Dysfunction of cGMP-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury

• Published in: The American journal of physiology Vol. 268; no. 6 Pt 1; p. L1029
• Main Authors: Fullerton, D A, McIntyre, Jr, R C, Hahn, A R, Agrafojo, J, Koike, K, Meng, X, Banerjee, A, Harken, A H
• Format: Journal Article
• Language: English
• Published: United States 01.06.1995
• Subjects: Acetylcholine - pharmacology; Animals; Calcimycin - pharmacology; Cyclic GMP - analogs & derivatives; Cyclic GMP - metabolism; Cyclic GMP - pharmacology; Endotoxins - toxicity; Guanylate Cyclase - metabolism; In Vitro Techniques; Lung - drug effects; Lung - pathology; Lung Injury; Male; Models, Cardiovascular; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Muscle, Smooth, Vascular - physiopathology; Nitroprusside - pharmacology; Peroxidase - metabolism; Phenylephrine - pharmacology; Potassium Chloride - pharmacology; Pulmonary Artery - drug effects; Pulmonary Artery - physiology; Pulmonary Artery - physiopathology; Rats; Rats, Sprague-Dawley; Reference Values; Salmonella typhimurium; Vasodilation - drug effects; Vasodilation - physiology
• ISSN: 0002-9513
• DOI: 10.1152/ajplung.1995.268.6.L1029

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.