fumarates and Ischemia

While performing surgical treatment of the localized form of renal cell cancer by means of open or laparoscopic partial nephrectomy, renal warm ischemia is an important issue. Using renal warm ischemia allows to prevent parenchymal bleeding, to optimize conditions for resection of the tumor and to increase significantly the efficiency of hemostasis. However, an important problem is the probability of ischemic hypoxic damage of the remaining part of the kidney tissue during renal warm ischemia and renal functional impairment in the postoperative period.. To compare nephroprotective activity of sodium fumarate, mannitol and furosemide using experimental model of 30- and 60-minute renal warm ischemia in rabbits.. The experiments were carried out on 360 conventional male-rabbits of the "Chinchilla" breed weighed 2,6+/-0,3 kg which were allocated into 10 groups. The control group No1 included intact animals, the control group No2 included the rabbits in which renal artery was not clamped. For the animals from the trial groups (No3-No10) the experimental model of 30- and 60-minute renal warm ischemia was used. In groups No3 and No4 no drugs were provided. Other rabbits undergone renal warm ischemia with a protection by sodium fumarate (groups No5 and No6 - 1,5 ml/kg IV), lasix (groups No7 and No8 - 3,0 mg/kg IV) and mannitol (No9 and No10 - 1,0 g/kg IV). The influence of renal warm ischemia on the renal tissue ultrastructure and the levels of NGAL, Cystatin-C and creatinine in blood and urine were studied.. During experimental pharmacologically uncorrected 30-minute renal warm ischemia in animals, edema of the terminal part of microvilli of the proximal tubules epithelium, an increase of lysosome number in the hyaloplasm of epithelial cells, appearance of flaky content of medium electronic density in the lumens of distal tubules and collecting tubules, as well as sharp peak-like increase of NGAL and cystatin-C in blood and urine were observed. Increasing the time of ischemia up to 60 minutes was accompanied by more severe disturbances. In groups where sodium fumarate, lasix and mannitol were used the observed ultrastructural disturbances were expressed to lesser extent, whereas sodium fumarate demonstrated the best nephroprotective activity. After using mannitol the severity of disturbances was less than in the groups where mannitol, lasix or sodium fumarate were not given. Lasix and sodium salt of fumaric acid showed a higher nephroprotective activity. The best results were received in the animals received sodium fumarate.. The studied drugs provided a nephroprotective effect regarding ischemia of rabbit kidney. The effect of sodium fumarate was the most pronounced, followed by furosemide and, to a lesser extent, mannitol. Use of sodium fumarate allows to protect and stimulate the kidney tissue effectively during oxygen deprivation under ischemic state.

Topics: Animals; Female; Fumarates; Furosemide; Humans; Ischemia; Kidney; Kidney Neoplasms; Lipocalin-2; Male; Mannitol; Rabbits; Warm Ischemia

The aim of this study was to evaluate the effects of aliskiren, direct renin inhibitor, as an antioxidant and tissue protective agent and evaluate the molecular, biochemical, and histopathological changes in experimental ischemia and ischemia/reperfusion injury in rat ovaries. Forty-eight female rats were randomly divided into eight groups: in Group 1, only sham operation was performed. Group 2 received 100 mg/kg aliskiren and sham operated. In Group 3, 3 h-period of bilateral ovarian ischemia was applied. Group 4 received a 3-h period of ischemia followed by 3 h of reperfusion. Groups 5 and 6 received 50 and 100 mg/kg, respectively, of aliskiren and bilateral ovarian ischemia was applied (after a 3-h period of ischemia, both ovaries were surgically removed). To Groups 7 and 8, 50 and 100 mg/kg of aliskiren were administered, respectively, and the induction of ischemia was performed. At the end of a 3-h period of ischemia, bilateral vascular clips were removed, and 3 h of reperfusion continued. After the experiments, IL-1β, IL-6, TNF-α, and iNOS mRNA expressions and SOD, GSH, MDA, renin, and angiotensin-II levels were determined and histopathological changes were examined in rat ovaries. Aliskiren treatment normalized excessive changes in cytokine and oxidative stress markers in both ischemia and ischemia/reperfusion injury. Histopathologically, treatment with aliskiren ameliorated the development of ischemia and/or ischemia/reperfusion tissue injury. This study concluded that aliskiren treatment is effective in reversing ischemia and/or ischemia/reperfusion induced ovary damage via the improvement of oxidative stress, reduction of inflammation, and suppression of the renin-angiotensin aldosterone system.

