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

Abstract

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.

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

“…This difference could lead to hypocontractile response to histamine in mesenteric but not in pulmonary arteries. Our findings may provide a basis for the results of past investigations that iNOS induction-associated vascular hypocontractility was not observed in the pulmonary circulation (Nelson et al, 1991;Suba et al, 1992;Spath et al, 1994;Fullerton et al, 1995) despite the presence of iNOS mRNA in pulmonary vessels in vivo LPS (Griffiths et al, 1995).…”

Contractions to Histamine in Pulmonary and Mesenteric Arteries from Endotoxemic Rabbits: Modulation by Vascular Expressions of Inducible Nitric-Oxide Synthase and Histamine H1-Receptors

“…Our results suggest that in vivo treatment with LPS leads to iNOS upregulation and vascular hypocontractility in mesenteric but less in pulmonary vessels. This finding may provide a basis for the results of past investigations that iNOS inductionassociated vascular hypocontractility was not observed in the pulmonary circulation (Nelson et al, 1991;Suba et al, 1992;Spath et al, 1994;Fullerton et al, 1995) despite the presence of iNOS mRNA in pulmonary vessels after in vivo LPS (Griffiths et al, 1995).…”

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

“…Pharmacologic maneuvers that increase intracellular levels of cAMP (42) or cGMP (43) result in a dephosphorylation of myosin, a redistribution of actin and myosin II, and a decrease in endothelial isometric tension, indicating that endothelial permeability is likely coupled to myosin light chain kinase activity. Finally, recent in vivo work has suggested that endotoxin-induced increases in vascular permeability are associated with accumulation of neutrophils and that dysfunction may be coupled to elevations in cGMP (44).…”