Dysfunction of cGMP-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury.
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.
Fullerton
D A
DA
University of Colorado Health Sciences Center, Denver 80262, USA.
McIntyre
R C
RC
Hahn
A R
AR
Agrafojo
J
J
Koike
K
K
Meng
X
X
Banerjee
A
A
Harken
A H
AH
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity*; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D055370:Lung Injury; D008297:Male; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D009599:Nitroprusside / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012486:Salmonella typhimurium; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D004731:Endotoxins; D009599:Nitroprusside; D010656:Phenylephrine; C016276:8-bromocyclic GMP; D000001:Calcimycin; D011189:Potassium Chloride; D009195:Peroxidase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000109:Acetylcholine