Specific pathogen-free male Dunkin-Hartley (Harlan Olac, Ltd., Bicester, England) guinea pigs (400 to 500 g) were anesthetized intraperitoneally with urethane (1.3glkg body weight) and were allowed to breathe spontaneously. An anesthesia-induced fall in body temperature was avoided by placing the animals in a heated chamber that kept the body temperature at'Jl" C. The animals were prepared for the measurement of pulmonary lung resistance (RL) as follows. Airflow (V) and tidal volume (VT) were determined by cannulating and connecting the trachea with a Fleisch flow head (No. 000) to a pneumotachograph. A Validyne MP45-2 (Validyne Corp., Northridge, CAl pressure transducer measured the transpulmonary pressure (PL) by determining pressure differences between the tracheal cannula and a cannula (polyethylene, PE, 120 mm length, outer diameter= 2.8 mm, inner diameter= 2.4 mm) filled with saline inserted in the esophagus. RL was determined breath by breath with a respiratory analyzer as described previously (21): RL was yielded by dividing dPL by d Vat isovolume points (50%). The animals could be connected to the nebulization chamber by opening a T valve in front of the flow head. A small polyethylene catheter (PE-50) was placed in the right jugular vein for intravenous administration of histamine. A polyethylene catheter (PE-50) was placed in the carotid artery and connected with a pressure transducer (Hottinger Baldwin Messtechnik, Darmstadt, Germany). Differences in blood pressure and heart beat frequency were displayed on a two-channel pen recorder.

The experimental protocol was as follows. After an equilibration period of 20 min, the guinea pigs inhaled 10 breaths of an aerosol containing (1) distilled water or (2) L-NAME (1.2 mM) or N9-monomethyl-L-arginine (L-NMMA, 1.2 mM). This procedure was repeated every 5 min for 30 min (total of 60 breaths). A histamine dose-response curve (0.4 to 2.0 Ilg/100 g BW) was constructed by giving intravenous injections at 10-min intervals. After a resting period of 20 min, the L-NAME-treated group was exposed to distilled water or L-Arg (2.0 mM) according to the preceding protocol, and a second histamine dose-response curve was created. As additional controls,(1) a group was treated two times with an aerosol containing distilled water to investigate whether the first histamine dose-response curve affected the second histamine dose-response curve, and (2) a group that was exposed to an aerosol containing L-NMMA received the inactive enantiomer D-Arg (2.0 mM) to investigate the specificity of L-Arg. RL is presented as the actual value minus the basal value.