BACKGROUND: A novel synthesized organic compound, FR167653, has been characterized as a potent suppressant of interleukin-1 and tumor necrosis factor-alpha. We designed this experimental study to evaluate the effect of FR167653 on ischemia-reperfusion injury of the rat lung. METHODS: Following general anesthesia, the left bronchus, pulmonary artery and vein were clamped for 1 hour. FR167653 was administered continuously beginning 30 minutes before the onset of ischemia and extending for 2 hours after reperfusion. Thirty-eight Wistar rats were divided into 4 groups according to the dose of FR167653 at the rate of 0.1, 0.05 and 0.025 mg/kg/hr in each group. After the optimal dose was obtained from the result of 1-week survival rate, the group with the optimal dose was compared with a control group by using such parameters as arterial oxygen saturation (SaO(2)), arterial oxygen tension (PaO(2)), cytokines, the expression of p38 MAP kinase and histologic study. RESULTS: Survival rate of the group received FR at the rate of 0.1 mg/kg/hr (FR0.1 group) was best among the 4 groups. SaO(2) levels and PaO(2) levels after 2-hour of reperfusion were significantly (p < 0.05, respectively) higher in the FR0.1 group than in the control group. After 2-hour reperfusion, IL-1 beta was lower in the FR0.1 group than in the control group, and the expression of p38 MAP kinase was reduced in the FR0.1 group compared with the control group. In histologic study after 2-hour of reperfusion, alveolar damage with edema and interstitial thickening localized along the alveolar duct were observed in the control group, whereas these findings were remarkably less evident in the FR0.1 group. CONCLUSIONS: We concluded that FR167653 ameliorates ischemia-reperfusion injury of the lung and may inhibit the production of proinflammatory cytokines by means of the inhibition of p38 MAP kinase.

Animals↗

PubMed2000

FK409 ameliorates ischemia-reperfusion injury in heart transplantation following 12-hour cold preservation.

OBJECTIVE: FK409 is the first spontaneous nitric oxide donor to increase plasma guanosine 3':5'-cyclic monophosphate. We designed this study to investigate whether the administration of FK409 during reperfusion ameliorated ischemia-reperfusion injury and enhanced post-transplant graft function in orthotopic heart transplantation following 12-hour cold preservation in a canine model. METHODS: We used 10 pairs of adult mongrel dogs, weighing 9.5 to 13.5 kg. Following cardiac arrest using cardioplegia, we washed out the coronary vascular beds with cold University of Wisconsin solution followed by 12-hour preservation. After preservation, we performed orthotopic transplantation. The experimental animals were divided into 2 groups. In the FK group (n = 5), FK409 (5 microg/kg/min) was administered intravenously, beginning 15 minutes before the onset of reperfusion and continuing for 45 minutes after reperfusion. In the control group (n = 5), saline vehicle was administered in the same manner. Two hours after transplantation, we assessed cardiac function, including cardiac output, left ventricular systolic pressure (LVP), and the maximum rates of positive and negative increase of LVP (+/-LV dP/dt) by comparing the recovery rate (%) of the cardiac function of the donor animal. We measured endothelin-1 levels in blood obtained from a catheter inserted into the coronary sinus 30, 60, and 120 minutes after reperfusion. RESULTS: Cardiac output was higher in the FK group than in the control group, but the difference was not significant (p = 0.08). Left ventricular systolic pressure and +/-LV dP/dt were significantly (p < 0.05) higher in the FK group than in the control group. Endothelin-1 levels were significantly (p < 0.05) lower in the FK group than in the control group 30 minutes after reperfusion. Transmission electron microscopy showed that the basal lamina of capillary vessels, glycogen granules, and mitochondrial structure were well-preserved in the FK group. CONCLUSIONS: In orthotopic transplantation models, FK409 is effective in ameliorating ischemia-reperfusion injury following preservation and in enhancing post-transplant cardiac function.

Adenosine↗

PubMed2000

FR167653 ameliorates pulmonary damage in ischemia-reperfusion injury in a canine lung transplantation model.

