endothelin-1 and dazmegrel

Prevention of the production of thromboxane A2--a potent vasoconstrictor and aggregating metabolite of arachidonic acid--or infusion of the stable analogues of prostacyclin--which is another cyclo-oxygenase metabolite of arachidonic acid--has been shown to be beneficial in cerebral vasoconstriction. Endothelin-1, a peptide derived from endothelial cells, has been shown to induce a long-lasting cerebral vasoconstriction both in vivo and in vitro. The purpose of this study was to investigate the role of a novel thromboxane A2-synthase inhibitor UK 38485 on the acute vascular and morphological effects of Endothelin-1 applied intra-arterially on rabbit basilar arteries. The inguinal region of twenty four anaesthetized albino rabbits of both sexes were dissected and a catheter was inserted into the aorta via the femoral artery, for control angiography of the basilar artery and intra-arterial injection of ET-1 (0.25 ng total dose) and UK 38485 at a dose of 0.05 microgram kg-1 min-1 for 20 min or saline. Angiographic vasoconstriction quantification and morphological investigations of both vessels and brain stem either by light microscopy or transmission electron microscopy were the techniques applied for the study. We found out that, although the systemic administration of UK 38485 resulted in a potent antagonism of the acute vasoconstriction as visualized in angiographic studies, it did not affect the morphological changes induced by Endothelin-1 on the vessel wall. The results indicated that there might have been an interaction between Endothelin-1 and the prostaglandin synthesis mechanism in acute cerebral vasoconstriction.

Topics: Animals; Basilar Artery; Drug Interactions; Endothelin-1; Enzyme Inhibitors; Female; Imidazoles; Male; Muscle, Smooth; Rabbits; Thromboxane-A Synthase; Ultrasonography; Vasoconstriction; Vasodilator Agents

Thromboxane A2 is a proaggregative vasoconstrictor that is synthesized and released in reperfusion injury. We aimed to investigate the effects of thromboxane synthase inhibitor, UK 38485, on endothelin-1,2 (ET) response of the renal endothelium and lipid peroxidation and protein oxidation in the early period of kidney transplantation. Four groups (n=8 in group IV and n=10 in the others) [corrected] of Sprague-Dawley rats were designed as Group I (sham nephrectomy), Group II (autotransplantation), Group III (allotransplantation) and Group IV (allotransplantation group in which the allografts were perfused with UK 38485. All subjects underwent right nephrectomy after transplantation. The grafts were flushed with 4 ml of ice-cold Ringer's lactate and in Group IV 10 microg of UK 38485 was added into the solution for each kidney. In allotransplantation groups, the kidneys were harvested from allogeneic white Wistar albino rats. The kidney grafts were allowed 120 min of reperfusion after 40 min of cold ischemic period. ET-1,2 plasma concentrations in the renal vein blood and diene conjugates (DC), hydroxyalkanals (HAA), hydroxyalkenals (HAE) and malondialdehyde (MDA) levels as the products of lipid peroxidation, protein carbonyls and protein sulfhydryls as the indicators of protein oxidation were analyzed in kidney tissue. Plasma ET-1,2 concentrations increased significantly in Group II and Group III (P<0.01) when compared to Group I but decreased in Group IV in comparison with Group III (P<0.05). DC, HAA, HAE and MDA levels increased in Groups II and III (P<0.001). Significant protein oxidation occurred only in Group III (P<0.01). Perfusion of the allografts with UK 38485 prevented lipid peroxidation and protein oxidation in Group IV. Histopathological changes were mild in the last group. We concluded that, in kidney transplantation, local administration of UK 38485 has cytopreservative effects on the allografts and this effect can be related to ET-1,2 concentrations.

Topics: Alkanes; Alkenes; Animals; Endothelin-1; Endothelin-2; Imidazoles; Kidney Transplantation; Male; Malondialdehyde; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Renal Circulation; Reperfusion Injury; Sulfhydryl Compounds; Thromboxane A2; Thromboxane-A Synthase; Transplantation, Homologous; Vasodilator Agents