Neutrophil depletion attenuates endotoxin-induced dysfunction of cGMP-mediated pulmonary vasorelaxation.
The effect of neutrophil depletion on endotoxin-induced dysfunction of guanosine 3',5'-cyclic monophosphate (cGMP)-mediated pulmonary vasorelaxation was studied in rats. Two mechanisms of neutrophil depletion were used: vinblastine (0.75 mg/kg iv) and rabbit anti-rat neutrophil antiserum (0.15 ml iv). Concentration-response curves were generated (10(-9) to 10(-6) M) for acetylcholine (ACh), A-23187, and sodium nitroprusside (SNP) in isolated pulmonary arterial rings preconstricted with phenylephrine 6 h after endotoxin (20 mg/kg ip). Absolute neutrophil count was significantly lowered from 1,050 +/- 206 (neutrophils/ml; mean +/- SE) in controls to 100 +/- 41 by vinblastine and to 50 +/- 29 by antiserum. Endotoxin produced histological evidence of pulmonary vascular endothelial damage and significantly increased lung neutrophil accumulation (myeloperoxidase assay, 5.1 +/- 0 vs. 1.2 +/- 0.1 in controls; 0.1 +/- 0.1 and 0.8 +/- 0.0 U/g lung wt after endotoxin in neutrophil-depleted rats by vinblastine and antiserum, respectively). Endotoxin produced significant impairment of endothelium-dependent cGMP-mediated pulmonary vasorelaxation by receptor-dependent (ACh) and -independent (A-23187) pathways as well as endothelium-independent relaxation (SNP). Neutrophil depletion significantly attenuated the endotoxin-induced impairment of all three of these mechanisms. We conclude that neutrophils contribute to endotoxin-induced impairment of GMP-mediated pulmonary vasorelaxation.
Sheridan
B C
BC
University of Colorado, Denver 80262, USA.
McIntyre
R C
RC
Agrafojo
J
J
Meldrum
D R
DR
Meng
X
X
Fullerton
D A
DA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity*; D007106:Immune Sera; D066298:In Vitro Techniques; D007958:Leukocyte Count / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014747:Vinblastine / Q000633:toxicity
D015415:Biomarkers; D004731:Endotoxins; D007106:Immune Sera; D009599:Nitroprusside; D000001:Calcimycin; D014747:Vinblastine; D009195:Peroxidase; D006152:Cyclic GMP; D000109:Acetylcholine