BACKGROUND: Interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha) are recognized as important factors in ischemia-reperfusion (I/R) injury. FR167653 has been characterized as a potent suppressant of IL-1 and TNF-alpha production. We previously reported that FR167653 suppressed the expression of IL-1 beta mRNA after reperfusion and ameliorated pulmonary I/R injury following 3-hour left lung warm ischemia in dogs. The aim of this study was to investigate the effects of FR167653 on I/R injury in a canine left, single, lung transplantation model. METHODS: We used 10 pairs of weight-matched dogs. We assigned 5 pairs to the FR group, in which each animal received FR167653 (1 mg/kg/hr) IV from 30 minutes before ischemia until 2 hours after reperfusion; we treated the transplanted lungs with FR167653 after the onset of reperfusion. The others were assigned to the control group. After 8-hour preservation with 4 degrees C Euro-Collins solution, orthotopic left, single, lung transplantation was performed. During a 5-minute clamping test at the right pulmonary artery of each recipient, the left (transplanted) pulmonary arterial pressure (L-PAP), left (transplanted) pulmonary vascular resistance (L-PVR), arterial oxygen pressure (PaO(2)), and alveolar-arterial oxygen pressure difference (A-aDO(2)) were measured. We harvested transplanted lung specimens for histologic study, and we counted polymorphonuclear neutrophils (PMNs), which were identified by staining with naphthol AS-D cholroacetate esterase. Pulmonary perfusion and ventilation scintigraphy (Tc-99m-MAA and Xe-133) were performed. We observed the animals for 3 days after transplantation. RESULTS: The PAP, L-PVR, PaO(2), and A-aDO(2) revealed significantly (p < 0.05) better function in the FR group than in the control group. Histologically, lung edema was milder, and PMN infiltration was significantly (p < 0.05) lower in the FR group than in the control group. Xe-133 and Tc-99m-MAA were widely distributed throughout the graft lung in the FR group. Three-day survival rates in FR and control groups were 60% and 20%, respectively. CONCLUSIONS: FR167653 appears to generate a protective effect on I/R injury in lung transplantation in dogs.

Animals↗

PubMed2000

Beneficial effects of novel nitric oxide donor (FK409) on pulmonary ischemia-reperfusion injury in rats.

BACKGROUND: Nitric oxide (NO) seems to play an important role in tissue injury during reperfusion of the lung. FK409 is the first spontaneous NO donor that increases plasma guanosine 3':5'-cyclic monophosphate. It is reported that FK409 prevented myocardial infarction following occlusion and reperfusion in rat coronary arteries. In this study, we evaluated the effects of FK409 on pulmonary ischemia-reperfusion injury in an in situ warm ischemia model of rats. METHODS: Animals were divided into 2 groups: the FK409 study group that was administered FK409 (0.4 mg/kg) before reperfusion and the control group, administered a saline vehicle only. Following a thoracotomy, the bronchus, pulmonary artery and vein were separately clamped for 1 hour. Arterial oxygen tension (PaO2), arterial oxygen saturation (SaO2), and endothelin-I (ET-I) were measured after 2 hours of reperfusion. Histologic and immunohistochemical studies were performed; polymorphonuclear neutrophils (PMNs) were counted after 2 hours of reperfusion. RESULTS: PaO2, SaO2, ET-I after 2 hours of reperfusion and the 7-day survival rate were significantly (p < 0.05) better in the FK409 group than the control group. Histologic damage was reduced in the FK409 group compared with the control group. PMN infiltration was also significantly (p < 0.05) lower in the FK409 group than in the control group. CONCLUSION: FK409 seems to protect against ischemia-reperfusion injury of the lung. This effect may be related to a homeostatic effect on pulmonary vascular beds and prevention of PMN sequestration.

Animals↗

PubMed2000

The effect of FK409-a nitric oxide donor-on canine lung transplantation.

