endothelin-1 and Postoperative-Complications

Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These pathogenic autoantibodies could serve as presymptomatic biomarkers and therapeutic targets, thereby providing improved medical management for these conditions.

Topics: Animals; Antihypertensive Agents; Autoantibodies; Autoantigens; Biomarkers; Complement Activation; Complement C3a; Cytokines; Dimerization; Disease Models, Animal; Drug Resistance; Endothelin-1; Female; Fetal Growth Retardation; Graft Rejection; Humans; Hypertension; Hypertension, Malignant; Immunization, Passive; Kidney Transplantation; Mice; Placenta; Postoperative Complications; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1; Vascular Endothelial Growth Factor Receptor-1

The purpose of this study was to assess the effect of preoperative dexamethasone (DEX) on the occurrence of postoperative atrial fibrillation (AF).. Prospective, randomized, double-blind, placebo-controlled clinical trial.. Tertiary referral center.. Seventy-eight adult patients undergoing combined valve and coronary artery bypass graft (CABG) surgery were randomized to receive either DEX or placebo.. The DEX group received dexamethasone, 0.6 mg/kg, after induction of anesthesia, and the placebo group received an equal volume of normal saline. Interleukin (IL)-6, -8, and -10; tumor necrosis factor alpha; and endothelin (ET)-1 were measured preoperatively and on postoperative days (POD) 1, 2, and 3. Complement (C-4) and C-reactive protein (CRP) were measured preoperatively and on POD 2. Exhaled nitric oxide (NO) was measured preoperatively, 15 minutes after aortic unclamping, and 1 hour after intensive care unit admission.. No significant difference in the incidence of AF was found between the placebo (41%) and DEX groups (30%) (95% confidence interval [-11%, 34%); p = 0.31). DEX significantly reduced at least 1 postoperative level of IL-6, IL-8, IL-10, CRP, and exhaled NO. DEX did not affect ET-1 or C-4 levels. IL-10 on POD 3 was positively correlated with postoperative hospital length of stay (r = 0.30, p = 0.01). Increased levels of IL-8 and IL-10 on POD 1 were positively correlated with the intubation time (r = 0.31, p = 0.01; r = 0.30, p = 0.01, respectively). Conversely, C-4 on POD 2 was negatively correlated with the intubation time and intensive care unit length of stay (r = -0.32, p = 0.006; r = -0.30, p = 0.01, respectively).. DEX did not affect the incidence of AF in patients undergoing combined CABG and valve surgery. However, it did modulate the release of several inflammatory and acute-phase response mediators that are associated with adverse outcomes.

Topics: Aged; Atrial Fibrillation; C-Reactive Protein; Cardiac Surgical Procedures; Complement C4; Coronary Artery Bypass; Dexamethasone; Double-Blind Method; Endothelin-1; Female; Glucocorticoids; Heart Valves; Humans; Interleukins; Male; Middle Aged; Nitric Oxide; Placebos; Postoperative Complications; Prospective Studies; Sodium Chloride; Time Factors; Tumor Necrosis Factor-alpha

To observe the effect of ranitidine on gastric acid, plasma endothelin, and calcitonin gene-related peptide (CGRP) in patients undergoing the brain operation, and to explore the possible pathogenesis of ranitidine on preventing from gastric mucosal injury under the stress.. Thirty patients who underwent brain surgery were randomly divided into 2 groups: Fifteen patients in the control group did not use ranitidine and the other 15 in the treatment group received ranitidine 150 mg intravenously twice daily besides the routine therapy. We continuously monitored the gastric pH value from 4 hours pre-operatively to 72 hours post-operatively in the 30 patients. We also determined the plasma endothelin and CGRP levels of the patients at the 4th hour pre-operatively and at the 4th, 24th, and 72nd hours post-operatively.. In the control group there was no significant difference between the mean intra-gastric pH values pre-operatively and post-operatively (P> 0.05). In the treatment group the level of intra-gastric pH was much higher than that in the control group (P< 0.05). In the control group, the level of plasma endothelin significantly higher and the level of calcitonin gene-related peptide significantly lower than that pre-operatively (P< 0.01), but the level of plasma endothelin significantly was lower and the level of calcitonin gene-related peptide obviously higher in the post-operative treatment group than that pre-operatively (P< 0.01).. The brain operation obviously influences the endogenous plasma endothelin and CGRP levels, but its influence on the intra-gastric acid is not visible. Ranitidine can obviously decrease the level of intra-gastric acid, and improve the macrocirculation of gastric mucous membrane by decreasing ET and increasing the CGRP level.

Topics: Adult; Anti-Ulcer Agents; Brain; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Gastric Acid; Humans; Infusions, Intravenous; Male; Middle Aged; Postoperative Complications; Ranitidine; Stomach Ulcer

The endothelium-derived vasoconstrictor endothelin-1 is increased after cardiopulmonary bypass in children with congenital heart defects. This study determines whether antioxidant therapy with Salvia miltiorrhiza injection, an herb extract containing phenolic compounds, prevents the postoperative increase of endothelin-1. The relationship between endothelin-1 and the endothelium-derived prostacyclin (prostaglandin I2) and thromboxane A2 postoperatively is also investigated.. Twenty children with congenital heart defects and pulmonary hypertension were randomly assigned to group A (placebo control, n=10) or B (200 mg/kg Salvia miltiorrhiza intravenously after anesthesia induction and at the time of rewarming, respectively; n =10) before cardiac surgery. Central venous blood samples were taken before operation (T(0)), 10 (T(1)) and 30 minutes (T(2)) after starting cardiopulmonary bypass, 10 (T(3)) and 30 minutes (T(4)) after aortic declamping, and 30 minutes (T(5)) and 24 hours (T(6)) after termination of cardiopulmonary bypass. Plasma lipid peroxidation product malondialdehyde, myocardial specific creatine kinase-MB activity, thromboxane B2, and 6-keto-prostaglandin F(1 alpha) (stable metabolites of thromboxane A2 and prostaglandin I2) were measured.. Malondialdehyde increased significantly at T(1) in group A and remained significantly higher than in group B thereafter (P <.05). Malondialdehyde in group B did not significantly increase over time. At T(5), plasma creatine kinase-MB, thromboxane B2, and endothelin-1 in group B were lower than in group A (P <.05); malondialdehyde correlated significantly with creatine kinase-MB (r = 0.71, P =.0005). At T(6), endothelin-1 negatively correlated with the 6-keto-prostaglandin F(1 alpha)/thromboxane B2 ratio (r = -0.64, P =.0025).. Antioxidant therapy reduces myocardial damage and attenuates postoperative vasoactive mediator imbalance.

