NITRIC-OXIDE SYNTHESIS INHIBITORS INDUCE AIRWAY HYPERRESPONSIVENESS IN THE GUINEA-PIG IN-VIVO AND IN-VITRO - ROLE OF THE EPITHELIUM

The administration by aerosol of the nitric oxide (N(omega)) synthesis inhibitors, N(omega)-nitro-L-arginine methyl ester (L-NAME) or N(g)-monomethyl-L-arginine (L-NMMA), to spontaneously breathing anesthetized guinea pigs resulted in a significant enhancement of lung resistance (RL) after increasing intravenous doses of histamine. The maximal response was increased (p < 0.01) by 126% (L-NAME) and 282% (L-NMMA) compared with the control groups. This effect was inhibited by giving an aerosol of the NO precursor L-arginine (L-Arg) but not by its inactive enantiomer D-arginine (D-Arg). Perfusion through the lumen of guinea pig tracheal tubes in vitro with nitric oxide synthesis inhibitors (120 muM) resulted in a significant increase in basal tone, suggesting a role for NO in the maintenance of basal tone. In addition, the histamine concentration-response curve was significantly shifted upward: the maximal response was increased (p < 0.01) by 335% (L-NAME) and 250% (L-NMMA) compared with the control group. This effect was concentration dependently inhibited by coincubation with L-Arg (120, 200, and 400 muM), but not with D-Arg (200 muM). Furthermore, removal of the epithelium resulted in an upward shift in the histamine concentration-response curve: the maximal response was increased by 185%. However, incubation with L-NAME did not further increase tracheal responsiveness to histamine, but addition of L-Arg (360 muM), when a plateau was reached, relaxed the tissues to control values. Nitric oxide synthesis inhibition did not change the responsiveness of intact tissues in vitro after intraluminal stimulation with leukotriene D4, serotonin, or the cholinergic agonist arecoline. The concentration-response curves made with the cholinergic agonists carbachol and methacholine were significantly enhanced (p < 0.01) after nitric oxide synthesis inhibition; however, the maximal contractions were increased by 36 and 40%, respectively. In conclusion, nitric oxide synthesis inhibition in the guinea pig respiratory tract resulted in a marked increase in airway contractions after stimulation with histamine, carbachol, and methacholine. Our findings suggest that the epithelium lining the airway smooth muscle probably contributes to nitric oxide synthesis.