EFFECT OF CP-96,345, A NONPEPTIDE NK1 RECEPTOR ANTAGONIST, AGAINST SUBSTANCE P-INDUCED, BRADYKININ-INDUCED 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 (R(L)) 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 R(L) 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 R(L) 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.