INDUCTION OF GUINEA-PIG AIRWAY HYPERRESPONSIVENESS BY INACTIVATION OFGUANYLATE-CYCLASE

To examine the role of cyclic 3',5'-guanosine monophosphate (cGMP) in airway responsiveness the effects of substances known to interfere wit h nitric oxide (NO) or cGMP were investigated on guinea pig airways. U sing a perfused organ bath system, it was possible to apply the chemic als from either the serosal or the mucosal side independently. In addi tion, levels of intracellular cGMP were determined in tissues after va rious treatments. Sodium nitroprusside(a donor of NO), zaprinast (a sp ecific inhibitor of cGMP phosphodiesterase) and 8-bromo-cGMP (8-Br-cGM P) caused a concentration-dependent relaxation of guinea pig trachea. These results indicate that cGMP is an important second messenger medi ating tracheal relaxations. The above mentioned drugs caused a more pr ofound relaxation when applied to the serosal side compared to the muc osal side, suggesting a barrier function of the epithelial layer. Incu bation on the mucosal side of the tissues with 100 mu M pyrogallol (a generator of superoxide that may inactivate NO) increased the contract ile response to histamine at concentrations 0.3-3.2 mu M (P < 0.05). T reatment of the preparations with 1 mM cystamine (an inactivator of gu anylate cyclase) caused a 5-fold increase in the sensitivity to histam ine (P < 0.05), indicating the involvement of the NO/cGMP pathway in t he development of airway hyperresponsiveness. Incubation of the tissue s with 100 mu M histamine elevated the intracellular cGMP levels 10-fo ld; this effect was completely prevented by incubation of the tissues with methylene blue (a potent inactivator of guanylate cyclase). Mucos al incubation of the tracheal tubes with 10 mu M methylene blue induce d an 8-fold increase in sensitivity to histamine (P < 0.01) and the E( max) was slightly increased. 25 min after instillation of 0.4 mu mol m ethylene blue into the airways of anaesthetized guinea pigs, the lung resistance in response to histamine was elevated up to 395 +/- 82% (P < 0.001). The present study revealed that inactivation of NO or guanyl ate cyclase enhances the histamine-induced contractions of guineapig t racheas. Therefore, it is suggested that the NO/cGMP pathway may be im plicated in the pathogenesis of airway hyperresponsiveness and that dr ugs which enhance cGMP levels in airway smooth muscle may be of signif icance in the treatment of airway obstruction and enhanced reactivity.