Platelet-activating factor-induced functional changes in the guinea pig trachea in vitro

The role of platelet-activating factor (PAF) in airway hyperresponsiveness was investigated in guinea pigs challenged in vivo for 7 days, 10 min per day, with aerosolized PAF. Tracheal smooth muscle strips set up in vitro for measuring isometric force exhibited increased sensitivity to histamine as compared to tissues from saline-challenged control animals. No significant differences in the concentration-response relationships in tissues from control and PAF-treated animals were seen for acetylcholine or KCl. The threshold concentration of histamine to elicit contraction was 10(-7) M for control and 10(-10) M for the PAF-treated tissues, and these changes persisted for several days following the last exposure to PAF. The histamine H2 receptor antagonist cimetidine, and the arachidonate cyclooxygenase inhibitor indomethacin potentiated histamine-induced contractions in tissues from both the control and the PAF-treated animals to similar magnitudes. Intracellular microelectrode studies showed similar resting membrane potentials (-51 mV) and maximum depolarizations to the three agonists in the cells from control and PAF-treated tissues. However, histamine depolarized the membrane greater in the range of 10(-7)-10(-5) M in the PAF-treated tissues than in the controls. Contractions to threshold concentrations of histamine were unaccompanied by any detectable changes in membrane potential. Histological studies showed eosinophilic infiltration of the submucosa of the trachea. The results suggest hypersensitivity to histamine in vitro following in vivo PAF challenge in guinea pig tracheal smooth muscle, with characteristic changes in the excitation-contraction coupling. These changes may be related to inflammation and cellular infiltration into the airways.