iloprost and dazmegrel

In order to elucidate the relation between tissue eicosanoids and liver injury due to bile duct obstruction, we have examined the effects of iloprost, a stable analogue of prostaglandin I2 (PGI2), and UK 38485 (UK), an inhibitor of thromboxane synthetase, on prostaglandin E2 (PGE2) and leukotriene C4(LTC4) in guinea pig liver. 56 male guinea pigs were divided into the following groups: (i) sham operations (SHAM), (ii) bile duct ligated (BDL) group, (iii) guinea pigs given UK (5 micrograms/kg body wt intraperitoneally 10 min, 8 h and 16 h after bile duct ligation), and (iv) guinea pigs treated with iloprost (ILO) (2 micrograms/kg body wt intraperitoneally 10 min, 8 h and 16 h after bile duct ligation). Liver damage was assessed by blind quantitation of liver cell necrosis. Bile duct ligation caused an increase in tissue PGE2-like activity and a decrease LTC4-like activity. But the most pronounced elevation of PGE2-like activity was observed in ILO treated group. The LTC4-like activity level improved significantly in the UK-treated BDL group compared with the BDL only and ILO treated animals. Also, UK was found to be beneficial in preventing the liver cell necrosis due to cholestasis. It is concluded that the ratio of PGE2/LTC4 in liver is a valuable marker for cholestatic injury.

Topics: Animals; Bile Ducts; Biomarkers; Cholestasis, Extrahepatic; Dinoprostone; Guinea Pigs; Iloprost; Imidazoles; Leukotriene C4; Ligation; Liver; Male; Necrosis; Thromboxane-A Synthase

To investigate the effect of iloprost (ZK 36374) and thromboxane synthetase inhibitor UK 38485 on endothelin release by the intestinal vascular endothelium after ischemia/reperfusion (IR) injury, five experimental groups were formed. The groups consisted of sham, control, iloprost treated (ILO), UK 38485 treated (TSI), and iloprost + UK 38485 treated (ILO + TSI) groups. The last three groups received the corresponding agents and then the superior mesenteric artery was clamped for 30 min followed by 90 min reperfusion. Endothelin levels in the portal blood and malondialdehyde (MDA), prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) levels in the intestinal tissue were determined. The MDA levels increased significantly in the control group and this increase was reversed in ILO, TSI, and ILO + TSI groups, the two drugs together showing a synergistic effect in preventing lipid peroxidation. The changes in the LTC4 levels were not significant among the groups. The increased endothelin levels in the control group were reversed in ILO and TSI groups but these two agents did not have a synergistic effect. Increased PGE2 levels were reversed with iloprost but neither UK 38485 nor the combination of the two agents was effective in decreasing PGE2 levels. It is concluded that endothelin release after mesenteric IR injury is relatively unrelated to lipid peroxidation and the lipoxygenase pathway. The cylooxygenase pathway has a direct effect on endothelin release and PGE2 may act as a mediator.

Topics: Animals; Dinoprostone; Endothelins; Endothelium, Vascular; Female; Iloprost; Imidazoles; Intestine, Small; Leukotriene C4; Malondialdehyde; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane-A Synthase

Tissue protective activities of Iloprost, a stable analogue of PGI2, and of UK 38485, an inhibitor of thromboxane synthetase, were investigated in rats, in which acute renal failure was elicited by the injection of glycerol. The effects of these compounds on PGE2- and LTC4-like activities in the kidney tissue were also studied. Glycerol injection caused acute kidney damage as evidenced by light microscopic examination and abundant hematuria. Glycerol injection also caused an increase in tissue PGE2- and LTC4-like activities. Although both metabolites were increased, the ratio of PGE2/LTC4 was found to be decreased when compared with the control value. Both Iloprost and UK 38485 partially prevented tissue damage due to glycerol and caused an increase in the ratio of PGE2/LTC4. The preventive effects of the drugs were more pronounced when both drugs were used in combination. The participation of arachidonic acid metabolites in the mechanism of the production of kidney damage due to glycerol and possible preventive effects of the compounds are discussed.

Topics: Acute Kidney Injury; Animals; Female; Glycerol; Iloprost; Imidazoles; Kidney Cortex; Kidney Tubules; Male; Rats; Reference Values; Thromboxane-A Synthase

Plasma thromboxane concentrations were found to be significantly elevated in acute necrotizing pancreatitis in rats, whereas prostaglandin I2 levels were not. The significance of these alterations was investigated. Pancreatitis was induced by injecting 5% sodium taurocholate into the pancreatic duct. Iloprost (ZK 36374, a stable analog of prostaglandin I2, 25 ng/kg body weight) decreased the mortality rate from 100% to 50%. When treatment with iloprost was combined with simultaneous administration of either Sibelium (flunarizine R 14,950, 0.2 mg/kg body weight) or dazmegrel (UK 38,485, 50 mg/kg body weight) an additional decrease in the mortality rate was recorded. Dazmegrel is a selective thromboxane A2 synthetase inhibitor and flunarizine (a calcium entry blocker) also inhibits the effects of elevated thromboxane A2 levels. With flunarizine and iloprost the mortality rate was 40% (P less than 0.05); with dazmegrel and iloprost it was 10% (P less than 0.01). The results of the present study suggest that thromboxane A2 and prostaglandin I2 play a role in the course of acute necrotizing pancreatitis.

