NITROGEN-DIOXIDE EXPOSURE INCREASES AIRWAY CONTRACTILE RESPONSE TO HISTAMINE BY DECREASING HISTAMINE N-METHYLTRANSFERASE ACTIVITY IN GUINEA-PIGS

To determine the mechanism responsible for nitrogen dioxide (NO2)-indu ced airway hyperresponsiveness, we examined the effects of NO2 exposur e on the contractile response to histamine and the level of histamine N-methyltransferase (HMT) activity, a histamine-degrading enzyme, in g uinea pig trachea in vitro. Guinea pigs were divided into seven groups . Each group received continuous NO2 exposure (2.0 ppm) for either 2, 6, 12, 24, 48, or 96 h. The remaining group did not receive NO2 exposu re (control). HMT activity in trachea was decreased from the control v alue of 70.3 +/- 7.7 pmol/min/mg protein to 34.6 +/- 6.7 pmol/min/mg p rotein by 12 h exposures of NO2. However, 24 and 48 h exposures of NO2 did not significantly alter HMT activity. In contrast, HMT activity e xceeded the control value by 96 h exposures of NO2 (85.5 +/- 5.1 pmol/ min/mg protein). Twelve hour exposures of NO2 shifted the concentratio n-response curves to histamine to lower concentrations and significant ly reduced the median effective concentration (EC(50)) of histamine (l og M) from the control value of -5.16 +/- 0.09 to -6.15 +/- 0.14 (P < 0.01), In contrast, the EC(50) concentration of histamine (log M) incr eased from the control value of -5.20 +/- 0.10 to -4.90 +/- 0.11 by 96 h exposures of NO2 (P < 0.05). However, NO2 exposure did not alter th e contractile response to acetylcholine. Morphologically, tracheal epi thelial cells had vacuoles after 12 h exposures of NO2, but denudation of the epithelium did not occur during this experiment, In situ hybri dization for HMT mRNA demonstrated that the level of HMT mRNA increase d dominantly in tracheal epithelial cells after 96 h exposures of NO2. The present results indicated that the decrease in the level of HMT a ctivity in the trachea was closely associated with the increase in the airway contractile response to histamine, suggesting that NO2-induced transient airway hyperresponsiveness to histamine is due to the decre ased capacity of histamine catabolism in airway.