1. The aims of the present study were to determine the characteristics of garlic extract-induced relaxation in rat isolated pulmonary arteries, its susceptibility to changes in oxygen tension and its protective effect against hypoxic pulmonary vasoconstriction. 2. In normoxia, garlic extract (3-500 microg/mL) produced a dose- and nitric oxide (NO)-dependent relaxation. Following 60 min hypoxia, maximum garlic relaxation was reduced compared with control (mean (-SEM) -86 +/- 3 vs-69 +/- 2% of phenylephrine (PE) precontraction, respectively), but recovered after 60 min reoxygenation (-85 +/- 3% PE precontraction). 3. Acetylcholine (0.1 micromol/L)-induced NO-dependent relaxation was reduced from a control value of -76 +/- 1% to -46 +/- 4% during hypoxia and was further reduced to -35 +/- 2 % after reoxygenation. 4. In endothelium-intact arteries, hypoxic exposure resulted in a triphasic response: early transient contraction (+24 +/- 4%), followed by transient relaxation (-37 +/- 7%) and then sustained contraction (+62 +/- 5%). 5. Pretreatment with NG-nitro-L-arginine methyl ester abolished the early transient contraction, moderately attenuated the sustained contraction and had no effect on the transient relaxation. Mechanical endothelial disruption inhibited all hypoxia-induced vascular changes. 6. Garlic pretreatment had no effect on the early transient contraction (+25 +/- 4%), but inhibited the transient relaxation (-5 +/- 3%; P<0.05) and the sustained contraction (+26 +/- 5%; 7. Garlic also significantly inhibited endothelin-l-induced contractions in a dose-dependent manner. 8. These findings show that garlic extract modulates the production and function of both endothelium-derived relaxing and constricting factors and this may contribute to its protective effect against hypoxic pulmonary vasoconstriction.