sabiporide and Disease-Models--Animal

Administration of NaHCO3 does not improve cellular function or reduce the mortality of acute lactic acidosis. This might be related to aggravation of intracellular acidosis, but it could also be due to activation of Na+/H+ exchanger with a deleterious increment in intracellular calcium ([Ca2+]i). This study examined the impact of coadministration of NaHCO3 and a selective inhibitor of Na+/H+ exchanger, sabiporide on cardiovascular function, changes in proinflammatory cytokines, and organ function in a model of acute lactic acidosis produced by hemorrhagic hypotension followed by infusion of lactic acid.. Experimental, prospective study.. Medical Center research laboratory.. Male Yorkshire pigs.. Anesthetized pigs were subjected to hypovolemia for 30 minutes and followed by DL-lactic acid infusion, and then either saline or sodium bicarbonate was infused.. Hypovolemia followed by a DL-lactic acid infusion resulted in severe acidemia with a blood pH~6.8. Administration of NaHCO3 did not improve cardiovascular performance or decrease the levels of proinflammatory responses, whereas administration of sabiporide prior to acid or NaHCO3 infusion improved cardiopulmonary performance and blood oxygenation, reduced nuclear factor-κB activation, neutrophil accumulation, and proinflammatory cytokine production, and attenuated organ injury. Exposure of rat cardiac myocytes to a pH of 7.2 led to a marked increase of [Ca2+]i, and release of lactate dehydrogenase from cells which were further augmented after increase in external pH by addition of NaHCO3. Both the increase in [Ca2+]i and release of lactate dehydrogenase were attenuated in the presence of sabiporide.. Coadministration of Na/H exchanger inhibitor with sodium bicarbonate improves cardiovascular performances, reduces proinflammatory responses, and attenuates organ injury. This improvement in these variables appears to be related to prevention of a rise in intracellular calcium occurring after both exposures to acid and bicarbonate.

Topics: Acidosis; Animals; Blood Gas Analysis; Calcium; Cytokines; Disease Models, Animal; Guanidines; Hemodynamics; Hydrogen-Ion Concentration; L-Lactate Dehydrogenase; Male; Sodium Bicarbonate; Sodium-Hydrogen Exchangers; Swine

The aim of the present study was to evaluate the efficacy of orally administered sabiporide, a selective Na(+)/H(+) exchanger inhibitor on whole body protection from severe sepsis in rats.. Series 1: Sepsis was induced by cecal ligation and puncture (CLP). Animals received treatment of vehicle or sabiporide (10 mg/kg, p.o.). The experiment was terminated 20 h after CLP. Series 2: At 20 h after CLP, the necrotic cecum was excised and the abdominal cavity was washed. The animals were then returned to their cages. The experiment was terminated 7 d after CLP.. Series 1: Compared with vehicle treatment, administration of sabiporide prevented hemodynamic derangement and improved cardiac function as evidenced by improved arterial pressure, left ventricle systolic pressure, ±dp/dt max, ejection fraction and fractional shorting, attenuated left ventricle end-diastolic pressure elevation, and wall motion abnormality. Furthermore, administration of sabiporide attenuated intestinal mucosal hyperpermeability and reduced accumulation of abdominal ascites. In addition, treatment with sabiporide also reduced plasma levels of tumor necrosis factor-α, interleukin 6, interleukin 10, cardiac troponin, aspartate aminotransferase, alanine aminotransferase, urea, and lactate, and attenuated neutrophil infiltration in the liver and gut. Series 2: Administration of sabiporide improved the 7-day survival rate after CLP in rats (42% in vehicle group versus 75% in sabiporide group).. Administration of sabiporide improved cardiovascular performance, lessened the inflammatory response, tissue hypoperfusion and multiorgan injury, and most importantly reduced mortality.

Topics: Animals; Ascites; Biomarkers; Cardiovascular Diseases; Disease Models, Animal; Drug Evaluation, Preclinical; Guanidines; Heart; Hemodynamics; Intestinal Mucosa; Male; Multiple Organ Failure; Permeability; Random Allocation; Rats; Rats, Sprague-Dawley; Sepsis; Sodium-Hydrogen Exchangers

In the present study, we investigated the effects of sabiporide, a specific NHE-1 inhibitor, on blood-brain barrier (BBB) endothelial dysfunction during ischemia/hypoxia in rat cerebral ischemia in vivo and bEnd.3 cells in vitro. Sabiporide significantly attenuated ischemia/hypoxia-induced BBB hyperpermeability and disruption of occludin and zonula occludens-1 both in vivo and in vitro. Sabiporide also inhibited the hypoxia-induced increase in [Ca(2+)](i) in bEnd.3 cells. Taken together, the protective effect of sabiporide on BBB permeability may be mediated through maintaining tight junction integrity and associated with its inhibitory effect on [Ca(2+)](i) overload under hypoxia. These results suggest that the BBB protective effect of sabiporide may be of therapeutical benefit in brain injury after an ischemic stroke.

