The effects of l-glutamine on pulmonary hypertension in the isolated perfused rabbit lung were investigated. Pulmonary hypertension was produced by the thromboxane-A2 mimetic U46619. l-Glutamine at a dose of 0.04 mM produced a sustained increase in pulmonary artery pressure (PAP) and subsequent administration of an equimolar dose of l-arginine did not affect PAP. l-Glutamine at a dose of 0.5 mM transiently increased PAP, which then decreased to baseline (pre-glutamine) values. When endogenous nitric oxide (NO) synthesis was inhibited with NG-nitro-l-arginine methylester, l-glutamine at a dose of 0.04 mM decreased PAP. These results demonstrate that the effect of l-glutamine on PAP during pulmonary hypertension depends upon dose, time and the presence of endogenous NO synthesis. We believe that the results can be explained by two different effects of l-glutamine, namely a direct inhibition of NO release by glutamine and the donation of nitrogen atoms by glutamine for additional NO or other vasodilator synthesis. Since plasma glutamine levels are 0.4-0.7 mM, endogenous l-glutamine may play a modulatory role during pulmonary hypertension.