Topics: Amides; Animals; Disease Models, Animal; Female; Fumarates; Ischemia; Ovarian Diseases; Protective Agents; Random Allocation; Rats; Rats, Wistar; Renin-Angiotensin System; Reperfusion Injury

Testicular torsion is a urological emergency. Failure of timely intervention for this issue leads the testicles to go into necrosis. If left untreated, it can lead to loss of the reproductive organs. The aim of this study was to examine the role of aliskiren in testicular torsion and detorsion injuries.. Rats were divided into 8 groups of 12 each, including no torsion-detorsion, no torsion-detorsion plus 200 mg/kg aliskiren orally, torsion, torsion-detorsion, torsion plus 100 mg/kg aliskiren orally, torsion plus 200 mg/kg aliskiren orally, torsion-detorsion plus 100 mg/kg aliskiren orally and torsion-detorsion plus 200 mg/kg aliskiren orally. Aliskiren was administered 30 minutes before ischemia and reperfusion, and also 24 hours before the experimental protocol in all treatment groups. Ischemia and reperfusion were each applied for 2 hours.. Testicular damage decreased superoxide dismutase and glutathione, and increased malondialdehyde in the testis tissues of rats. Aliskiren administration increased superoxide dismutase and glutathione, and decreased malondialdehyde in the testis tissues. Values were measured by a biochemical autoanalyzer. In addition, this torsion-detorsion damage caused a significant increase in levels of the inflammatory cytokine and agents interleukin-1β and inducible nitric oxide synthase, as examined by real-time polymerase chain reaction. Aliskiren administration decreased these parameters. On pathological evaluation administration of a 200 mg/kg dose of aliskiren was found to protect the testis. Renin-angiotensin-aldosterone system inhibition by aliskiren caused an increase in serum renin levels and a decrease in serum angiotensin II levels.. It appears that aliskiren protects the testis from ischemia-reperfusion damage by regulating inflammation and the oxidant-antioxidant balance via renin-angiotensin-aldosterone system inhibition.

Topics: Amides; Animals; Fumarates; Ischemia; Male; Rats; Rats, Wistar; Renin-Angiotensin System; Spermatic Cord Torsion; Testis

Topics: Amides; Animals; Fumarates; Ischemia; Male; Renin-Angiotensin System; Spermatic Cord Torsion; Testis

Renin is the rate limiting step for the activation of the renin-angiotensin-aldosterone system, which is linked to the development of endothelial dysfunction, hypertension and atherosclerosis. However, the specific role of renin during physiological responses to tissue ischemia is currently unknown. Aliskiren is the only direct renin inhibitor that is clinically used as an orally active antihypertensive drug. Here we tested the hypothesis that aliskiren might improve neovascularization in response to ischemia.. At a dose that did not modulate blood pressure (10 mg/kg), aliskiren led to improved blood flow recovery after hindlimb ischemia in C57BL/6 mice (Doppler flow ratios 0.71 ± 0.07 vs. 0.55 ± 0.03; P < 0.05). In ischemic muscles, treatment with aliskiren was associated with a significant increase of vascular density, reduced oxidative stress levels and increased expression of VEGF and eNOS. Aliskiren treatment also significantly increased the number of bone marrow-derived endothelial progenitor cells (EPCs) after hindlimb ischemia. Moreover, the angiogenic properties of EPCs (migration, adhesion, integration into tubules) were significantly improved in mice treated with aliskiren. In vitro, aliskiren improves cellular migration and tubule formation in HUVECs. This is associated with an increased expression of nitric oxide (NO), and a significant reduction of oxidative stress levels. Importantly, the angiogenic properties of aliskiren in vitro and in vivo are completely abolished following treatment with the NOS inhibitor l-NAME.. Direct renin inhibition with aliskiren leads to improved ischemia-induced neovascularization that is not dependant on blood pressure lowering. The mechanism involves beneficial effects of aliskiren on oxidative stress and NO angiogenic pathway, together with an increase in the number and the functional activities of EPCs.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Bone Marrow Cells; Cell Adhesion; Cell Movement; Endothelial Cells; Endothelial Progenitor Cells; Fumarates; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Ischemia; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxidative Stress; Oxygen; Reactive Oxygen Species; Renin; Renin-Angiotensin System; Superoxides