Topics: Analysis of Variance; Animals; Blood-Brain Barrier; Brain; Calcium; Carbon Isotopes; Cells, Cultured; Cytoskeletal Proteins; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Evans Blue; Gene Expression; Guanidines; Infarction, Middle Cerebral Artery; Male; Membrane Proteins; Mice; Neuroglia; Occludin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium-Hydrogen Exchangers; Sucrose; Tight Junctions

Aim of this study was to compare effects of BIIB-722, a novel Na(+)/H(+) exchanger-1 inhibitor, and ischemic preconditioning (IP) on infarct size and metabolism of area at risk in rats. Regional ischemia was induced by 40-min occlusion of a diagonal branch of left anterior descending coronary artery (LAD); it was followed by 60-min reperfusion. Intravenous bolus injection of BIIB-722 (3 mg/kg) dissolved in 280 mM xylitol was performed before regional ischemia or during the first minute of reperfusion. In the control group 280 mM xylitol was infused before ischemia or at the beginning of reperfusion at the same mode. IP was initiated by two cycles of 5-min LAD occlusion followed by 5-min reperfusion prior to sustained regional ischemia. Microdialysis technique was used to monitor pH and inorganic phosphate (P(i)) in the interstitial fluid of the area at risk. Metabolic state of the area at risk was assessed by ATP, phosphocreatine (PCr) and lactate levels; cellular membrane damage was evaluated by total creatine (SigmaCr=PCr+Cr) tissue content. Myocardial infarct size was determined by computer planimetry after staining of left ventricular slices with 2,3,5-triphenyltetrazolium chloride. BIIB-722 administration before or after ischemia, as well as IP, had no effect on cardiac hemodynamics and acid-base indices of arterial blood throughout the experiments. The infarct size/area at risk ratio was 43.5+/-5.2% in control and was reduced to 11.4+/-3.1% with IP, and to 17.0+/-3.6% and 25.8+/-2.6% with BIIB-722 infused on early reperfusion and before ischemia, respectively. BIIB-722 administration during the first minute of reperfusion as well as IP significantly augmented ATP and PCr contents, reduced lactate level and decreased ECr loss at the area at risk by the end of reperfusion as compared with values in control. Additionally significantly higher rates of pH recovery and reduction of P(i) concentration in the interstitial fluid were observed during reperfusion compared with these indices in control. BIIB-722 administration before ischemia had much effects on contents of energy and carbohydrate metabolites at area at risk. The results obtained indicate that ability of BIIB-722 to limit infarct size and improve metabolism in the area at risk is comparable to cardioprotective effects of IP. Therefore this study substantiates a possibility of application of a novel Na(+)/H(+) exchange inhibitor for clinical investigations.

Topics: Adenosine Triphosphate; Animals; Cation Transport Proteins; Disease Models, Animal; Guanidines; Injections, Intravenous; Ischemic Preconditioning, Myocardial; Lactic Acid; Male; Membrane Proteins; Myocardial Infarction; Myocardium; Phosphocreatine; Rats; Rats, Wistar; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers; Treatment Outcome

We investigated the effects of an Na(+)/H(+) exchanger inhibitor, sabiporide, on excitotoxicity in cultured neuronal cells and in vivo. Sabiporide attenuated glutamate- or NMDA (N-methyl-d-aspartic acid)-induced neuronal cell death. Sabiporide also reduced glutamate or NMDA-induced increase in [Ca(2+)](i). In in vivo brain ischemia model, sabiporide produced protective effects, decreasing the infarct size and edema volume. Our results suggest that sabiporide elicits neuroprotective effect both in vitro and in vivo.

Topics: Animals; Brain Infarction; Brain Ischemia; Calcium; Cell Death; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Extracellular Space; Glutamic Acid; Guanidines; Mice; N-Methylaspartate; Neurons; Reperfusion; Sodium-Hydrogen Exchangers; Tetrazolium Salts; Thiazoles