Topics: Adolescent; Antioxidants; Biological Assay; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Chemotherapy, Adjuvant; Child; Child, Preschool; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Endothelin-1; Female; Heart Defects, Congenital; Humans; Infusions, Intravenous; Intraoperative Period; Male; Multivariate Analysis; Phytotherapy; Postoperative Complications; Probability; Prognosis; Salvia miltiorrhiza; Sensitivity and Specificity; Severity of Illness Index; Thromboxane B2; Treatment Outcome

Endothelin-1 (ET-1) is the most potent known vasoconstrictor. Elevated plasma levels have been demonstrated in patients with myocardial infarction, cardiogenic and septic shock, and respiratory, heart, and kidney failure, as well as in those undergoing elective abdominal aortic aneurysm (AAA) repair. However, endothelin levels have not previously been examined in patients undergoing repair of ruptured AAA. We hypothesized that hemorrhagic shock, lower torso ischemia, and reperfusion associated with ruptured AAA repair lead to increased synthesis and secretion of ET-1, which, in turn, predispose to organ failure, one of the principal causes of death in this condition.. Fourteen patients were studied. Plasma levels of big ET-1 and ET-1 were measured immediately before operation and immediately before, 5 minutes, and 6 hours after aortic clamp release.. All patients survived for at least 24 hours after operation. Big ET-1 levels were above the normal range at one or more sample points in all patients, and the ET-1 levels were above the normal range in all survivors and four of five nonsurvivors. Five patients who died of organ failure had significantly lower big ET-1 levels at all sample points and significantly lower ET-1 levels after 5 minutes of reperfusion when compared with survivors. Preoperative ET-1 levels were significantly lower in eight patients who subsequently developed kidney failure than in six patients who did not.. Contrary to our original hypothesis, these novel data demonstrate that patients with ruptured AAA in whom fatal postoperative organ failure develops have significantly lower perioperative endothelin levels than survivors.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Aneurysm, Ruptured; Aortic Aneurysm, Abdominal; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Multiple Organ Failure; Postoperative Complications; Postoperative Period; Preoperative Care; Probability; Prospective Studies; Risk Assessment; Sensitivity and Specificity; Statistics, Nonparametric; Survival Rate; Treatment Outcome

A prospective randomized study was performed to test whether removal of endothelin-1, by ultrafiltration techniques, will reduce pulmonary hypertension after operations for congenital heart disease.. Twenty-four patients with pulmonary hypertension (systolic pulmonary/systemic arterial pressure ratio > 60%) undergoing cardiac operations were randomized into a control group (n = 12) having conventional ultrafiltration and an experimental group (n = 12) undergoing dilutional ultrafiltration during and modified ultrafiltration after cardiopulmonary bypass. Plasma endothelin-1, nitric oxide metabolites, and cyclic guanosine monophosphate were assayed before bypass, 10 minutes into bypass, after bypass, and 0, 3, 6, and 12 hours after the operation in both groups, as well as in the ultrafiltrates and after modified ultrafiltration in the experimental group. Both groups received alpha-blockers (chlorpromazine and/or prazosin) postoperatively using the same guidelines.. The ultrafiltrates contained significant amounts of endothelin-1 (1.81 +/- 0.86 pg/ml, dilutional, and 6.44 +/- 1.82 pg/ml, modified ultrafiltrate). Endothelin-1 and the pulmonary/systemic pressure ratio were significantly lower in experimental compared with control patients. Nitric oxide metabolites and cyclic guanosine monophosphate increased similarly in both groups for 12 hours after the operation (p = not significant). Three of 12 control patients (25%) but no experimental patients had pulmonary hypertensive crises (p = 0.07). The experimental patients required significantly less ventilatory support (67 +/- 47 hours vs 178 +/- 139 hours for control patients, p = 0.048).. Dilutional and modified ultrafiltration reduce endothelin-1 and the pulmonary/systemic pressure ratio postoperatively and may become an important adjunct for preventing pulmonary hypertension after operations for congenital heart disease in high-risk patients.

Topics: Cardiopulmonary Bypass; Cyclic GMP; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Postoperative Complications; Prospective Studies

There is a growing body of evidence that perfusion temperature during cardiopulmonary bypass (CPB) influences postoperative systemic vascular resistance (SVR). The reason for this is not clear. Extracorporeal circulation can provoke raised plasma levels of endothelin-1 (ET-1), a very potent vasoconstrictor peptide produced by endothelial cells. We therefore analysed the effect of CPB temperature on postoperative vascular resistance and plasma concentrations of ET-1.. Thirty four patients undergoing elective coronary artery bypass grafting procedures were randomly assigned for either normothermic (37 degrees C, n = 17) or hypothermic CPB (28 degrees C, n = 17). Serial measurements of SVR and plasma ET-1 concentrations were performed before, during, and until 9 h after CPB measured.. As a consequence of CPB, plasma ET-1 levels increased slightly in both groups. In normothermic patients, ET-1 reached maximal levels at the end of CPB whereas ET-1 levels in patients after hypothermic CPB had a tendency to further increase during the stay in the intensive care unit. Plasma ET-1 levels were significantly higher in patients 9 h postoperatively after hypothermic CPB (1.94 +/- 0.28 vs. 1.30 +/- 0.12 pg/ml, P = 0.033), which was associated with significantly higher systemic vascular resistance index (SVRI) in these patients (area under the curve; 1978 +/- 76 vs. 1626 +/- 69 dyne s/cm5 per m2, P = 0.003). Plasma ET-1 levels showed a positive correlation with postoperative SVRI (P = 0.008, r = 0.51) and a negative correlation with minimal rectal temperature during CPB (P = 0.006, r = 0.55).. These results suggests that the hemodynamic differences after normothermic and hypothermic CPB might be mediated, at least in part, by temperature dependent changes in ET-1 plasma levels.