BACKGROUND: Nitric oxide (NO) is known to have beneficial effects in ischemia-reperfusion (I/R) injury through maintaining endothelial integrity, inhibiting leukocyte adhesion and platelet aggregation, and inducing vasodilation. The effect of FK409 (FK), a spontaneous NO donor, was investigated in a canine lung transplantation model. METHODS: Ten pairs of weight-matched dogs were used. Five pairs were assigned to the FK group, to which FK (5 microg/kg/min) was administered intravenously from 30 minutes prior to ischemia until the induction of ischemia in the donor, and from 15 minutes prior to reperfusion until 45 minutes after reperfusion in the recipient. The others were assigned to the control group. After 8-hour preservation in 4 degrees C Euro-Collins solution, orthotopic single-lung transplantation was performed. During a 5-minute clamping test of the right pulmonary artery, left pulmonary arterial pressure (L-PAP), left pulmonary vascular resistance (L-PVR), arterial oxygen pressure (PaO(2)), and alveolar-arterial oxygen pressure difference (A-aDO(2)) were measured. The lung specimens were harvested for histologic study, and polymorphonuclear neutrophils (PMNs) were counted. Pulmonary perfusion and ventilation scintigraphy (Tc-99m-MAA and Xe-133) were performed. RESULTS: PAP, L-PVR, PaO(2), and A-aDO(2) revealed significantly (p < 0.05) better function in the FK group than in the control group. Histologically, edema was more mild, and PMN infiltration was significantly (p < 0.05) lower in the FK group than in the control group. Xe-133 and Tc-99m-MAA were widely distributed throughout the graft lung in the FK group. The 2-day survival rate was 100% in the FK group, which was significantly (p < 0.05) better than the rate (40%) in the control group. CONCLUSIONS: FK appears to generate a protective effect on I/R injury in lung transplantation.

Animals↗

PubMed2000

Optimal end point of FR167653 administration and expression of interleukin-8 messenger RNA on extended liver resection with ischemia in dogs.

BACKGROUND: FR167653 is a potent suppressant of interleukin-1 and tumor necrosis factor production. We previously reported that FR167653 inhibited the expression of interleukin-1 messenger RNA (mRNA) after ischemia-reperfusion and provided a protective effect against ischemia-reperfusion injury after extended liver resection. In this study we investigated the optimal end point of FR167653 administration and the inhibition of interleukin-8 (IL-8) mRNA expression caused by the administration of FR167653 during extended liver resection with ischemia in a dog model. STUDY DESIGN: The right portal pedicle was clamped for 60 minutes but the left portal vein was left patent to avoid portal congestion. After reperfusion 75% of the liver was resected. EXPERIMENT I: Adult mongrel dogs were divided into three groups: the control group (n = 9); the FR-2 group (n = 6), which received FR167653 through the portal vein starting 30 minutes before the onset of ischemia until 2 hours after reperfusion; and the FR-6 group (n = 6), which received FR167653 starting 30 minutes before ischemia until 6 hours after reperfusion. Hepatic venous blood was collected to measure liver enzymes. Liver specimens were harvested for histologic study 6 hours after reperfusion and polymorphonuclear neutrophils were counted. EXPERIMENT II: The expression of IL-8 was measured by reverse-transcriptase polymerase chain reaction. RESULTS: Aspartate aminotransferase and alanine aminotransferase levels after reperfusion and hyaluronic acid levels 6 hours after reperfusion were significantly (p < 0.05) lower in the FR-2 and FR-6 groups than in the control group. There were no significant differences between the FR-2 and FR-6 groups after reperfusion. Histologically liver tissue damage was mild in the FR-2 and FR-6 groups, and polymorphonuclear neutrophil infiltration was significantly lower in the FR-2 and FR-6 groups than in the control group. The 3-day survival rate was statistically (p < 0.05) better in the FR-2 and FR-6 groups than in the control group. IL-8 mRNA expression was inhibited in the FR-treated group. CONCLUSIONS: FR167653 should be administered until shortly after reperfusion and need not be administered for many hours after reperfusion. FR167653 inhibits IL-8 mRNA production and inhibits polymorphonuclear neutrophil infiltration.

Alanine Transaminase↗