MEN16132, a kinin B2 receptor antagonist, prevents the endogenous bradykinin effects in guinea-pig airways.
Kinins have been suggested to be involved in human airway diseases such as asthma and rhinitis. MEN16132 is a non-peptide kinin B(2) receptor antagonist able to inhibit the responses produced by intravenous bradykinin into the airways, as bronchoconstriction and microvascular leakage; we tested the effect of MEN16132 on endogenously generated bradykinin through the dextran sulfate-induced contact activation of kinin-kallikrein cascade in guinea-pigs. After dextran sulfate administration (1.5 mg/kg i.v.), the pulmonary insufflation pressure was monitored and the microvascular leakage of upper and lower airways was assessed using Evans blue as tracer of plasma protein extravasation. Our results demonstrated that topical MEN16132 strongly inhibited the dextran sulfate-induced bronchoconstriction (0.3 mM solution aerosol for 5 min) and plasma protein extravasation in both lower airways (3-10 microM solution aerosol for 5 min) and nasal mucosa (0.3 nmol/nostril); Icatibant, the peptide antagonist of kinin B(2) receptor, exerted a 3-30-fold less potent inhibitory effect than MEN16132. We conclude that local application of MEN16132 into the airways abolishes the responses produced by the endogenous generation of bradykinin and it can be useful as new pharmacological tool to check the role of kinins in human diseases.
Pharmacology Department, Menarini Ricerche S.pA.,Via Rismondo 12A, 50131 Florence, Italy.
Claudio
C
Valenti
Cecilia
C
Cialdai
Sandro
S
Giuliani
Manuela
M
Tramontana
Laura
L
Quartara
Carlo Alberto
CA
Maggi
D000281:Administration, Intranasal; D000336:Aerosols; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects*; D016264:Dextran Sulfate; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D016234:Kallikrein-Kinin System / Q000187:drug effects; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
C506838:(4-amino-5-(4-(4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)tetrahydro-2H-4-pyranoylcarbonyl)piperazino)-5-oxopentyl)(trimethyl)ammonium; D000336:Aerosols; D001798:Blood Proteins; D065094:Bradykinin B2 Receptor Antagonists; D013449:Sulfonamides; C065679:icatibant; D016264:Dextran Sulfate; D009952:Ornithine; D001920:Bradykinin