Topics: Adult; Aged; Cardiopulmonary Bypass; Coronary Disease; Critical Care; Endothelin-1; Female; Hemodynamics; Humans; Hypothermia, Induced; Male; Middle Aged; Postoperative Complications; Treatment Outcome; Vascular Resistance

Restenosis remains the main complication after percutaneous coronary interventions in patients with coronary heart disease. The causes of its development include, in particular, genetic factors. We studied polymorphic loci of genes encoding endothelin-1 (EDN1 rs5370), endothelin-1 receptor (EDNRA rs5333), endothelin-converting enzyme (ECE1 rs1076669), and endothelial NO synthase (eNOS rs1549758, eNOS rs1799983, and eNOS rs2070244) in the context of in-stent restenosis development. It was found that the analyzed polymorphisms of the endothelin system genes were more significant for patients aged ≥ 65 years, while the polymorphic loci of the endothelial NO synthase gene (eNOS rs1799983 and eNOS rs1549758) were predominantly associated with time of in-stent restenosis. The obtained results can be useful for comprehensive assessment of the restenosis risk factors and the choice of optimal treatment for patients with coronary heart disease before elective surgical intervention.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Graft Occlusion, Vascular; Humans; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Percutaneous Coronary Intervention; Polymorphism, Single Nucleotide; Postoperative Complications; Receptor, Endothelin A; Stents

Currently there is no consensus on the optimal management of small-for-size syndrome following liver transplantation. Here we describe a technique to alleviate portal hypertension and improve the hepatocyte reperfusion in small-for-size liver transplantation in a Lewis rat model.. The rats underwent trans-portal vein intra-hepatic portosystemic shunt using a self-developed porous conical tube (TPIPSS: Fig. 1) on small-for-size liver transplants (SFS) with right lobe graft. The treatment effect was evaluated by comparing hemodynamic parameters, morphological changes, serum parameters, ET-1 and eNOS expression, hepatocyte proliferation and apoptosis, CYP3A2 levels, postoperative complications, and survival between the two groups with SFS liver transplants.. Porous conical prosthesis prolonged the filling time of small-for-size grafts. Moreover, grafts with TPIPSS showed a lower portal vein pressure, improved microcirculatory flow, alleviated histological changes, decreased ET-1 and increased eNOS expressions, and significantly less damage to liver function comparing to grafts without TPIPSS. Mean survival and overall 30-day survival were significantly higher in the TPIPSS group.. These results demonstrate that porous conical tube as trans-portal vein intra-hepatic portosystemic shunt device is an effective way to alleviate portal vein hypertension and improve hepatocyte reperfusion after small-for-size liver transplantation.

Topics: Animals; Apoptosis; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Cell Proliferation; Cytochrome P-450 CYP3A; Endothelin-1; Hemodynamics; Liver Circulation; Liver Transplantation; Male; Nitric Oxide Synthase Type III; Organ Size; Porosity; Portal Vein; Postoperative Complications; Prosthesis Design; Rats, Inbred Lew; Syndrome; Vena Cava, Inferior

Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans.. In 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; P = .007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; P = .01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; P = .003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; P = .44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (P = .047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; P = .02).. Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

Topics: Allografts; Biomarkers; California; Coronary Angiography; Coronary Disease; Coronary Vessels; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Factors; ROC Curve; Survival Rate; Ultrasonography, Interventional

This study aimed to evaluate the potential risk factors for postoperative late low intraocular pressure (IOP) in patients with primary open-angle glaucoma (POAG) after trabeculectomy.. Adult patients who were diagnosed with POAG and scheduled to undergo primary unilateral trabeculectomy in our hospital were consecutively included. Blood samples before the surgery and aqueous humor samples during the surgery of each participant were collected. Patient demographics, preoperative assessments, and laboratory tests were compared in patients with or without late low IOP. The risk factors for late low IOP were evaluated using logistic regression modeling. The predictive value of endothelin-1 (ET-1) in aqueous humor for late low IOP was evaluated by receiver operating characteristic curve analysis.. Thirty-nine of 222 enrolled patients were cases of late low IOP with an incidence of 17.6% (39/222). The multivariate logistic regression analysis indicated that ET-1 concentration in aqueous humor was the only independent risk factor for late low IOP after trabeculectomy (odds ratio, 0.89; 95% confidence interval, 0.79-0.98; P=0.021). Receiver operating characteristic curve analysis showed that ET-1 concentration in aqueous humor was a predictor for late low IOP after trabeculectomy with an area under the curve of 0.639, a specificity of 84.62%, and a sensitivity of 39.89%, respectively (P=0.006).. Our study indicated that ET-1 concentration in aqueous humor was an independent risk factor for late low IOP in patients with POAG after trabeculectomy.

