Evidence that epithelium-derived relaxing factor released by bradykinin in the guinea pig trachea is nitric oxide.

Abstract

Bradykinin, applied locally to the airways, is a weak bronchoconstrictor agent in guinea pigs in vivo and it may cause constriction or dilatation of guinea pig airways smooth muscle in vitro. We examined the motor effect of bradykinin perfused through the lumen of isolated guinea pig tracheal tubes with or without nitric oxide (NO) synthase inhibitors. In the presence of NG-nitro-D-arginine methyl ester (D-NAME) or NG-monomethyl-D-arginine (D-NMMA) intraluminal bradykinin caused a moderate concentration-dependent relaxation. In contrast, in the presence of NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) tracheas developed a sustained increase in tone, and bradykinin caused a marked, concentration-dependent contraction, both effects being reversible by pretreatment with L-arginine, but not with D-arginine. The ability of bradykinin to relax (in the presence of D-NAME) or contract (in the presence of L-NAME) guinea pig tracheal tubes was not affected by indomethacin. Bradykinin contracted epithelium-denuded tracheas in the presence of either L-NAME or D-NAME. Both contraction and relaxation by bradykinin were blocked by the kinin B2 receptor antagonist, HOE 140. Baseline production of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in strips of guinea pig trachealis in vitro was markedly reduced by L-NAME, but not by D-NAME. Bradykinin increased baseline cyclic GMP concentration. These results indicate that bradykinin releases NO or a NO-related molecule, which, possibly by increasing cyclic GMP concentrations, mediates relaxation and opposes contraction induced by bradykinin itself, and further, that bradykinin releases NO from the tracheal epithelium.

Second messengers, ion channels and pharmacology of airway smooth muscle

“…NO has also been shown to cause airway smooth muscle to relax in vitro [44]: NO is probably produced primarily from the epithelium following stimulation with agents such as bradykinin. In keeping with this, bradykinin is able to cause elevation of cyclic GMP levels and relaxation of guinea pig tracheal muscle in preparations containing intact epithelium but not those which are epitheliumdenuded [45,46].…”

Nitric Oxide in Health and Disease of the Respiratory System

“…Bradykinin, endothelin-1, substance P, adenosine, and calcitonin-gene related peptide, applied to the inside of intact tracheal tubes, provoke concentration-dependent relaxations (9,93,(101)(102)(103)316). The relaxations are reversed into contractions (or contractions are markedly potentiated) by NOS inhibitors, indicating that the relaxant effect in the airways is mediated by the release of endogenous NO (9,93,(101)(102)(103)316).…”

Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Inhibits Neointima Formation Induced by Interruption of Blood Flow in Mice

“…34,35 L-NAME by itself did not affect remodeling in animals treated with Ad.CMV-LacZ. This is in apparent discordance with studies of vascular remodeling in endothelial NO synthase knockout mice, which show increased wall thickness after carotid ligation, compared with wild-type control mice.…”