NITRIC-OXIDE PATHWAY-MEDIATED RELAXANT EFFECT OF BRADYKININ IN THE GUINEA-PIG ISOLATED TRACHEA

1 The effects of two nitric oxide (NO) biosynthesis-inhibitors NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) on the relaxation induced by bradykinin (BK, 100nM), isoprenaline (Iso, 1 mu M) and sodium nitroprusside (SNP, 1 mu M) were investigated in epithelium-intact strips of guinea-pig isolated trachea. 2 Relaxations induced by BK (100 nM) in guinea-pig tracheal strips under spontaneous tone were inhibited in a concentration-related manner by L-NOARG and L-NMMA (1 to 100 mu M), with IC(50)s (and 95% confidence limits) of 9.1 (6.9- 11.6) mu M and 7.0 (4.2- 12.3) mu M, respectively. However, at the maximal concentration (100 mu M) used, neither of these drugs inhibited completely BK-induced relaxation (maximal inhibition of 74 +/- 7 and 67 +/- 7%, respectively). On the other hand, D-NMMA, the D-enantiomer of L-NMMA, up to 100 mu M failed to inhibit BK-induced relaxation. The relaxation induced by Iso (1 mu M) and SNP (1 mu M) were not affected by either L-NOARG or L-NMMA (30 mu M). 3 The inhibition of BK-induced relaxation caused by L-NOARG and L-NMMA was partially reversed by addition of excess of L-arginine but not D-arginine (1 mM). 4 Like L-NOARG and L-NMMA, methylene blue (10 mu M), an agent that inhibits the activation of soluble guanylate cyclase by NO, also significantly inhibited BK-induced relaxation, leaving responses to Iso unaffected. 5 Indomethacin (0.3 nM to 10 nM), a cyclo-oxygenase inhibitor, concentration-dependently inhibited BK-mediated relaxation, with an IC50 of 2.6 (1.7- 3.8) nM, without affecting Iso and SNP-mediated relaxant responses. 6 A combination of a very low concentration of indomethacin (1 nM) and either L-NOARG or L-NMMA (100 mu M) changed the response of tracheal preparations to BK (100 nM) from a relaxation to a sustained contraction. 7 These findings indicate that BK-induced relaxation in guinea-pig trachea is mediated jointly by the release of NO or a NO-related substance and a prostanoid, probably prostaglandin E(2).