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-nitrosog lutathione (GSNO), were evaluated with regard to their bronchodilating properties, both after infusion via the pulmonary circulation and aft er inhalation, in the isolated perfused and ventilated guinea pig lung . Infused GSNO induced bronchorelaxation of lungs that were precontrac ted with methacholine. During a 15-min period of single-passage perfus ion with GSNO (10 mu M), 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 ni trite. Low levels of nitric oxide (NO) were detected in the perfusion buffer when GSNO was present. This was due to the presence of contamin ating transition metals, because EDTA and 2,2'-dipyridyl largely reduc ed the formation of NO. The NO-scavenging agents oxyhemoglobin and rbo xyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide abolished leve ls of NO in the buffer but did not abolish GSNO-induced bronchodilatio n, The effects of infused GSNO are therefore attributed to an action o f the intact S-nitrosothiol and not to NO released from GSNO in the pe rfusion buffer. Similarly, perfusion with S-nitrosated glutathione iso propyl ester, cysteinyl glycine, N-acetyl-L-cysteine or N-acetyl-D,L-p enicillamine, but not with nitrosated bovine serum albumin or sodium n itrite, was found to induce bronchodilation. Inhalation of nebulized G SNO induced bronchodilation of methacholine-precontracted lungs with a rapid onset of action, although it was a less potent bronchodilator t han salbutamol, The results show that infused or inhaled S-nitrosothio ls have bronchodilating properties in the isolated perfused and ventil ated guinea pig lung.