Mechanisms involved in the relaxant response of bradykinin in epithelium intact strips of the guinea-pig trachea.

Kinins caused graded relaxations in guinea-pig trachea with epithelium under spontaneous or carbachol-induced tone. The order of potency was: [Tyr8]bradykinin > lysyl-bradykinin > bradykinin > methionyl-lysyl- bradykinin. The bradykinin B1 receptor agonist des-Arg9-bradykinin (1 microM) was inactive. Relaxation in response to bradykinin (100 nM) was unaffected by tetrodotoxin (0.3 microM), nicardipine (1 microM), Ca(2+)-free solution without or plus ryanodine (10 microM), propranolol (1 microM), glibenclamide (1 microM), staurosporine (0.3 microM), nickel chloride (100 microM) or [D-p-Cl-Phe6,Leu17]VIP (a vasoactive intestinal peptide receptor antagonist, 0.03 microM), but was partially inhibited by apamin (0.3-1 microM). Both HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin) and NPC 17761 (D-Arg0[Hyp3,D-HypeE(trans-thiophenyl)7,Oic8]bra dykinin) (0.1-1000 nM) caused graded, reversible and selective inhibition of the bradykinin (100 nM) relaxation, with IC50 values of 1.4 and 19.1 nM, respectively. HOE 140 and NPC 17761 (0.1-10 nM) produced a graded shift to the right of the bradykinin concentration-response curves associated with a reduction of the maximum relaxation. The kinin B1 receptor antagonist, des-Arg9-[Leu8]bradykinin (1 microM), was inactive. Thus, bradykinin-induced relaxation in guinea-pig trachea results from activation of bradykinin B2 receptors and can be antagonized with high affinity in a selective and reversible manner, through noncompetitive mechanism, by both HOE 140 and NPC 17761. In addition, the bradykinin response does not involve neural pathways, extracellular Ca2+ influx or mobilization of intracellular Ca2+ stores sensitive to ryanodine, but is modulated by small conductance Ca(2+)-activated K+ channels.