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.