Topics: Adult; Aged; Aqueous Humor; Endothelin-1; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypotension; Postoperative Complications; Postoperative Period; Prognosis; Prospective Studies; Trabeculectomy

This study analysed the association between endothelin-1 (ET-1) and left atrial dimension (LAD) and evaluated whether ET-1 can be a predictor of postoperative atrial fibrillation (POAF) after mitral valve surgery.. This is a prospective study that enrolled 80 patients who underwent isolated mitral valve surgery. Plasma concentrations of ET-1 from peripheral venous blood were tested. POAF was detected using a telemetry strip or 12-lead electrocardiogram until the time of discharge.. Patients undergoing mitral valve surgery with preoperative sinus rhythm (n = 80; average age 63.9 ± 7.9 years) were recruited to this study. POAF was documented in 31 (38.8%) patients. Preoperative plasma ET-1 levels were higher in patients with POAF compared to those without POAF (2.23 ± 0.67 vs 1.68 ± 0.59 pg/ml; P < 0.001). The plasma concentrations of ET-1 were positively correlated with LAD (Pearson's r = 0.421; P < 0.001). Multivariate logistic regression analysis revealed that LAD (odds ratio 1.170, 95% confidence interval 1.039-1.317; P = 0.009) and preoperative plasma ET-1 levels (upper versus lower 50th percentile: odds ratio 3.713, 95% confidence interval 1.085-12.701; P = 0.037) were predictors of POAF after mitral valve surgery.. Plasma levels of ET-1 were positively correlated with LAD in patients with mitral valve disease. An elevated preoperative plasma ET-1 level can be used as a predictor of POAF after mitral valve surgery.

Topics: Aged; Atrial Fibrillation; Dilatation; Electrocardiography; Endothelin-1; Female; Heart Atria; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Male; Middle Aged; Mitral Valve; Odds Ratio; Postoperative Complications; Prospective Studies; Treatment Outcome

Acute kidney injury (AKI) after liver transplantation (LT) is a common event, but its pathogenesis remains unclear. The aim of this prospective study is to investigate the potential relationship between postreperfusion gene expression, serum mediators, and the onset of AKI after LT. Sixty-five consecutive patients undergoing LT were included in the study. Reverse transcription polymerase chain reaction (PCR) was performed on liver biopsies. Gene expression of 23 genes involved in ischemia/reperfusion injury (IRI) was evaluated. The serum concentrations of endothelin (ET)-1 and inflammatory cytokines were analyzed. AKI after LT developed in 21 (32%) recipients (AKI group). Reverse transcription PCR of reperfusion biopsy in the AKI group showed higher expression of several genes involved in IRI compared with the non-AKI group. Fold changes in the gene expression of ET-1, interleukin (IL) 18, and tumor necrosis factor α (TNF-α) were associated with creatinine peak value. AKI patients also had significantly higher ET-1, IL18, and TNF-α postoperative serum levels. Multivariate analysis showed that ET-1 (odds ratio [OR], 16.7; 95% confidence interval [CI], 3.34-83.42; P = 0.001) and IL18 (OR, 5.27; 95% CI, 0.99-27.82, P = 0.048) serum levels on postoperative day 1 were independently predictive of AKI. Receiver operating characteristic analysis demonstrated that the combination of biomarkers ET-1+IL18 was highly predictive of AKI (area under the receiver operating characteristic curve, 0.91; 95% CI, 0.83-0.99). Early allograft dysfunction and chronic kidney disease stage ≥ 2 occurred more frequently in AKI patients. These results suggest that the graft itself, rather than intraoperative hemodynamic instability, plays a main role in AKI after LT. These data may have mechanistic and diagnostic implications for AKI after LT. Liver Transplantation 24 922-931 2018 AASLD.

Topics: Acute Kidney Injury; Adult; Aged; Allografts; Biomarkers; Biopsy; Creatinine; Endothelin-1; Female; Gene Expression Profiling; Graft Rejection; Humans; Interleukin-18; Liver; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Reperfusion Injury; Time Factors; Tumor Necrosis Factor-alpha

Pre-treatment with dietary ω3 polyunsaturated fatty acids (ω3-PUFA) has been reported to reduce the incidence of new-onset atrial fibrillation (AF) following cardiac surgery. In a canine cardiac surgery model, we evaluated the impact of dietary ω3-PUFA on atrial electrophysiological properties, inflammatory markers, the atrial endothelin-1 (ET-1) system, and the expression and distribution of connexin 43.. Adult mongrel dogs received either normal chow (NC, n = 11) or chow supplemented with fish oil (FO, 0.6 g ω3-PUFA/kg/day, n = 9) for 3 weeks before surgery. A left thoracotomy was performed, and the left atrial appendage (LAA) was excised. Atrial pacing/recording wires were placed, and the pericardium/chest was closed. The atrial ratio of ω6/ω3 lipids decreased from 15-20 in NC to 2-3 in FO. FO treatment lowered pre-surgical and stabilized post-surgical arachidonate levels. Peak neutrophil to lymphocyte ratio was lower and decayed faster in FO-treated animals. Extensive inflammatory cell infiltration was present in NC atria, but was reduced in FO-treated dogs. FO-treated animals had lower post-surgical atrial expression of inducible nitric oxide synthase (iNOS) and reduced plasma ET-1. Expression of ET-1 and inositol trisphosphate receptor type-2 proteins in the LAA was also reduced. FO treatment prolonged post-operative atrial effective refractory period, slowed heart rate, and enhanced heart rate variability. Importantly, AF (>30 s) was inducible in four of six NC dogs, but no FO dogs.. Dietary FO attenuated AF inducibility following cardiac surgery by modulating autonomic tone and heart rate. FO also reduced atrial inflammation, iNOS, and ET-1 expression.