Aliskiren is a direct renin inhibitor which is suggested to modify proangiogenic cells in addition to lower blood pressure. Given that angiogenesis is impaired in the presence of diabetes mellitus, we would like to investigate whether and how aliskiren enhances endothelial progenitor cells (EPCs) and improves ischemic-induced neovasculogenesis by an effect independent of blood pressure reduction in diabetic animals.. Streptozotocin-induced diabetic mice were administered with either aliskiren (5 or 25 mg/kg/day) using an osmotic pump or hydralazine (2 or 10 mg/kg/day) given in drinking water for two weeks prior to a hind-limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs, respectively.. In streptozotocin-induced diabetic mice, aliskiren enhanced the recovery of limb perfusion and capillary density, increased the number of circulating Sca-1+/Flk-1+ EPC-like cells, and elevated the levels of the plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α in a dose-dependent manner, whereas there were no such effects in hydralazine-treated mice. Intraperitoneal administration of anti-SDF-1 neutralizing monoclonal antibodies abolished the effects of aliskiren.. Independent of the reduction of blood pressure, aliskiren enhanced ischemia-induced neovasculogenesis in a dose-dependent manner via VEGF/SDF-1α related mechanisms in diabetic mice.

Topics: Amides; Animals; Antibodies, Monoclonal; Blood Pressure; Chemokine CXCL12; Diabetes Mellitus, Experimental; Endothelial Progenitor Cells; Fumarates; Humans; Hydralazine; Ischemia; Mice; Neovascularization, Physiologic; Renin; Vascular Endothelial Growth Factor A

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.

Topics: Adenosine Monophosphate; Animals; Aspartic Acid; Citric Acid Cycle; Disease Models, Animal; Electron Transport; Electron Transport Complex I; Fumarates; Ischemia; Malates; Male; Metabolomics; Mice; Mitochondria; Myocardial Infarction; Myocardium; Myocytes, Cardiac; NAD; Reactive Oxygen Species; Reperfusion Injury; Stroke; Succinate Dehydrogenase; Succinic Acid

Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, P<0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, P<0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

Topics: Amides; Animals; Antihypertensive Agents; Caspase 3; Collagen Type I; Disease Models, Animal; Female; Fibrosis; Fumarates; Glucuronidase; Ischemia; Kidney; Kidney Failure, Chronic; Klotho Proteins; Mice; Mice, Inbred Strains; Renal Artery; Renin; Surgical Instruments

Topics: Amides; Animals; Female; Fumarates; Ischemia; Kidney; Kidney Failure, Chronic; Renin

Topics: Acetone; Alanine; Amino Acids; Animals; Asparagine; Aspartic Acid; Brain Chemistry; Cerebral Cortex; Citrates; Citric Acid Cycle; Fructosephosphates; Fumarates; gamma-Aminobutyric Acid; Glutamates; Glutamine; Glycerophosphates; Ischemia; Ketoglutaric Acids; Malates; Male; Methods; Phosphates; Rats; Succinates

Topics: Acetoacetates; Adenosine Triphosphate; Animals; Buffers; Carbon Radioisotopes; Chromatography, Paper; Citrates; Citric Acid Cycle; Fumarates; Hydroxybutyrates; In Vitro Techniques; Ischemia; Ketoglutaric Acids; Ketone Bodies; Liver; Malates; Mitochondria, Liver; Oxidation-Reduction; Pyruvates; Rats; Succinates; Temperature

Topics: Adult; Aged; Cerebrovascular Disorders; Female; Fumarates; Humans; Ischemia; Male; Middle Aged; Vascular Diseases

Topics: Animals; Arteries; Coronary Vessels; Cycloheptanes; Dogs; Fumarates; Ischemia; Myocardial Infarction; Parasympatholytics; Propylamines; Regional Blood Flow; Vasodilator Agents

Topics: Adult; Arteries; Arteriosclerosis Obliterans; Arteritis; Blood Circulation; Cerebral Arteries; Cycloheptanes; Female; Fumarates; Humans; Ischemia; Leg; Male; Parasympatholytics; Propylamines; Raynaud Disease; Spasm; Thromboangiitis Obliterans; Vascular Diseases