tcv-309 and Ischemia

This study was designed to verify the involvement of platelet-activating factor (PAF) in renal damage associated with hepatic ischemia and reperfusion (HIR) injury through the release of endothelin (ET)-1 and to determine the modulating effect of a specific PAF receptor antagonist on these insults in rats.. Male rats pretreated with either normal saline as a vehicle (NS group) or intravenous TCV-309, a PAF receptor antagonist (TCV group), were subjected to 120 min of total hepatic ischemia under an extracorporeal portosystemic shunt. Plasma aspartate transaminase, creatinine, blood urea nitrogen, and ET-1 levels and the relative renal wet weight were determined under nonischemic conditions and at 1, 3, and 6 hr of reperfusion after hepatic ischemia. Changes in mean arterial blood pressure and renal tissue blood flow measurements in the kidney were determined throughout the experiment.. Increased plasma aspartate transaminase, creatinine, blood urea nitrogen, and ET-1 levels and the relative renal wet weight after HIR in the NS group were significantly suppressed by TCV-309 pretreatment. Mean arterial blood pressure and renal tissue blood flow after HIR in the TCV group were significantly improved when compared with those in the NS group. These effects resulted in attenuation of structural hepatic and renal damage with the improvement of 7-day survival (62%).. The present study demonstrates that renal damage as well as critical liver injury is produced after reperfusion following 120 min of total hepatic ischemia. A PAF receptor antagonist may be therapeutically useful to protect against these types of damage via indirect modulation of plasma ET-1 levels.

Topics: Animals; Aspartate Aminotransferases; Blood Pressure; Blood Urea Nitrogen; Creatinine; Endothelin-1; Ischemia; Isoquinolines; Kidney; Liver; Liver Circulation; Male; Platelet Activating Factor; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Reperfusion Injury; Tetrahydroisoquinolines

The purpose of this study was to investigate whether treatment with TCV-309, a PAF antagonist, improves life-sustaining function of renal grafts that have suffered warm ischemia (WI) prior to cold storage (CS) and whether TCV-309 influences leukocyte sequestration in tissues. Syngeneic kidneys with 20 min of WI and 24 hr of CS were transplanted into bilateral nephrectomized rats. In the treated group, TCV-309 was administered (i.v. 1 mg/kg) 5 min before reperfusion. Rats in the control group received saline. On day 14, 80% rats survived in the treated group, which was higher than the controls (0%). At 24 hr of reperfusion, myeloperoxidase (MPO) activity, a marker enzyme for PMNs, in the treated kidney was significantly lower than the controls, but did not differ from the normal values. The MPO activity in the controls was higher than the normal values. In conclusion, the PAF antagonist improves posttransplant function of rat kidneys subjected to a period of WI and CS. PMNs are involved in postischemic renal injury, which is, at least partially, mediated by PAF. The effectiveness of PAF antagonist in treatment of recipients may lead to its clinical application in transplantation of ischemically injured kidneys.

Topics: Animals; Hot Temperature; Immunity, Cellular; Ischemia; Isoquinolines; Kidney; Kidney Cortex; Kidney Transplantation; Lung; Macrophages; Monocytes; Neutrophils; Organ Preservation; Peroxidase; Platelet Activating Factor; Platelet Aggregation Inhibitors; Pyridinium Compounds; Rats; Rats, Inbred Lew; Reperfusion Injury; Tetrahydroisoquinolines; Time Factors

Topics: Animals; Ischemia; Isoquinolines; Kidney; Kidney Tubules, Proximal; Male; Microvilli; Mitochondrial Swelling; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Inbred Lew; Reperfusion Injury; Tetrahydroisoquinolines; Time Factors

Liver failure is often accompanied by shock, which is usually refractory to conventional vasopressive therapy, and it is believed that some potent chemical mediators are involved in this process. The platelet activating factor (PAF) is a newly discovered inflammatory mediator that has a remarkable hypotensive action. In the present study, the possible role of PAF in shock after ischemic liver failure was investigated. Partial hepatic ischemia was induced in Wistar rats by clamping the hepatic afferent vessels to almost 70% of the whole liver for 90 min. One group of rats was pretreated with 10 micrograms/kg of TCV-309, a PAF antagonist. Pretreatment with TCV-309 inhibited the shock that ultimately occurred in the untreated rats; the survival rate 16 h after hepatic ischemia was 20% in the untreated control group but 100% in the group pretreated with TCV-309. The level of PAF in the plasma after hepatic ischemia was 2,939 +/- 2,412 pg/ml, which was significantly higher than that of the surgical control (920 +/- 188 pg/ml). These findings strongly suggest that anoxical disintegration of the liver derives PAF which causes shock. Thus, a PAF antagonist is expected to be an effective prophylactic treatment for patients who are at risk of developing shock from an ischemic liver.

Topics: Animals; Hypotension; Ischemia; Isoquinolines; Liver; Liver Failure; Male; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Wistar; Shock; Tetrahydroisoquinolines

Topics: Animals; Creatinine; Ischemia; Isoquinolines; Kidney; Male; Microscopy, Video; Organ Preservation; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Inbred Lew; Reperfusion Injury; Temperature; Tetrahydroisoquinolines

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Ischemia; Isoquinolines; Liver; Male; Molecular Structure; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Wistar; Tetrahydroisoquinolines; Thromboxane B2

The effects of TCV-309, a specific platelet-activating factor (PAF) antagonist, and OP-41483, a prostaglandin I2 analogue, on warm ischemia/reperfusion injury of the rat liver were studied. Rats were divided into five groups by the duration of warm ischemia and the treatment used. The NS1 group (normal saline pretreatment) had 60 min of warm ischemia, while the NS2 group (normal saline pretreatment), the PGI2 group (OP-41483, 500 ng/kg/min pretreatment), the TCV group (TCV-309, 3 micrograms/kg), and the PGI2+TCV group (both the above dosages) underwent 120 min of warm ischemia. Postoperative survival after 30 days, bile secretion, serum endotoxin levels, and tissue glutathione levels after 60 min of reperfusion were compared between the groups. The survival rates for the NS1, NS2, PGI2, TCV, and PGI2+TCV groups were 80%, 0%, 50%, 80%, and 86.7%, respectively. Bile secretion, which has a strong correlationship with hepatic cellular ATP level, was strongly correlated with survival. The NS2 group had a high serum endotoxin level--however, the PGI2 and PGI2+TCV groups had normal levels. Although there were some discrepancies between survival and the tissue glutathione level, combined treatment with the PGI2 analogue and TCV-309 was most effective in inhibited oxidative stress. In conclusion, TCV-309 increased the survival rate after 120 min of warm hepatic ischemia without endotoxemia by the PGI2 analogue. This finding suggest that warm ischemia/reperfusion injury is related to the generation of PAF. Combined pretreatment with TCV-309 and a PGI2 analogue may be useful in liver transplantation.

Topics: Animals; Bile; Endotoxins; Epoprostenol; Glutathione; Ischemia; Isoquinolines; Liver; Male; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Wistar; Reperfusion Injury; Tetrahydroisoquinolines

Topics: Animals; Dogs; Ischemia; Isoquinolines; Leukocyte Count; Lung; Lung Compliance; Platelet Activating Factor; Pulmonary Circulation; Pyridinium Compounds; Reperfusion Injury; Tetrahydroisoquinolines; Vascular Resistance