Inhibitory actions of cyclic AMP on neurogenic plasma extravasation in rat airways

To determine whether neurogenic inflammation can be inhibited by cyclic AMP, which is suggested to have an inhibitory effect on neuropeptide release from airway sensory nerves, we examined plasma extravasation in the airways of anesthetized rats in vivo with Evans blue dye as a marker. Neurogenic inflammation was produced by antidromic electrical stimulation of the right vagus nerve (4 Hz, 1 ms, 4 V for 1 min). Electrical stimulation significantly increased leakage of dye in the trachea and right bronchus. Forskolin (from 0.01 to 100 pM/kg), dibutyryl cyclic AMP (db cyclic AMP; from 10 pM/kg to 100 nM/kg) and fenoterol (from 100 to 1 nM/kg) dose dependently inhibited the leakage of dye induced by electrical stimulation in the trachea and right bronchus. Substance P (1 microgram/kg) increased Evans blue dye extravasation in the same way as the leakage induced by electrical stimulation. Forskolin (from 0.1 to 1 pM/kg), db cyclic AMP (1 nM/kg) and fenoterol (10 nM/kg) failed to inhibit substance P-induced leakage, but showed significant inhibitory effects on the leakage induced by electrical stimulation in the trachea and right bronchus. However, further increases in the concentrations of forskolin, db cyclic AMP and fenoterol significantly inhibited substance P-induced leakage of dye in both tissues. These results suggest that cyclic AMP inhibits neurogenic plasma leakage by presynaptic inhibition of the release of neuropeptides from sensory nerves as well as by postsynaptic effects on the vascular endothelium.