Characterization of bronchodilator effects and fate of S-nitrosothiols in the isolated perfused and ventilated guinea pig lung.
In this study the effects of S-nitrosothiols, in particular S-nitrosoglutathione (GSNO), were evaluated with regard to their bronchodilating properties, both after infusion via the pulmonary circulation and after inhalation, in the isolated perfused and ventilated guinea pig lung. Infused GSNO induced bronchorelaxation of lungs that were precontracted with methacholine. During a 15-min period of single-passage perfusion with GSNO (10 microM), maximally 10% was taken up and/or degraded by the lung. A spontaneous breakdown of GSNO in the perfusion buffer was also observed, which was partially accompanied by the formation of nitrite. Low levels of nitric oxide (NO) were detected in the perfusion buffer when GSNO was present. This was due to the presence of contaminating transition metals, because EDTA and 2,2'-dipyridyl largely reduced the formation of NO. The NO-scavenging agents oxyhemoglobin and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide abolished levels of NO in the buffer but did not abolish GSNO-induced bronchodilation. The effects of infused GSNO are therefore attributed to an action of the intact S-nitrosothiol and not to NO released from GSNO in the perfusion buffer. Similarly, perfusion with S-nitrosated glutathione isopropyl ester, cysteinyl glycine, N-acetyl-L-cysteine or N-acetyl-D,L-penicillamine, but not with nitrosated bovine serum albumin or sodium nitrite, was found to induce bronchodilation. Inhalation of nebulized GSNO induced bronchodilation of methacholine-precontracted lungs with a rapid onset of action, although it was a less potent bronchodilator than salbutamol. The results show that infused or inhaled S-nitrosothiols have bronchodilating properties in the isolated perfused and ventilated guinea pig lung.
Bannenberg
G
G
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Xue
J
J
Engman
L
L
Cotgreave
I
I
Moldéus
P
P
Ryrfeldt
A
A
D000336:Aerosols; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001993:Bronchodilator Agents; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D008168:Lung / Q000378:metabolism; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D016210:Methacholine Chloride / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000096:biosynthesis; D009603:Nitroso Compounds / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D026422:S-Nitrosoglutathione; D013438:Sulfhydryl Compounds / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
D000336:Aerosols; D001993:Bronchodilator Agents; D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D016210:Methacholine Chloride; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D005978:Glutathione