Dysfunction of cgmp-mediated pulmonary vasorelaxation in endotoxin
-induced acute lung injury.
Fullerton, David A., Md, Robert C. McIntyre, Jr. Md, Angela R. Hahn
Bs, Jeanette Agrafojo Bs, Kaoru Koike Md, Xianzhong Meng Md, Anirban
Banerjee Phd, Alden H. Harken Md.
University of Colorado Health Sciences Center, Denver, Colorado
APStracts 2:0026L, 1995.
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 10-6M) for acetylcholine (ACh), A23187, sodium nitroprusside (SNP)
and for 8-Br cGMP (10-9 to 10-4M) in isolated pulmonary arterial
rings preconstricted with phenylephrine six hours after endotoxin (20
mg/kg, IP). Endotoxin-treatment produced significantly increased lung
neutrophil accumulation (myeloperoxidase assay, 28+/-6 units/gm lung
tissue versus 1.8+/-1 in controls) and lung leakage (I125 labeled
albumin lung/blood ratio, 0.06+/-0.01 versus 0.028+/-0.01 in controls) as
well as histologic evidence of pulmonary vascular endothelial damage.
The concentration-response curves demonstrated that pulmonary
vasorelaxation by mechanisms which require generation of cGMP by
either endothelial-dependent (both receptor-dependent, ACh, and
receptor-independent, A23187) or endothelial -independent (SNP)
pathways were significantly impaired following endotoxin-treatment.
Relaxation by stimulation with the cGMP analogue, 8-Br cGMP, was not
different from control. Pulmonary vascular smooth muscle is able to
relax in response to cGMP following endotoxin, but relaxation by
endothelial-dependent and -independent pathways which require
generation of cGMP is significantly impaired.
Received 5 December 1994; accepted in final form 13 February 1995.
APS Manuscript Number L345-4.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 February 1995.