cyclic-gmp and Neutropenia

Topics: Actins; Agammaglobulinemia; Ascorbic Acid; Ataxia Telangiectasia; Blood Transfusion; Cell Adhesion; Cell Membrane; Chemotaxis; Cyclic GMP; Dysgammaglobulinemia; Exocrine Pancreatic Insufficiency; Female; Humans; IgA Deficiency; Immunoglobulin E; Levamisole; Male; Maternal-Fetal Exchange; Membrane Proteins; Microtubules; Myosins; Neutropenia; Phagocyte Bactericidal Dysfunction; Phagocytes; Pregnancy

We measured changes in nitric oxide (NO) concentration in the cerebral cortex during experimental carbon monoxide (CO) poisoning and assessed the role for N-methyl-d-aspartate receptors (NMDARs), a glutamate receptor subtype, with progression of CO-mediated oxidative stress. Using microelectrodes, NO concentration was found to nearly double to 280 nM due to CO exposure, and elevations in cerebral blood flow, monitored as laser Doppler flow (LDF), were found to loosely correlate with NO concentration. Neuronal nitric oxide synthase (nNOS) activity was the cause of the NO elevation based on the effects of specific NOS inhibitors and observations in nNOS knockout mice. Activation of nNOS was inhibited by the NMDARs inhibitor, MK 801, and by the calcium channel blocker, nimodipine, thus demonstrating a link to excitatory amino acids. Cortical cyclic GMP concentration was increased due to CO poisoning and shown to be related to NO, versus CO, mediated guanylate cyclase activation. Elevations of NO were inhibited when rats were infused with superoxide dismutase and in rats depleted of platelets or neutrophils. When injected with MK 801 or 7-nitroindazole, a selective nNOS inhibitor, rats did not exhibit CO-mediated nitrotyrosine formation, myeloperoxidase (MPO) elevation (indicative of neutrophil sequestration), or impaired learning. Similarly, whereas CO-poisoned wild-type mice exhibited elevations in nitrotyrosine and myeloperoxidase, these changes did not occur in nNOS knockout mice. We conclude that CO exposure initiates perivascular processes including oxidative stress that triggers activation of NMDA neuronal nNOS, and these events are necessary for the progression of CO-mediated neuropathology.

Topics: Animals; Brain Chemistry; Calcium Channel Blockers; Carbon Monoxide Poisoning; Cyclic GMP; Dizocilpine Maleate; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Indazoles; Laser-Doppler Flowmetry; Male; Maze Learning; Mice; Mice, Knockout; Microelectrodes; Neurons; Neurotoxicity Syndromes; Neutropenia; Neutrophils; NG-Nitroarginine Methyl Ester; Nimodipine; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Platelet Count; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Tyrosine

The major hemodynamic feature of endotoxin (ETX)-induced acute lung injury is pulmonary hypertension secondary to increased pulmonary vascular resistance. Endotoxin causes dysfunction of pulmonary vasorelaxation, which is associated with increased lung neutrophil accumulation. We hypothesized that neutrophils mediate the dysfunction of cGMP-mediated pulmonary vasorelaxation in acute lung injury. In a rat model of ETX-induced lung injury, our purpose was to determine the effect of neutrophil depletion on the following mechanisms of pulmonary vasomotor control: endothelium-dependent cGMP-mediated relaxation (response to acetylcholine) and endothelium-independent relaxation (response to sodium nitroprusside).. Rats were studied 6 hours after ETX (20 mg/kg). Neutropenia (< 75 neutrophils/microL) was induced with anti-neutrophil serum 24 hours before ETX. Saline injected rats were controls. Dose-response curves to acetylcholine and sodium nitroprusside were generated in isolated pulmonary artery rings preconstricted with phenylephrine (n = 10 rings/5 rats per group). Lungs were harvested (n = 4 rats/group) and lung neutrophil accumulation was assessed with a myeloperoxidase assay.. Endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation was dysfunctional in ETX-induced ALI. Neutrophil depletion prevented lung neutrophil accumulation and attenuated pulmonary vasomotor dysfunction after endotoxin.. These data suggest that neutrophils contribute to pulmonary endothelium and smooth muscle dysfunction in acute lung injury induced by endotoxemia.

Topics: Acetylcholine; Animals; Bacterial Toxins; Cyclic GMP; Endotoxins; Leukocyte Count; Male; Neutropenia; Neutrophils; Nitroprusside; Peroxidase; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Salmonella typhimurium; Vascular Resistance; Vasomotor System

Neutrophil depletion is commonly used to examine the role of neutrophils in lung injury. However, the effect of neutrophil depletion per se on mechanisms of pulmonary vascular smooth muscle relaxation is unknown. The purpose of this study was to examine the effect of neutropenia on the following mechanisms of cGMP-mediated pulmonary vasorelaxation: (1) receptor-dependent endothelium-dependent relaxation (response to acetylcholine (ACh)), (2) receptor-independent endothelium-dependent relaxation (response to the calcium ionophore A23187), and (3) endothelium-independent relaxation (response to sodium nitroprusside (SNP)). Neutropenia (<75 neutrophils/mu l) was induced with anti-neutrophil antibody serum 24 hr prior to lung harvest in five rats. Saline-injected rats were controls (n = 5). Dose-response curves to ACh, A23187, and SNP were generated in isolated pulmonary artery rings preconstricted with phenylepherine. Statistical comparison was performed using one-way ANOVA with post-hoc Bonferroni-Dunn, and P < 0.05 was accepted as significant. Relaxation to ACh, A23187, and SNP was complete in both control and neutropenic rats. Thus, antibody-mediated depletion does not impair endothelial-dependent or -independent cGMP-mediated pulmonary vasorelaxation.

Topics: Acetylcholine; Animals; Calcimycin; Cyclic GMP; Endothelium, Vascular; Immune Sera; Lung; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Neutropenia; Neutrophils; Nitroprusside; Rats; Rats, Sprague-Dawley; Vasomotor System

Bone marrow cells were collected from normal dogs, normal dogs made neutropenic with cyclophosphamide, and 11 dogs affected with cyclic hematopoiesis (CH) on 3 consecutive days of separate 12- to 14-day cycles. The mononuclear marrow cells from both groups of control dogs and from the CH dogs on each of 12-cycle days were cultured for 2.5 hr in serum-free media. The amounts of prostaglandins (PGF2 alpha and PGE) and cyclic GMP (cGMP) measured in the media were found to vary with the cycle in the CH dog. PGF2 alpha was highest as the dogs recovered from the neutropenia and lowest 4 days before the onset of the next neutropenic episode. Cyclic GMP was lowest 4-5 days before the onset of neutropenia, then dramatically increased as the neutropenic period approached. Cyclic GMP was highest when PGF2 alpha was lowest. Normal dogs, made neutropenic with a single dose of cyclophosphamide, had elevations of PGF2 alpha but not PGE or cGMP during the recovery period of active granulopoiesis.

Topics: Agranulocytosis; Animals; Bone Marrow Cells; Cells, Cultured; Cyclic AMP; Cyclic GMP; Cyclophosphamide; Dinoprost; Dogs; Hematopoiesis; Neutropenia; Periodicity; Prostaglandins; Prostaglandins E; Prostaglandins F