Topics: Animals; Atrial Fibrillation; C-Reactive Protein; Cardiac Surgical Procedures; Connexin 43; Dogs; Endothelin-1; Fatty Acids, Omega-3; Female; Heart Rate; Inositol 1,4,5-Trisphosphate Receptors; Lipids; Male; Nitric Oxide Synthase Type II; Peroxidase; Phosphorylation; Postoperative Complications; Receptors, Endothelin

Endothelin-1 (ET-1) is an endogenous vasoconstrictive peptide hormone and asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of nitric oxide synthase. We hypothesized that both could contribute to pulmonary hypertension in patients with left-to-right shunt after intracardiac repair.. We prospectively analyzed ET-1 and ADMA plasma levels in 31 patients (m = 16; f = 15) at an age of 0.6 [0.2-27] years (median [range]) with left-to-right shunt (ASD II: n = 12; VSD: n = 11; AVSD: n = 8) presenting with a Qp/Qs of 2.7 [1.4-6.3] and a pulmonary arterial mean pressure (PAP) of 23 [13-57] mmHg. Blood specimens were taken prior to cardiopulmonary bypass (CPB), after weaning from CPB and at 3, 6, 12 and 24 h after CPB.. 12/31 patients were found to have pulmonary hypertension prior to intracardiac repair and 11/12 patients showed persistent pulmonary hypertension during the first 24 h after CPB. Patients with pulmonary hypertension at 12 h after CPB showed significant higher plasma ET-1 compared with patients with normal PAP (1.4 [0-7.9] versus 0.5 [0-2.5] pg/ml; P = 0.048 (Mann-Whitney)). Plasma ADMA decreased from 1.3 [0.75-2.3] micromol/l before CPB to 0.7 [0.4-2.1] micromol/l at 12 h (P < 0.05). However patients with pulmonary hypertension did not show different ADMA plasma levels.. Increased plasma ET-1 but not inhibition of nitric oxide synthase by ADMA is associated with pulmonary hypertension after intracardiac repair.

Topics: Adolescent; Adult; Arginine; Biomarkers; Cardiopulmonary Bypass; Child; Child, Preschool; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide Synthase; Pancreatitis-Associated Proteins; Postoperative Complications; Prospective Studies; Statistics, Nonparametric; Time Factors; Treatment Outcome; Young Adult

To examine the change in N-terminal pro-brain natriuretic peptide (Nt-proBNP) and big endothelin (big ET) in patients undergoing coronary artery bypass grafting (CABG), and to evaluate their value in predicting postoperative mortality and complication.. Forty-seven patients undergoing coronary artery bypass grafting under on-pump (CCABG) and 43 patients undergoing off-pump bypass (OPCAB) were included for study. The levels of Nt-proBNP and big ET were determined before and 24 hours after operation in all patients.. (1)There were no differences between two groups. The serum levels of Nt-proBNP and big ET increased significantly 24 hours after operation. Compared with those before operation, Nt-proBNP [(1 083.5 +/- 717.9) pmol/L] in CCABG group was increased [(1 579.2 +/- 719.7)pmol/L, t = -4.30, P<0.01], big ET was increased from (1.10 +/- 1.82 ) pmol/L to (1.68 +/- 1.73)pmol/L(t = -5.35, P<0.01) 24 hours after operation; Nt-proBNP [(999.6 +/- 843.6) pmol/L] in OPCAB group was increased [(1 460.8+/-830.0) pmol/L, t = -4.20, P<0.01], big ET was increased from (1.35 +/- 1.65) pmol/L to (1.73 +/- 1.50) pmol/L (t = -2.46, P=0.018) 24 hours after operation. (2)The level of Nt-proBNP before operation was showed to be negatively correlated with left ventricular ejection fraction (LVEF) (r = -0.43, P<0.001). (3)By univariate and multivariate Logistic regression analysis, the association of clinical variable with postoperative complication was assessed. Multivariable predictors, including the level of LVEF (OR = 1.045, 95%CI:0.999-1.092, P = 0.050) and Nt-proBNP 24 hours after operation (OR = 0.990, 95%CI:0.999-1.000, P = 0.014), were significantly associated with a higher postoperative mortality, lower cardiac output, and higher incidence of myocardial infarction and congestive heart failure. Receiver operating characteristic curves (ROC) for Nt-proBNP 24 hours after operation was valid for the prediction of postoperative complication, and the area under the curve was 0.698 (95% CI:0.585-0.811, P<0.003), sensitivity and specificity were 88.9% and 57.1%, respectively.. Significant increase in Nt-proBNP and ET is found after CABG. BNP and LVEF are showed to be risk factors for postoperative complications in patients undergoing CABG.

Topics: Aged; Coronary Artery Bypass; Endothelin-1; Female; Humans; Intraoperative Period; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Postoperative Complications

Ischemic preconditioning (IP) and intermittent inflow occlusion (IO) have provided beneficial outcomes in hepatic resection. However, comparison of these two procedures against warm hepatic ischemia-reperfusion injury has not been studied enough.. Pigs that had undergone 65% hepatectomy were subjected to Control (120 min continuous ischemia, n = 6), IP (10 min ischemia and 10 min reperfusion, followed by 120 min continuous ischemia, n = 6), and IO (120 min ischemia in the form of eight successive periods of 15 min ischemia and 5 min reperfusion, n = 6). We evaluated hepatocyte injury by aspartate aminotransferase, lactate dehydrogenase and hepaplastin test, hepatic microcirculation by hepatic tissue blood flow (HTBF) and endothelin (ET)-1, inflammatory response by tumor necrosis factor-alpha (TNF-alpha), and histopathology after reperfusion.. IP prevented hepatocyte injury, HTBF disturbance, and hepatocyte necrosis in histopathology as well as IO. These two groups showed significantly better outcomes than Control. IP produced significantly less ET-1 and TNF-alpha than IO.. IP ameliorated hepatic warm ischemia-reperfusion injury. Furthermore, IP gained more advantages in preventing chemokine production such as ET-1 and inflammatory response over IO. IP could take the place of IO for hepatectomy.

