Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase.
Exhaled nitric oxide (NO) may be derived from constitutive NO synthase (NOS) in normal airways, but the increased concentration in asthma is likely to be derived from inducible NOS expressed in inflamed airways. To investigate this, we administered a nonselective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and a selective inhibitor of inducible NOS, aminoguanidine, by nebulization in a double-blind, placebo-controlled manner in both normal subjects and subjects with asthma. L-NAME resulted in a significant reduction in exhaled NO compared with saline control in eight normal subjects (maximum fall from baseline, 53 +/- 7.6% versus 8.9 +/- 6.5%; P < 0.05) and in seven patients with asthma (maximum fall, 67 +/- 7.4% versus 10 +/- 7.4% versus 10 +/- 9.3%; p < 0.05). Aminoguanidine at the same molar concentration decreased exhaled NO in subjects with asthma (maximum fall, 53 +/- 7.2% versus 7.1 +/- 10.4%; p < 0.05), but caused no significant change in normal volunteers (maximum fall, 28 +/- 9.3 versus 15 +/- 11). No rise in blood pressure, fall in FEV1, or adverse effects were observed in either subject group. We have demonstrated that NOS inhibitors can safely be given by inhalation in a single does in normal subjects and subjects with asthma. The raised exhaled NO concentration in patients with asthma may be attributable to induction of NOS, with that in normal subjects reflecting basal constitutive NOS activity.
Yates
D H
DH
Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom.
Kharitonov
S A
SA
Thomas
P S
PS
Barnes
P J
PJ
D000280:Administration, Inhalation; D000328:Adult; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*
D006146:Guanidines; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester