lu-208075 and Disease-Models--Animal

In non-alcoholic steatohepatitis (NASH), decreased nitric oxide and increased endothelin-1 (ET-1, also known as EDN1) released by sinusoidal endothelial cells (LSEC) induce hepatic stellate cell (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, and ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model. Diet-induced NASH rats were treated with atorvastatin (10 mg/kg/day), ambrisentan (30 mg/kg/day or 2 mg/kg/day) or a combination of both for 2 weeks. Hemodynamic parameters were registered and liver histology and serum biochemical determinations analysed. Expression of proteins were studied by immunoblotting. Conditioned media experiments were performed with LSEC. HSCs were characterized by RT-PCR, and a collagen lattice contraction assay was performed. Atorvastatin and ambrisentan act synergistically in combination to completely normalize liver hemodynamics and reverse histological NASH by 75%. Atorvastatin reversed the sinusoidal contractile phenotype, thus improving endothelial function, whereas ambrisentan prevented the contractile response in HSCs by blocking ET-1 response. Additionally, ambrisentan also increased eNOS (also known as Nos3) phosphorylation levels in LSEC, via facilitating the stimulation of endothelin-receptor-B in these cells. Furthermore, the serum alanine aminotransferase of the combined treatment group decreased to normal levels, and this group exhibited a restoration of the HSC quiescent phenotype. The combination of atorvastatin and ambrisentan remarkably improves liver histology and PH in a diet-induced NASH model. By recovering LSEC function, together with inhibiting the activation and contraction of HSC, this combined treatment may be an effective treatment for NASH patients.

Topics: Alanine Transaminase; Animals; Atorvastatin; Biomarkers; Collagen; Disease Models, Animal; Drug Synergism; Endothelial Cells; Endothelin-1; Enzyme Activation; Hemodynamics; Hepatic Stellate Cells; Insulin Resistance; Liver; Liver Cirrhosis; Nitric Oxide Synthase Type III; Non-alcoholic Fatty Liver Disease; Phenylpropionates; Pyridazines; Weight Gain

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

The objective of this study is to determine if ambrisentan (ET. Male 12-week-old humanized sickle mice (HbSS) and their genetic controls (HbAA) were treated with vehicle, HU, ambrisentan, or HU with ambrisentan for 2 weeks and renal structure and function were assessed.. Vehicle treated HbSS mice exhibited significant proteinuria compared to vehicle treated HbAA mice. HbSS mice also displayed significantly elevated plasma ET-1 concentrations and decreased urine osmolality compared to HbAA controls. Proteinuria was significantly lower in both HU and ambrisentan treated animals compared to vehicle treated HbSS mice; however, there was no additional improvement in HbSS mice treated with combined ambrisentan and HU. The combination of HU and ambrisentan resulted in significantly lower KIM-1 excretion, glomerular injury, and interstitial inflammation than HU alone.. These findings indicate that HU and ET

Topics: Anemia, Sickle Cell; Animals; Antisickling Agents; Disease Models, Animal; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Humans; Hydroxyurea; Kidney Diseases; Male; Mice; Phenylpropionates; Pyridazines

Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model. We sought to differentiate single drug therapy from combination therapy in female rats with severe disease. One week after left pneumonectomy, we induced PH in young female Sprague-Dawley rats with an injection of monocrotaline (45 mg/kg). Female rats were then randomized to receive combination therapy (ambrisentan plus tadalafil), ambrisentan monotherapy, tadalafil monotherapy, or vehicle. We measured RV size and function on two serial echocardiograms during the development of disease. We measured RV systolic pressure (RVSP) invasively at

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Female; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Monocrotaline; Phenylpropionates; Pneumonectomy; Pulmonary Artery; Pyridazines; Rats; Rats, Sprague-Dawley; Tadalafil; Vascular Remodeling; Vasoconstriction; Ventricular Dysfunction, Right; X-Ray Microtomography

BackgroundThe pathogenesis of idiopathic nephrotic syndrome (INS) remains unclear, although recent studies suggest endothelin 1 (ET-1) and CD80 of podocytes are involved. We investigated the potential of antagonist to ET-1 receptor type A (ETRA) as therapeutic agent through the suppression of CD80 in a rat model of INS.MethodsPuromycin aminonucleoside (PAN) was injected to Wister rats to induce proteinuria: some were treated with ETRA antagonist and others were treated with 0.5% methylcellulose. Blood and tissue samples were collected. Quantitative PCR was used to determine the expression of Toll-like receptor-3 (TLR-3), nuclear factor-κB (NF-κB), CD80, talin, ETRA, and ET-1 in the kidney. To confirm the level of CD80 protein expression, immunofluorescence staining and western blot analysis of the renal tissue were performed.ResultsAmount of proteinuria in the treatment group was significantly lower than the other groups. The same-day body weight, serum creatinine values, and blood pressure were not significantly different. ETRA antagonist restores podocyte foot process effacement as well as the aberrant expression of TLR-3, nuclear factor-κB (NF-κB), and CD80 in PAN-injured kidneys.ConclusionsThe ETRA antagonist may be promising drug for INS as it showed an antiproteinuric effect. Its action was considered to be through suppression of CD80 expression on podocytes.

Topics: Animals; B7-1 Antigen; Blood Pressure; Body Weight; Creatinine; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Kidney; Kidney Diseases; Kidney Glomerulus; Nephrosis; Nephrotic Syndrome; NF-kappa B; Phenylpropionates; Podocytes; Proteinuria; Puromycin Aminonucleoside; Pyridazines; Rats; Rats, Wistar; Receptor, Endothelin A; Toll-Like Receptor 3

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ET

Topics: Anemia, Sickle Cell; Animals; Disease Models, Animal; Endothelin A Receptor Antagonists; Female; Humans; Kidney Diseases; Male; Mice; Phenylpropionates; Pyridazines; Time Factors

Pulmonary arterial hypertension (PAH) is characterized by obstructive lesions and vasoconstriction of the pulmonary arteries. Early therapeutic interventions with vasodilator drugs are thought to be beneficial in PAH. However, it remains unknown whether the severity of intimal obstruction is associated with increased pulmonary arterial pressure and whether reduction of vasoconstriction in the earlier stage by these drugs has a beneficial effect. Therefore, the aims of this study were to investigate these issues in a rat model of severe PAH. Methods A rat model of severe PAH was created by injection of a vascular endothelial growth factor receptor blocker in combination with hypoxia for the first 3 weeks followed by normoxia for the next 9 weeks. To assess intimal obstruction, "the pulmonary artery occlusion index (PAOI)" was developed to digitize all lesions. The small pulmonary arteries were assessed by this index, and the association between right ventricular systolic pressure (RVSP) and PAOI was investigated. An endothelin receptor antagonist, ambrisentan, was administered by gavage to rats during either hypoxia (Prevention study group, n=25) or normoxia (Early treatment group, n=15).. PAOI showed a positive correlation with RVSP, and both RVSP and PAOI increased gradually over time. There were no severe occlusive lesions in either group, but the density of partially occlusive lesions was significantly decreased in the Prevention study group.. A novel PAOI index was developed, and this index was strongly correlated with RVSP. Furthermore, ambrisentan reduced luminal occlusive lesions more effectively when treatment was given during the first 2 weeks of hypoxia.

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Hemodynamics; Hypertension, Pulmonary; Male; Phenylpropionates; Pyridazines; Rats; Rats, Sprague-Dawley; Tunica Intima; Vascular Remodeling

Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension.. This study aimed to survey the influences of ET-1 in cirrhosis-related angiogenesis. Common bile duct ligation was performed on Spraque-Dawley rats to induce cirrhosis. Since the 14th day after the operation, rats randomly received distilled water (DW, control), bosentan [a nonselective ET receptor (ETR) blocker] or ambrisentan (a selective ETA R blocker) for 4 weeks. On the 43rd day, portal and systemic haemodynamics, liver biochemistry, portosystemic shunting degree, mesenteric vascular density, mRNA and/or protein expressions of relevant angiogenic factors were evaluated.. In cirrhotic rats, bosentan significantly reduced portal pressure. Ambrisentan did not influence haemodynamics and liver biochemistry. Both of them significantly improved the severity of portosystemic collaterals and decreased the mesenteric vascular density. Compared with the DW-treated cirrhotic rats, splenorenal shunt and mesenteric inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), vascular endothelial growth factor mRNA expressions and mesenteric iNOS, COX2, VEGF, phospho-VEGF receptor 2, Akt and phospho-Akt protein expressions were down-regulated in both groups.. In rats with liver cirrhosis, both nonselective and selective ETA R blockade ameliorate the severity of portosystemic shunting and mesenteric angiogenesis via the down-regulation of VEGF pathway and relevant angiogenic factors. ET receptors may be targeted to control the severity of portosystemic collaterals and associated complications in cirrhosis.

Topics: Animals; Bosentan; Collateral Circulation; Cyclooxygenase 2; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Hypertension, Portal; Liver Cirrhosis; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type II; Phenylpropionates; Phosphoproteins; Portal Pressure; Proto-Oncogene Proteins c-akt; Pyridazines; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart rate, peripheral blood flow, carotid and pulmonary arterial pressures, breathing rate, and vastus lateralis muscle oxygenation, but under inspired hypoxia, only the combination treatment significantly enhanced muscle oxygenation. Our results suggest that sympathomimetic agents combined with endothelin-A receptor blockers offset altitude-induced fatigue in rats by synergistically increasing the delivery rate of oxygen to hypoxic muscle by concomitantly augmenting perfusion pressure and improving capillary conductance in the skeletal muscle. Our findings might therefore serve as a basis to develop an effective treatment to prevent high-altitude illness and fatigue in humans.

Topics: Acclimatization; Altitude; Altitude Sickness; Animals; Cell Hypoxia; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Ephedrine; Fatigue; Injections, Intraperitoneal; Methylphenidate; Phenylpropionates; Pyridazines; Rats; Sympathomimetics

Excess soluble fms-like tyrosine kinase 1 (sFlt-1) of vascular endothelial growth factor receptor 1 secreted from the placenta causes pre-eclampsia-like features by antagonizing vascular endothelial growth factor signaling, which can lead to reduced endothelial nitric oxide synthase (eNOS) activity; the effect of this concomitant decrease in eNOS activity is unknown. We tested whether the decrease in nitric oxide occurring in female mice lacking eNOS aggravates the pre-eclampsia-like phenotype induced by increased sFlt-1. Untreated eNOS-deficient female mice had higher BP than wild-type mice. Adenovirus-mediated overexpression of sFlt-1 increased systolic BP by approximately 27 mmHg and led to severe loss of fenestration of glomerular capillary endothelial cells in both eNOS-deficient and wild-type mice. However, only the eNOS-deficient sFlt-1 mice exhibited severe foot process effacement. Compared with wild-type sFlt-1 mice, eNOS-deficient sFlt-1 mice also showed markedly higher urinary albumin excretion (467±74 versus 174±23 μg/d), lower creatinine clearance (126±29 versus 452±63 μl/min), and more severe endotheliosis. Expression of preproendothelin-1 (ET-1) and its ET(A) receptor in the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1 mice. Furthermore, the selective ET(A) receptor antagonist ambrisentan attenuated the increases in BP and urinary albumin excretion and ameliorated endotheliosis in both wild-type and eNOS-deficient sFlt-1 mice. Ambrisentan improved creatinine clearance and podocyte effacement in eNOS-deficient sFlt-1 mice. In conclusion, reduced maternal eNOS/nitric oxide exacerbates the sFlt1-related pre-eclampsia-like phenotype through activation of the endothelin system.

Topics: Albuminuria; Animals; Disease Models, Animal; Endothelin-1; Female; Glomerular Filtration Rate; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; Phenotype; Phenylpropionates; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Pyridazines; Random Allocation; Receptors, Endothelin; Sensitivity and Specificity; Vascular Endothelial Growth Factor Receptor-1

Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%. The nonselective endothelin type A and B receptor antagonists bosentan (100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted rings by 30±5% and 24±3%, respectively. Combinations of 30 nmol/L tadalafil with 100 nmol/L bosentan or 30 nmol/L macitentan relaxed endothelin-contracted rings by 53±5% or 46±7%, respectively; these values are similar to the calculated sums of the individual effects of these compounds. Denudation of endothelium from pulmonary arterial rings abolished the vasodilator response to 30 nmol/L tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L tadalafil were additive but not synergistic. These data can be interpreted to suggest that ambrisentan and tadalafil synergistically inhibit endothelin-1-induced constriction of rat intrapulmonary arteries and that endothelin type B receptors in endothelium are necessary to enable a synergistic vasorelaxant effect of the drug combination.

Topics: Animals; Blotting, Western; Carbolines; Disease Models, Animal; Drug Synergism; Endothelin-1; Hypertension, Pulmonary; Male; Phenylpropionates; Pulmonary Artery; Pyridazines; Rats; Rats, Sprague-Dawley; Tadalafil; Vasoconstriction; Vasodilator Agents

Endothelins are involved in tissue inflammation, pain, edema and cell migration. Our genome-wide microarray analysis revealed that endothelin-1 (ET-1) and endothelin-2 (ET-2) showed a marked up-regulation in dorsal root ganglia during the acute phase of arthritis. We therefore examined the effects of endothelin receptor antagonists on the development of arthritis and inflammatory pain in monoarthritic mice.. Gene expression was examined in lumbar dorsal root ganglia two days after induction of antigen-induced arthritis (AIA) using mRNA microarray analysis. Effects of drug treatment were determined by repeated assessment of joint swelling, pain-related behavior, and histopathological manifestations during AIA.. Daily oral administration of the mixed ET(A) and ET(B) endothelin receptor antagonist bosentan significantly attenuated knee joint swelling and inflammation to an extent that was comparable to dexamethasone. In addition, bosentan reduced inflammatory mechanical hyperalgesia. Chronic bosentan administration also inhibited joint swelling and protected against inflammation and joint destruction during AIA flare-up reactions. In contrast, the ET(A)-selective antagonist ambrisentan failed to promote any detectable antiinflammatory or antinociceptive activity.. Thus, the present study reveals a pivotal role for the endothelin system in the development of arthritis and arthritic pain. We show that endothelin receptor antagonists can effectively control inflammation, pain and joint destruction during the course of arthritis. Our findings suggest that the antiinflammatory and antinociceptive effects of bosentan are predominantly mediated via the ET(B) receptor.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Arthralgia; Arthritis, Experimental; Bosentan; Disease Models, Animal; Edema; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Female; Ganglia, Spinal; Mice; Mice, Inbred C57BL; Nociception; Phenylpropionates; Pyridazines; Secondary Prevention; Sulfonamides

The potential pathophysiological role of platelet-endothelium interactions was investigated during ischemia/reperfusion (I/R), and the effect of a selective endothelin(A) receptor antagonist (ET(A)-RA) was evaluated in an acute pancreatitis model. Acute pancreatitis was induced by warm ischemia (60 min) in Wistar rats, and its effects with and without antagonist treatment were investigated. Equivalent sham-operated animals were also studied. Microcirculatory changes were assessed by in vivo microscopy, and serum levels for lipase/amylase and histological specimens were investigated. Capillary constriction to 83.7 +/- 6.7% of sham-operated diameters was observed after 60 min of ischemia. A capillary density of 56.8 +/- 9.3% of the sham-operated group (396.3 +/- 15.8 mm(-1)) was measured after reperfusion. Stagnant leukocytes (329.5 +/- 30.4%) and platelets (337.5 +/- 32.3%) increased in postcapillary venules (P < 0.05). Administration of the ET(A)-RA significantly reduced I/R injury. Capillary diameters were maintained (101.4 +/- 4.5%), and capillary density was improved to 73.3 +/- 7.6% of sham-operated animals (P < 0.05). Stagnant leukocytes (152.3 +/- 10.6%) and platelets (207.1 +/- 19.8%) in sinusoids and postcapillary venules were reduced (P < 0.05). The extent of acute pancreatitis was reduced in the therapy group as indicated by serum lipase/amylase values and histological tissue damage (P < 0.05). Thus, ET(A)-RA therapy was effective in reducing I/R-induced pancreatitis in this experimental model.