Topics: Animals; Aspartate Aminotransferases; Blood Flow Velocity; Endothelin-1; Hepatectomy; Inflammation; Ischemic Preconditioning; L-Lactate Dehydrogenase; Liver; Male; Microcirculation; Necrosis; Postoperative Complications; Reperfusion Injury; Specific Pathogen-Free Organisms; Swine; Time Factors; Tumor Necrosis Factor-alpha

The current study was planned to investigate intestinal blood flow alterations and the role of ET-1 receptor blockade in the formation of postoperative intraperitoneal adhesion formation.. Twenty-eight adult Wistar Albino rats weighing between 250 g and 300 g were divided into four groups. Control group (group 1; n=7) did not undergo any operation. Sham group (group 2; n=7) had only laparotomy. In the adhesion group (group 3; n=7), peritoneal patch (1x1 cm) excision from the right abdominal wall and cecal abrasion were done as "adhesion model operation". One week following this, treatment group (group 4; n=7) received a non-selective ET-1 receptor blocking agent bosentan (30 mg/kg, IP) intra-abdominally, once a day for four days. Intestinal blood flow through the superior mesenteric artery was measured, on postoperative seventh day. Adhesion severity and extension as well as myeloperoxidase activity in the adhesion were calculated.. Mean intestinal blood flow significantly increased in adhesion group (81.9+/-5.6 ml/100 g) when compared to group 1 (65.5+/-1.2 ml/100 g). Bosentan caused a significant decrease (44.3+/-6.9 ml/100 g) in intestinal blood flow when compared to group 1 and group 2. Sham group (62.2+/-1 ml/100 g) had similar blood flow level with the control group (65.5+/-1.2 ml/100 g). Adhesion scores were similar in adhesion and Bosentan groups. Sham group had almost no adhesions. Myeloperoxidase activity in adhesion tissue was significantly higher in bosentan group.. Non-selective ET-1 receptor blockade has no effect on prevention of the formation of intra-abdominal adhesion, but causes a decrease in intestinal blood flow. Adhesion formation increases intestinal blood flow. Adhesion formation is accompanied by increased polymorphonuclear infiltration despite bosentan treatment.

Topics: Abdomen; Animals; Antihypertensive Agents; Blood Flow Velocity; Bosentan; Disease Models, Animal; Endothelin-1; Intestines; Mesenteric Arteries; Peritoneal Diseases; Postoperative Complications; Pulsatile Flow; Rats; Rats, Wistar; Sulfonamides; Tissue Adhesions

Cyclosporine (CyA) is associated with many side effects, including endothelial dysfunction and transplant vasculopathy (TxV). We previously demonstrated that CyA results in impairment of nitric oxide bioavailability and enhanced sensitivity to endothelin-1 (ET-1). In this study, we evaluated rapamycin (SRL) for its effects on the endothelium.. Lewis rats (n = 8) were injected with SRL (1.5 mg/kg), CyA (5 mg/Kg), or saline (Con) intraperitoneally daily for 2-weeks. Thoracic aortic segments were assessed for endothelial-dependent (Edep) and independent (Eind) relaxation after exposure to acetylcholine and sodium nitroprusside by deriving the percent maximum relaxation (Emax). ET-1 plasma levels were also measured. Thoracic aortic expression of endothelial nitric oxide synthase (eNOS), ET(A) and ET(B) receptors (Rc), were determined. Oxidative injury was assessed by changes in 8-isoprostane levels. CyA exposure resulted in lower Edep vasorelaxation compared with control and SRL (Emax: SRL, 58+/-4%; CyA, 24+/-7%; Con, 52+/-8%; P=0.001). No differences in Eind vasorelaxation were seen. CyA exposure also increased sensitivity to ET-1 (% maximum contraction [Cmax]: Con, 211+/-8%; SRL, 230+/-5%; CyA, 259+/-3%; P=0.04). Only SRL treatment reduced ET-1 plasma levels. CyA reduced eNOS expression by 30% and increased ETA Rc expression by 34% compared with both Con and SRL (P=0.02). CyA resulted in higher 8-isoprostane levels (CyA, 50+/-2%; SRL, 3+/-3%; Con, 2+/-5%; P=0.02).. CyA results in vascular dysfunction characterized by impairment of Edep vasorelaxation and enhanced sensitivity to vasospasm. SRL did not impair Edep vasorelaxation or increase sensitivity to vasospasm while lowering ET-1 levels and preserving eNOS protein expression. We conclude that SRL is less deleterious to the vasculature than CyA and may prevent TxV by these mechanisms.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Cyclosporine; Dinoprost; Endothelin-1; Endothelium, Vascular; Enzyme Induction; Gene Expression Regulation; Immunosuppressive Agents; Male; Models, Animal; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroprusside; Organ Transplantation; Oxidative Stress; Postoperative Complications; Rats; Rats, Inbred Lew; Receptor, Endothelin A; Receptor, Endothelin B; Sirolimus; Vasoconstriction; Vasodilation

Topics: Animals; Blood Pressure; Coronary Artery Bypass, Off-Pump; Coronary Artery Disease; Coronary Circulation; Creatine Kinase; Creatine Kinase, MB Form; Endothelin-1; Humans; Isoenzymes; Myocardial Contraction; Myocardial Reperfusion; Nitric Oxide; Postoperative Complications; Stroke Volume; Treatment Outcome

