1. The aim of this study was to characterize the kinin receptor in the human nasal airway using [125I]-Hoe 140 binding to a membrane preparation from human nasal turbinates and to compare Ki values from binding displacement by antagonists with the functional effects of these drugs in vivo. We also investigated the effect of Hoe 140 ([D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-bradykinin), on bradykinin release into the nasal airway. 2. In a membrane preparation from human nasal turbinates removed during surgery, [125I]-Hoe 140 labelled a single, saturable binding site. The equilibrium dissociation constant (at 20 degrees C) for [125I]-Hoe 140 binding to the receptor was 0.46 +/- 0.08 nM. The Bmax was 0.136 +/- 0.003 pmol mg-1 protein and the Hill coefficient was 1.01 +/- 0.07. 3. The association rate constant for [125I]-Hoe 140 binding to the receptor was 0.20 +/- 0.06 nM-1 min-1 and the dissociation rate constant was 0.14 +/- 0.01 min-1. These values were determined at 4 degrees C. The equilibrium dissociation constant calculated from these rate constants was 0.70 nM. 4. Bradykinin and the B2 receptor antagonists, NPC 567, NPC 17731, NPC 17761, [1-adamantane acetyl-D-Arg0, Hyp3, Thi5,8, D-Phe7]-bradykinin, WIN 64338 and Hoe 140 displaced [125I]-Hoe 140 binding: the Ki values from binding displacement are consistent with values expected from a B2 receptor. The B1 agonist, [des-Arg9]-bradykinin and the B1 antagonist, [des-Arg9]-Hoe 140 failed to displace [125I]-Hoe 140 binding at concentrations up to 1 microM. 5. The bradykinin antagonist, Hoe 140, 10 to 200 micrograms, given by intranasal aerosol, produced a dose-related inhibition of the reduction in minimal nasal cross-sectional area (Amin) induced by bradykinin in normal subjects and by house dust mite antigen in subjects with allergic rhinitis to house dust mite. Hoe 140, 10 to 200 micrograms, also caused a dose-related inhibition of the release of albumin into the nasal cavity following challenge with bradykinin. 6. [1-Adamantane acetyl-D-Arg0, Hyp3, Thi5,8, D-Phe7]-bradykinin, 30 to 200 micrograms, caused a dose-related inhibition of the reduction in Amin and the release of albumin into the nasal cavity induced by bradykinin. NPC 567 ([D-Arg0, Hyp3, D-Phe7]-bradykinin) failed to inhibit the reduction in Amin or the release of albumin into the nasal cavity at a dose of 10 mg. 7. Challenge of allergic subjects with house dust mite antigen caused a significant elevation of the bradykinin concentration in nasal lavage fluid and a reduction in Amin. Hoe 140, 100 micrograms, prevented the antigen-induced reduction in Amin and also abolished the antigen-induced increase of bradykinin in nasal lavage fluid. 8. We conclude that there is a B2 bradykinin receptor in the human nasal airway which mediates nasal blockage and plasma extravasation induced by either bradykinin or antigen challenge. It is possible that Hoe 140 inhibits kallikrein in the human nasal airway as well as blocking the B2 receptor.

01 Aug 1995·European Journal of PharmacologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Valfredo Schlemper ; João B. Calixto

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.

01 Apr 1995·British Journal of PharmacologyQ2 · MEDICINE

Mechanisms of bradykinin‐induced contraction of the guinea‐pig gallbladder in vitro

Q2 · MEDICINE

Article

Author: Ana M. Silva ; Daniela A. Cabrini ; João B. Calixto

The mechanisms underlying bradykinin (BK)‐mediated contractions in strips of guinea‐pig gallbladder (GPG) were examined by use of selective bradykinin (BK) receptor agonists and antagonists.

Addition of BK and related kinins (0.1 pM‐10μm) after 2 h of equilibration of the preparation caused graded contractions characterized by two distinct phases: high affinity (0.1 pM‐1 nM) and low affinity (3 nM‐10 μm). The rank order of potency for the first phase (mean EC50, PM) was: BK (1.36) = Hyp3‐BK (1.44) = Lys‐BK (1.54)>Tyr8‐BK (2.72)> Met‐Lys‐BK (4.30). The rank order of potency for the second phase (mean EC50, nM, at concentration producing 50% of the contraction caused by 80 mM KC1) was: Hyp3‐BK (8.95)> Met‐Lys‐BK (12.78)>Tyr8‐BK (33.75)> Lys‐BK (60.92)> BK (77.35). The contractile responses (g of tension) to 3 μm of BK (the highest concentration tested) were: Hyp3‐BK, 1.76 ±0.09; BK, 1.65 ±0.12; Lys‐BK, 1.45 ±0.13; Tyr8‐BK, 1.36 ±0.15 and Met‐Lys‐BK, 1.36 ±0.15. The selective B1 agonist, des‐Arg9‐BK, caused only a weak contraction with maximal response (0.21 ± 0.05 g), which corresponded to approximately 10% of that induced by BK.

BK‐induced contraction in GPG was inhibited by indomethacin (3 μm) or ibuprofen (30 μm), and was partially reduced by phenidone (30 μm), but was not affected by atropine (1 μm), nicardipine (1 μm), Ca2+‐free medium plus EGTA, dazoxiben (30 μm), L‐655,240 (10 nM, a selective receptor antagonist of thromboxane A2), MK‐571 (0.1 μm, a selective leukotriene D4 receptor antagonist), tetrodotoxin (0.3 μm), CP 96,345 (0.3 μm, a NK1 receptor antagonist), mepyramine (1 μm), glibenclamide (1 μm), H‐7 (3 μm), staurosporine (100 nM), or phorbol 12‐myristate 13‐acetate (1 μm). However, BK‐induced contractions in GPG maintained in Ca2+‐free medium were markedly attenuated by ryanodine (10 μm).

Prostaglandin E2, prostaglandin F2α or U46619 (0.1 nM to 100 μm), caused concentration‐dependent contractions in GPG with mean EC50S of 3.1 μm; 1.7 μm and 0.47 nM and maximal responses of 1.36 ±0.15; 1.32 ±0.20 and 0.96 ± 0.09 g, respectively.

The selective B2 receptor antagonists, Hoe 140, NPC 17731 and NPC 17761 (0.01‐1 μm), caused concentration‐dependent displacements to the right of the contractile concentration‐response curve for BK. The selective B1 receptor antagonist, des‐Arg9‐[Leu8]‐BK (1 μm), did not affect BK‐induced GPG contraction.

These data suggest that both high and low affinity BK responses in GPG are mediated by activation of B2 receptors, and that BK‐mediated contraction in GPG depends on the release of intracellular Ca2+ sources sensitive to ryanodine. In addition, BK‐induced contraction in GPG is mediated by release of proinflammatory eicosanoid(s) derived from the cyclo‐oxygenase pathway from arachidonic acid metabolism unrelated to thromboxane A2, and seems not to be coupled to activation of a protein kinase C‐dependent mechanism.

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Indication	Highest Phase	Country/Location	Organization	Date
Sepsis	Preclinical	-	Scios, Inc.	01 Jan 1993

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