Topics: Acute Disease; Amylases; Animals; Blood Platelets; Disease Models, Animal; Endothelin A Receptor Antagonists; Female; Lipase; Microcirculation; Pancreas; Pancreatitis; Phenylpropionates; Platelet Adhesiveness; Pyridazines; Rats; Rats, Wistar; Receptor, Endothelin A; Reperfusion Injury

The objective of this study was to investigate the effect of a specific endothelin-A receptor antagonist on mRNA expression of genes encoding vasoactive mediators and proinflammatory cytokines following complete vascular exclusion of the porcine liver. Fourteen adult German Landrace pigs were subjected to 120 minutes of warm hepatic ischemia by total vascular exclusion. The animals were divided into two groups: the control group received saline solution and the therapy group was given the selective endothelin-A receptor antagonist BSF 208075. Liver tissue samples were collected 1 hour after reperfusion and mRNA expression for preproendothelin-1, prointerleukin-1beta, prointerleukin- 6, pro-tumor necrosis factor-alpha and endothelial nitric oxide synthase was analyzed quantitatively using the TaqMan system. Additionally, immunohistochemical analysis using a semiquantitative score for endothelin-1 and endothelin-A receptor was performed. One hour after reperfusion, quantitative reverse transcriptase-polymerase chain reaction revealed significantly lower expression of preproendothelin-1, pro-tumor necrosis factor-alpha, and prointerleukin-6 in the therapy group compared to controls. Immunohistochemical analysis demonstrated significantly reduced endothelin-1 immunostaining after therapy. Treatment with the selective endothelin-A receptor antagonist exerts a protective effect on the microcirculation after liver ischemia and reperfusion. We were able to show that the endothelin-A receptor antagonist not only has effects on the expression of vasoactive genes, it also decreases gene expression of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6.

Topics: Angiogenic Proteins; Animals; Cardiovascular Agents; Cytokines; Disease Models, Animal; Down-Regulation; Endothelin A Receptor Antagonists; Endothelin-1; Female; Interleukin-1beta; Interleukin-6; Liver; Microcirculation; Nitric Oxide Synthase Type III; Phenylpropionates; Pyridazines; Receptor, Endothelin A; Reperfusion Injury; RNA, Messenger; Swine; Time Factors; Tumor Necrosis Factor-alpha; Warm Ischemia

The aim of this study was to investigate a possible protective role of a selective endothelin-A receptor antagonist on hepatic microcirculation after ischemia/reperfusion. In a rat model, warm ischemia of the left liver lobe was induced for 90 minutes under intraperitoneal anesthesia with xylazine and ketamine. Shamoperated and untreated ischemic groups and a group treated with BSF 208075 were investigated. The effect of the endothelin-A receptor antagonist on ischemia/reperfusion was assessed by in-vivo microscopy and measurement of aspartate aminotransferase and alanine aminotransferase levels. In the untreated group, sinusoidal constriction to 70% of basal diameters was observed, leading to a significant decrease in perfusion rate. In addition, we found an increased percentage of stagnant leukocytes and platelets in sinusoids and in postsinusoidal venules (P < 0.05). A significant increase in liver enzymes was detected 6 hours after reperfusion (P < 0.05). In the treatment group, sinusoidal diameters were maintained at 108%, and perfusion rate was significantly increased (P < 0.05). Hepatocellular damage was decreased and leukocyte and platelet-endothelium interactions were reduced (P < 0.05). Our results provide evidence that the new therapeutic approach using an endothelin-A receptor antagonist is effective in reducing hepatic ischemia/reperfusion injury. It could be shown for the first time that endothelin receptor blockade also influences platelet-endothelium interactions.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cardiovascular Agents; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Leukocyte Rolling; Liver; Liver Circulation; Microcirculation; Microscopy, Fluorescence; Microscopy, Video; Phenylpropionates; Platelet Adhesiveness; Pyridazines; Rats; Rats, Wistar; Receptor, Endothelin A; Reperfusion Injury