title: Attenuation of pulmonary leukocyte sequestration during extracorporeal circulation by a new c-AMP phosphodiesterase inhibitor.
abstract: Activated leukocytes may have an important role in developing complement-related lung injury, with pulmonary leukocyte sequestration in the presence of blood-material interaction in cardiopulmonary bypass and hemodialysis. The authors evaluated the effects of a new cAMP phosphodiesterase inhibitor (DN-9693) on leukocyte aggregation in vitro, utilizing canine heparinized blood and pulmonary leukocyte sequestration during extracorporeal circulation (ECC) in dogs. On in vitro evaluation, DN-9693 inhibited the leukocyte aggregation response to leukotriene B4 in a dose response manner; the aggregation response elicited by contact with a membrane lung was inhibited by a 50% inhibition dose of approximately 0.2 mumol/L. Leukocyte kinetics were assessed in a venovenous bypass system with a silicone hollow fiber membrane lung. The control group (n = 6) without DN-9693 developed a reduction in the arterial leukocyte count of 55 +/- 17% at 2 minutes of ECC. The transpulmonary difference in leukocyte count (pulmonary artery count minus systemic artery count) was significantly increased (P less than 0.05) from -175 +/- 206/microliters at baseline to 1225 +/- 330/microliters after 2 minutes of ECC. In the DN-group (n = 4, DN-9693; 60-80 micrograms/kg/min), there was no significant reduction in the arterial leukocyte count during ECC, and the transpulmonary difference showed no significant increases (75 +/- 386/microliters; baseline, versus 125 +/- 263/microliters; 2 minutes of ECC). These results suggest that DN-9693 inhibits the aggregation of leukocytes in the presence of blood-material interaction in vitro, and also prevents pulmonary leukocyte sequestration induced by ECC, with attenuation of systemic leukocyte depletion.
authors.affiliation: Department of Surgery, Osaka University Medical School, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohtani
authors.forename: H
authors.initials: H
authors.lastname: Matsuda
authors.forename: R
authors.initials: R
authors.lastname: Shirakura
authors.forename: Y
authors.initials: Y
authors.lastname: Sawa
authors.forename: R
authors.initials: R
authors.lastname: Matsuwaka
authors.forename: S
authors.initials: S
authors.lastname: Kuki
authors.forename: S
authors.initials: S
authors.lastname: Nakano
authors.forename: Y
authors.initials: Y
authors.lastname: Kawashima
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D000818:Animals; D001998:Bronchopulmonary Sequestration / Q000473:pathology* / Q000517:prevention & control; D002449:Cell Aggregation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005112:Extracorporeal Circulation; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects*; D007975:Leukotriene B4 / Q000494:pharmacology; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D011799:Quinazolines; D007975:Leukotriene B4; C049662:1,5-dihydro-7-(1-piperidinyl)-imidazo(2,1-b)quinazolin-2(3H)-one; D015105:3',5'-Cyclic-AMP Phosphodiesterases