title: Thromboxane synthetase inhibition decreases polymorphonuclear leukocyte activation following hindlimb ischemia.
abstract: Ischemia of the lower extremity has been shown to cause pulmonary leukostasis and increased pulmonary artery pressure. Thromboxane (TX) has been implicated as a mediator in this process. The effect of OKY-046, a TX synthetase inhibitor, on polymorphonuclear leukocyte (PMN) production of superoxide anion (O2-) as determined by ferricytochrome reduction was examined. Fourteen dogs were subjected to 6 hours of bilateral gracilis muscle ischemia followed by 1 hour of reperfusion. O2- production from resting PMNs and PMNs stimulated with opsonized zymosan (OZ, 0.1 mg/ml) was measured prior to ischemia or drug treatment (baseline), and following reperfusion in both treated (n = 7) and control groups (n = 7). Serum TX levels were measured using a radioimmunoassay. Following reperfusion, TX levels in the treated group were decreased as compared with the control group (18 +/- 2 pg/ml vs. 72 +/- 26 pg/ml, P less than 0.05). Superoxide production by both resting and stimulated PMNs was also decreased in the treated group; from 0.98 +/- 0.16 nmol to 0.43 +/- 0.12 nmol O2- in the resting state (P less than 0.05) and from 13.3 +/- 1.5 nmol to 9.0 +/- 1.1 nmol O2- after stimulation (P less than 0.005). O2- production was increased in the control group following reperfusion as compared with baseline samples, and this increase was attenuated by treatment with OKY-046. TX synthetase inhibition decreases activation of PMNs following hindlimb ischemia.
authors.affiliation: Section of Vascular Surgery, University of Medicine and Dentistry of New Jersey, Newark 07103.
authors.forename: R A
authors.initials: RA
authors.lastname: Cambria
authors.forename: R J
authors.initials: RJ
authors.lastname: Anderson
authors.forename: G
authors.initials: G
authors.lastname: Dikdan
authors.forename: T W
authors.initials: TW
authors.lastname: Lysz
authors.forename: I I
authors.initials: II
authors.lastname: Hobson RW
mesh_terms: D000818:Animals; D004285:Dogs; D005260:Female; D007275:Injections, Intravenous; D007511:Ischemia / Q000150:complications*; D007866:Leg / Q000098:blood supply*; D008171:Lung Diseases / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D013481:Superoxides / Q000097:blood*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D008689:Methacrylates; D013481:Superoxides; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase; C034364:ozagrel