DYSFUNCTION OF CGMP-MEDIATED PULMONARY VASORELAXATION IN ENDOTOXIN-INDUCED ACUTE LUNG INJURY

Endothelial-dependent and -independent cGMP-mediated mechanisms of pul monary vasorelaxation were studied in endotoxin-induced acute lung inj ury in the rat. Concentration-response curves were generated (10(-9) t o 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 preconstricte d with phenylephrine 6 h after endotoxin treatment (20 mg/kg ip). Endo toxin treatment produced significantly increased lung neutrophil accum ulation (myeloperoxidase assay, 28 +/- 6 units/g lung tissue vs. 1.8 /- 1 in controls) and lung leakage (lung/blood I-125-labeled albumin r atio, 0.06 +/- 0.01 vs. 0.028 +/- 0.01 in controls) as well as histolo gical evidence of pulmonary vascular endothelial damage. The concentra tion-response curves demonstrated that pulmonary vasorelaxation by mec hanisms that require generation of cGMP by either endothelial-dependen t (both receptor-dependent, ACh, and receptor-independent, A23187) or endothelial-independent (SNP) pathways were significantly impaired aft er endotoxin treatment. Relaxation by stimulation with the cGMP analog ue 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 tha t require generation of cGMP is significantly impaired.