Effect of CP-96,345, a non-peptide NK1 receptor antagonist, against substance P-, bradykinin- and allergen-induced airway microvascular leakage and bronchoconstriction in the guinea pig.
We have investigated the effect of a new non-peptide NK1 receptor antagonist, CP-96,345, against substance P (SP)-, bradykinin (BK)- and allergen-induced airway microvascular leakage, bronchoconstriction and hypotension in anesthetized guinea pigs. Lung resistance (RL) and mean systemic blood pressure (BP) were measured for 6 min after challenge, followed by measurement of extravasation of Evans blue dye into airway tissues, used as an index of airway microvascular leakage. I.v. (2 nmol/kg) and inhaled (1 mM, 45 breaths) SP, i.v. (15 nmol/kg) and inhaled (1 mM, 45 breaths) BK and aerosolized allergen (5 mg/ml of ovalbumin, 30 breaths) induced a significant increase in RL and leakage of dye at all airway levels, and decreased BP significantly except for inhaled BK. CP-96,345 (2 mg/kg i.v.) abolished the dye extravasation induced by both SP. CP-96,345 partly inhibited the responses induced by both BK but not by allergen. CP-96,345 markedly inhibited the increase in RL and fall in BP induced by SP but not by BK or allergen. NK1 receptor-mediated mechanisms may contribute to SP- and BK-induced airway microvascular leakage and SP-induced bronchoconstriction and hypotension. These mechanisms are not important in the acute airway responses induced by inhaled allergen.
Sakamoto
T
T
Department of Thoracic Medicine, National Heart and Lung Institute, London, UK.
Barnes
P J
PJ
Chung
K F
KF
D000280:Administration, Inhalation; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001920:Bradykinin / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D016084:Bronchoconstriction / Q000187:drug effects*; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006168:Guinea Pigs; D007114:Immunization; D007275:Injections, Intravenous; D008833:Microcirculation / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D013373:Substance P / Q000008:administration & dosage / Q000037:antagonists & inhibitors*
D000485:Allergens; D001713:Biphenyl Compounds; D013373:Substance P; D001920:Bradykinin; C066892:CP 96345