Topics: Acute Disease; Animals; Epoprostenol; Flunarizine; Iloprost; Imidazoles; Male; Necrosis; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Thromboxane A2; Vasodilator Agents

The effects of ZK 36374, a prostacyclin analogue and UK 38485, a thromboxane synthetase inhibitor were studied in guinea pigs after performing mesenteric arterial occlusion. In this study, while ZK 36374 significantly lowered the alkaline phosphatase and creatine phosphokinase values two hours after mesenteric arterial occlusion when compared with the control group (p less than 0.005), UK 38485 did not induce any change. In guinea pigs, when given together, ZK 36374 and UK 38485 lowered the enzyme levels to preligation values and the difference was nonsignificant (p greater than 0.1). The histopathologic investigation of the small intestine after giving ZK 36374 and UK 38345 together revealed minimal changes. These findings stress the importance of preserving the PGI2 levels in the PGI2/TXA2 ratio in preventing the increase of lysosomal enzyme levels and histopathologic changes after mesenteric arterial occlusion in guinea pigs.

Topics: Alkaline Phosphatase; Animals; Creatine Kinase; Drug Evaluation, Preclinical; Female; Guinea Pigs; Iloprost; Imidazoles; Intestine, Small; Male; Mesenteric Arteries; Mesenteric Vascular Occlusion; Thromboxane-A Synthase

Topics: Animals; Basilar Artery; Epoprostenol; Female; Iloprost; Imidazoles; Ischemic Attack, Transient; Male; Prostaglandins F, Synthetic; Rabbits; Vasodilation; Vasodilator Agents

The effect of thromboxane A2 inhibitors and iloprost, a stable analogue of prostacyclin, on angiotensin II-induced oedema was studied in the isolated perfused rat lung. Angiotensin II, infused into the pulmonary artery, produced oedema of the lung, as evidenced by the increase in lung weight and in perfusion pressure. UK 38485, a thromboxane A2-synthetase inhibitor, and BM 13177, a thromboxane A2 receptor blocker, attenuated the oedema producing and vasoconstrictor effects of angiotensin II. A similar effect was obtained with iloprost at very low concentrations. Other agonists such as noradrenaline, phenylephrine and high K+ in the medium produced increases in perfusion pressure, but failed to elicit an increase in lung weight. Only serotonin, at relatively higher concentrations again increased lung weight, which was prevented by prior addition of UK 38485, BM 13177 and iloprost into the medium. These results were taken as an evidence indicating thromboxane A2 and prostacyclin-mediated effects of angiotensin II in the isolated perfused rat lung and the possible role of these unstable metabolites of arachidonic acid in the production of lung oedema.

Topics: Angiotensin II; Animals; Anti-Arrhythmia Agents; Blood Pressure; Catecholamines; Epoprostenol; Female; Iloprost; Imidazoles; In Vitro Techniques; Lung; Male; Organ Size; Pulmonary Edema; Rats; Serotonin; Thromboxane A2; Thromboxane-A Synthase

This study was undertaken to evaluate the efficacy of iloprost and UK 38485 in the prevention of gastric lesions due to restraint-cold stress, ethanol or indomethacin. Prior injection of iloprost to the rats significantly prevented the increase in ulcer index by restraint- cold stress or indomethacin but nonsignificantly reduced the ulcer index induced by ethanol. UK 38 485 at lower doses caused a highly significant decrease in the ulcer index induced by all noxious stimuli used in this study. UK 38 485 also reduced the increased 3H back diffusion due to restraint-cold stress. Higher doses of the compound, however, failed to decrease the mucosal damage due to restraint-cold stress. Combination of iloprost and UK 38 485 produced a further significant decrease in the ulcer index induced by all noxious stimuli and increased 3H back diffusion induced by restraint-cold stress. In relation to these results the importance of PGI2/TXA2 ratio in the production of gastric mucosal lesions is discussed.

Topics: Animals; Epoprostenol; Ethanol; Female; Gastric Mucosa; Iloprost; Imidazoles; Indomethacin; Male; Rats; Stomach Ulcer; Stress, Physiological; Thromboxane A2; Thromboxane-A Synthase