Endothelial-dependent and -independent cGMP-mediated mechanisms of pulmonary vasorelaxation were studied in endotoxin-induced acute lung injury in the rat. Concentration-response curves were generated (10(-9) to 10(-6) M) for acetylcholine (ACh), A23187, and sodium nitroprusside (SNP) and for 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) (10(-9) to 10(-4) M) in isolated pulmonary arterial rings preconstricted with phenylephrine 6 h after endotoxin treatment (20 mg/kg ip). Endotoxin treatment produced significantly increased lung neutrophil accumulation (myeloperoxidase assay, 28 +/- 6 units/g lung tissue vs. 1.8 +/- 1 in controls) and lung leakage (lung/blood 125I-labeled albumin ratio, 0.06 +/- 0.01 vs. 0.028 +/- 0.01 in controls) as well as histological evidence of pulmonary vascular endothelial damage. The concentration-response curves demonstrated that pulmonary vasorelaxation by mechanisms that require generation of cGMP by either endothelial-dependent (both receptor-dependent, ACh, and receptor-independent, A23187) or endothelial-independent (SNP) pathways were significantly impaired after endotoxin treatment. Relaxation by stimulation with the cGMP analogue 8-BrcGMP was not different from control. Pulmonary vascular smooth muscle is able to relax in response to cGMP after endotoxin treatment, but relaxation by endothelial-dependent and -independent pathways that require generation of cGMP is significantly impaired.