Epidemiological data show that the cause of brain death as well as the condition of the organ donor have considerable influence on the outcome of kidney transplantation. An early immunogenic up-regulation, which already exists at the time of organ removal seems to be primarily responsible. So far it has remained unclear which donor factors cause this effect. In a prospective study of 37 organ donors a 0-hour biopsy was performed at the time of explantation to measure the expression of HLA-DR and endothelin-1 (ET-1) immunohistologically using the alkaline phosphatase anti-alkaline phosphatase (APAAP) method. The transplant outcome and the immunohistological results were correlated with various donor factors. Statistically significant correlations were seen with the following parameters: the donor serum creatinine prior to explantation correlated with the incidence of delayed graft function (DGF: 104 +/- 39 vs 78 +/- 35 micromol/L versus no DGF n = 37; P = .043). Early graft loss after transplantation correlated significantly with increased numbers of leukocytes as well as with decreased O2 saturation in the donor immediately before explantation (leucocytes: 16.7 +/- 6.8 vs 12.6 +/- 4.6/nL, n = 37; P = .036; O2 saturation: 94.1% +/- 6.9%, vs 97.7% +/- 2.3%, n = 37; P = .026). Further, donor-independent factors that correlated with acute rejections included cold ischemic time (P = .031), HLA mismatches (P = .028), and occurrence of DGF (P = .033). The degree of HLA-DR expression (range 0 to 2) correlated significantly with early graft loss (2.0 +/- 0.2 vs 1.33 +/- 0.9 for graft function, n = 37; P = .01) as well as the ET-1 expression with DGF (2.0 +/- 0.3 vs 1.5 +/- 0.7 versus no DGF, n = 37; P = .016). In summary, marginal donors should be seen as high immunological risk situations that need careful conditioning.

Topics: Biopsy; Endothelin-1; Follow-Up Studies; Histocompatibility Testing; HLA-DR Antigens; Humans; Kidney Transplantation; Leukocyte Count; Nephrectomy; Postoperative Complications; Prospective Studies; Statistics, Nonparametric; Time Factors; Tissue and Organ Harvesting; Tissue Donors; Treatment Failure; Treatment Outcome

The success of a free flap transplantation is based on a sufficient microanastomosis which meets the following requirements: a pedicle placed without kinking or twisting, a good drainage, a well defined recipient vessel and integrity of the endothelium. The aim of this study was to determine whether operation-related ischaemia through flap transplantation and tourniquet induces an increase of Endothelin-1 plasma levels as one cause of vasospasm during microvascular procedures. We focused our attention in particular on the reperfusion period which is often limited to an irreversible perfusion failure of microcirculation due to free radicals, interleukin and Endothelin-1. Twenty-one patients with tissue injury of the lower leg were included in our study, fourteen underwent a latissimus dorsi muscle transplantation with a combined ischaemia, seven patients had a tourniquet ischaemia for tumour resection, debridement and local flap transfer. The duration of ischaemia varied due to the course of operation. The withdrawal of venous blood via central vein catheter, flap vein and wound bed followed a fixed time table pre- and post-reperfusion (T1: preoperative day via cubital vein, T2: 6th postoperative day, T3: 5 min, T4: 10 min, T5: 15 min, T6: 1 h post-declamping and after tourniquet ischaemia via central vein catheter and T7: within 5 min from the flap vein immediate after recharging the flap). The vessel anastomosis determined the withdrawal from the local wound bed. ET-1 in venous blood samples were measured with ELISA. The duration of ischaemia in the tourniquet group ranged from 22 min up to 210 min with a mean of 76.58 min and in the latissimus group from 87 min up to 203 min with a mean of 139.21 min. The mean ET-1 plasma concentration measured systemically before operation in the 21 patients was 0.51 +/- 0.08 pg/ml (Mean +/- SD). This result corresponds with data published in literature. The locally measured plasma levels of ET-1 after tourniquet and flap ischaemia were increased with 0.34 up to 3.90 pg/ml (0.95 +/- 0.79 pg/ml [Mean +/- SD]) for the tourniquet group and with 0.34 up to 14.87 pg/ml (1.85 +/- 3.64 pg/ml [Mean +/- SD]) for the latissimus group. This is an increase compared to systemically measured values as 0.75 +/- 0.06 pg/ml (Mean +/- SD) for the tourniquet group and 0.58 +/- 0.21 pg/ml (Mean +/- SD) for the latissimus group. We conclude that Endothelin-1 is increased locally in the early reperfusion period after free latissimus dorsi-t

Topics: Adult; Anastomosis, Surgical; Bone Neoplasms; Endothelin-1; Female; Follow-Up Studies; Fractures, Open; Graft Survival; Humans; Leg; Leg Injuries; Male; Microsurgery; Middle Aged; Postoperative Complications; Reference Standards; Reperfusion Injury; Risk Factors; Smoking; Soft Tissue Injuries; Soft Tissue Neoplasms; Surgical Flaps; Tourniquets

Tacrolimus and cyclosporin A (CsA), the mainstay of preventive therapy for solid organ rejection, may cause various side-effects, such as hypertension and nephrotoxicity. Furthermore, tacrolimus is associated with cardiac hypertrophy. In the immediate post-transplant period, both drugs raise the levels of Endothelin-1 (ET), a potent vasoconstrictor; and of B-type Natriuretic Peptide (BNP), a sensitive marker of left ventricular volume overload, which may precede echocardiographic changes of cardiac dysfunction. The aim of the study was to investigate the presence of cardiac damage, by echocardiography and by the biochemical markers BNP and ET, in post-orthotopic liver transplantation (OLT) children, receiving long-term immunosuppressive therapy. ET (ELISA) and BNP (RIA) were measured in plasma of 18 children, post-OLT and 18 healthy controls. Children post-OLT were echocardiographically assessed for left ventricular mass (interventricular septum and posterior wall dimensions), systolic function (ejection fraction, fractional shortening) and diastolic parameters (mitral valve E and A waves, deceleration time, isovolumic relaxation time). None of the post-transplant recipients had a history or physical examination consistent with cardiac disease and all recipients were normotensive. Echocardiography revealed no systolic or diastolic dysfunction in any of the recipients. The mean ET and BNP levels tended to be higher among children post-liver transplant, compared with healthy controls (ET: 4.22 +/- 5.35 pg/mL vs. 2.1 +/- 2.0 pg/mL; BNP: 7.05 +/- 4.4 pg/mL vs. 5.87 +/- 2.0 pg/mL, respectively, mean +/- s.d.) although differences did not reach statistical significance. Three children (17%) had elevated BNP and/or ET levels. A strong correlation was observed between ET and BNP levels in post-OLT children (r = 0.79, p < or = 0.05). No correlation was found between ET or BNP levels and echocardiographic findings. In children receiving long-term immunosuppressive therapy post-OLT, although cardiac function is grossly preserved, ET and BNP levels tend to be higher than in healthy, age-matched children. Thus, elevated levels of BNP and/or ET may identify patients with early cardiac damage.

