department of Pharmacology, Stuart Pharmaceuticals, Wilmington, Delaware.
Liberati
N J
NJ
McCarthy
M M
MM
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001273:Atmosphere Exposure Chambers; D002217:Carbachol / Q000008:administration & dosage / Q000494:pharmacology; D004333:Drug Administration Routes; D004338:Drug Combinations; D004417:Dyspnea / Q000139:chemically induced / Q000503:physiopathology; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D017999:Leukotriene E4; D008297:Male; D008954:Models, Biological; D011433:Propranolol / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects*; D013189:SRS-A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000336:Aerosols; D004338:Drug Combinations; D013189:SRS-A; D017999:Leukotriene E4; D006632:Histamine; D002217:Carbachol; D011433:Propranolol; D007213:Indomethacin