title: Attenuation of canine warm ischemic small bowel injury by novel combination of nitric oxide donor, FK409, and cytokine suppressive anti-inflammatory agent FR167653.
abstract: Organ ischemia-reperfusion injury is caused by two consecutive steps, microcirculatory disturbance and neutrophil-endothelial cell interactions, which are caused by inflammatory cytokines. We examined the hypothesis that combination therapy with a donor (FK409) of nitric oxide, one of the potent mediators with diverse roles as a vosodilator and a platelet inhibitor, together with the cytokine suppressor agent (FR167653) attenuates warm ischemic injury in canine small bowel. Small bowel ischemia was initiated by clamping the superior mesenteric artery and vein. Animals were divided into two groups: a control group (n = 5) subjected to 2-hour small bowel ischemia only, and a combination therapy group (FK/FR group, n = 5) that received FK409 (300 mcg/kg/h) plus FR167653 (1 mg/kg/h) intravenously before and after the ischemic event. We evaluated animal survival, small bowel tissue blood flow, and enzyme release from the small bowel. All controls died from severe acidosis within 2 days and all the FK/FR animals survived 7 days (P < .05). The FK/FR group recovered more than 70% of blood flow immediately after the revascularization, while the flow was less than 40% among the controls. Serum creatine phosphokinase values in the control group after reperfusion were significantly higher than those in the FK/FR group. In conclusion improvement of the microcirculation by FK409 and inhibition of cytokine release by FR167653 together attenuated warm ischemic small bowel injury.
authors.affiliation: Second Department of Surgery, Hirosaki University School of Medicine, Hirosaki, Japan. etotsuka@cc.hirosaki-u.ac.jp
authors.forename: E
authors.initials: E
authors.lastname: Totsuka
authors.forename: A
authors.initials: A
authors.lastname: Murata
authors.forename: A
authors.initials: A
authors.lastname: Nishimura
authors.forename: M
authors.initials: M
authors.lastname: Umehara
authors.forename: M
authors.initials: M
authors.lastname: Nara
authors.forename: H
authors.initials: H
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Nozaki
authors.forename: M
authors.initials: M
authors.lastname: Takiguchi
authors.forename: N
authors.initials: N
authors.lastname: Wajima
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Seino
authors.forename: S
authors.initials: S
authors.lastname: Narumi
authors.forename: K
authors.initials: K
authors.lastname: Hakamada
authors.forename: M
authors.initials: M
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004285:Dogs; D007421:Intestine, Small / Q000098:blood supply*; D007511:Ischemia / Q000517:prevention & control*; D023421:Models, Animal; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C104334:FR 167653; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D011720:Pyrazoles; D011725:Pyridines; C061872:FK 409