Involvement of B2 receptors in the bradykinin-induced relaxation of guinea-pig isolated trachea.
1. The aim of this study was to determine the receptor type and involvement of arachidonic acid metabolites in bradykinin-induced relaxation of the guinea-pig isolated trachea. 2. In the resting tracheal preparation, bradykinin (0.1 nM-30 microM induced a concentration-related contractile response (pD2 = 8.8 +/- 0.3). The maximal tension (1056 +/- 321 mg) was observed at 0.3 microM bradykinin. In contrast, when tracheal preparations were pre-contracted with histamine (30 microM leading to a half-maximum response), a concentration-related relaxation was observed with bradykinin. At the highest concentration of bradykinin used (3 microM), a reversal of 63 +/- 13% of the contractile response to histamine was observed. Both effects of bradykinin were inhibited by the cyclo-oxygenase inhibitor, indomethacin (1 microM). In concentration-response curves, melittin (10 nM-1 microM), a direct activator of phospholipase A2, mimicked both effects of bradykinin. The highest concentration of melittin used (1 microM), induced a tension of 813 +/- 120 mg and led to the reversal of 41 +/- 8% of the contractile response to histamine. The contractile effect of melittin was inhibited in the presence of both indomethacin (1 microM) and AA861 (1 microM), a 5-lipoxygenase inhibitor. 3. [Des Arg9]-bradykinin (1 nM-3 microM), a B1-receptor agonist, was unable to relax precontracted guinea-pig tracheal preparations. The relaxation induced by bradykinin was antagonized by the B2 receptor antagonists, Hoe 140 (D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin) and NPC 17761 (D-Arg0[Hyp3,D-HypE(trans-thiophenyl)7,Oic8]bradykinin ). Hoe 140 (0.1 microM to 0.6 microM) behaved as a non-competitive antagonist with an apparent pA2 = 7.2 +/- 0.4, whereas NPC 17761 (0.3 to 1 microM) competitively antagonized bradykinin-induced relaxation with a pKB = 7.3 +/- 0.2. The Schild regression slope did not differ from unity, 0.96 +/- 0.20, P<0.05.4. These data demonstrate that bradykinin-induced relaxation of guinea-pig trachea occurs via the activation of bradykinin B2-receptors. The stimulation of B2-bradykinin receptors induces the activation of the cyclo-oxygenase pathway, leading either to contraction or relaxation depending on the tone of the trachea.
Da Silva
A
A
Laboratoire de Neuroimmunopharmacologie, INSERM-U405, Université Louis Pasteur Strasbourg I, Faculté de Pharmacie, Illkirch, France.
Amrani
Y
Y
Trifilieff
A
A
Landry
Y
Y
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D008555:Melitten / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D012063:Relaxation; D015244:Thiorphan / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects*
D018343:Receptors, Adrenergic, beta-2; C083947:NPC 17761; D008555:Melitten; C065679:icatibant; D015244:Thiorphan; D001920:Bradykinin