Topics: Adolescent; Biomarkers; Cardiovascular Diseases; Child; Child, Preschool; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Heart Function Tests; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Natriuretic Peptide, Brain; Postoperative Complications; Time Factors

We evaluated the protective effects of retrograde coronary sinus perfusion to offset potential systolic and diastolic dysfunction (myocardial stunning) after temporary regional ischemia needed for off-pump coronary artery bypass grafting.. Twenty Yorkshire-Duroc pigs (31.8 +/- 3.9 kg) underwent 15 minutes of mid-left anterior descending coronary artery ischemia in the beating heart. In 8 pigs, no protective measures were used. In 12 pigs, an aorta-coronary sinus shunt (with conventional cannulas) allowed retrograde perfusion during temporary ischemia; in 6 of these pigs, no leakage to the right atrium was ensured. Regional endocardial contraction was measured with sonomicrometer crystals. Systolic dysfunction (impaired regional shortening), diastolic dysfunction (contraction extending into early diastole), and coronary sinus nitric oxide and endothelin-1 levels were recorded.. Before ischemia, contraction did not extend into the diastolic interval. During ischemia, paradoxic bulging occurred in all hearts except in the occlusive coronary sinus shunt group (16% +/- 6% of baseline, P <.01). Sixty minutes after ischemia, systolic segment shortening recovered 36% +/- 24% without retrograde perfusion versus 56% +/- 20% and 61% +/- 14% with coronary sinus shunting (P <.05). Diastolic dysfunction (as percentage of diastolic time in contraction) was 38% +/- 16% in the nontreated group versus 22% +/- 22% and 9% +/- 9% (P <.05) after shunting and occlusive shunting, respectively. This correlated with a left ventricular end-diastolic pressure increase of 4 mm Hg in the ischemic group versus no change in the retrograde perfusion groups. Nitric oxide decreased 15% without shunting and increased 8% after occlusive coronary sinus shunting (P <.05).. Retrograde coronary sinus perfusion during simulated off-pump coronary revascularization diminishes systolic and diastolic dysfunction. An aortic-coronary sinus shunt is a rapid, recognized approach that can improve myocardial muscle and endothelial safety during off-pump coronary artery bypass grafting.

Topics: Animals; Biomarkers; Blood Pressure; Coronary Artery Bypass; Coronary Artery Disease; Coronary Circulation; Creatine Kinase; Creatine Kinase, MB Form; Disease Models, Animal; Endothelin-1; Female; Infusion Pumps, Implantable; Isoenzymes; Male; Models, Cardiovascular; Myocardial Contraction; Myocardial Reperfusion; Nitric Oxide; Postoperative Complications; Stroke Volume; Swine; Ventricular Fibrillation

Hepatic stellate cells (HSCs) can easily be activated by ischemia/reperfusion, and this activation results in hepatic microcirculatory disturbance by cell contraction. ROCK is one of the key regulators of the motility of HSCs, and Y-27632 suppresses the activation of HSCs. We examined whether Y-27632 treatment prevents primary graft non-function caused by 45-min warm ischemia in orthotopic liver transplantation (OLT). Donor and recipient rats were administered Y-27632 (3-30 mg/kg). Y-27632 treatment at 30 mg/kg in both donor and recipient prevented congestion of the grafted livers, as demonstrated by analysis of hemoglobin (Hb) content in the grafted livers, using in-vivo near-infrared spectroscopy. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hyaluronic acid at 4 h after OLT in the 30-mg/kg Y-27632-treated group were significantly lower than those in the control group. Specimens from the untreated control recipients showed sinusoidal congestion and massive fresh hepatocyte necrosis, whereas specimens from the Y-27632-treated recipients demonstrated minimal histological changes. Moreover, Y-27632 pre-treatment dramatically improved the survival of recipients. These results suggest that Y-27632 would be clinically useful for preventing liver failure associated with ischemia/reperfusion in liver transplantation.

Topics: Amides; Animals; Antihypertensive Agents; Dose-Response Relationship, Drug; Endothelin-1; Graft Survival; Hemoglobins; Ischemia; Liver Transplantation; Male; Oxyhemoglobins; Postoperative Complications; Pyridines; Rats; Rats, Wistar; Reperfusion; Time Factors; Transplantation, Isogeneic

Graft coronary artery disease (GCAD) is characterized by vascular narrowing resulting from intimal hyperplasia. Endothelin (ET)-1, derived from the vascular endothelium and macrophages, stimulates vascular smooth muscle cells (SMCs), which leads to neointimal formation in donor graft coronary arteries. In this study, we hypothesized that antisense (AS) oligodeoxynucleotides (ODN) for preproendothelin-1 (ppET-1) delivered to rat cardiac allografts by means of hyperbaric pressure would reduce the incidence of GCAD.. PVG donor hearts were infused with ppET-1 AS ODN (80 micromol/liter), sense ODN, scrambled ODN or saline alone and incubated in a pressure chamber at 75 psi or ambient pressure for 45 minutes. Cardiac allografts were heterotopically transplanted into ACI rats treated with cyclosporine (7.5 mg/kg, Days 0 to 9). Allografts were procured at post-operative days (POD) 7 or 90. Reverse transcription-polymerase chain reaction (RT-PCR) assay for ET-1 mRNA and ET01 immunohistochemistry (IHC) were performed at PODs 7 and 90. Elastic staining and IHC with anti-macrophage and alpha-SMC actin antibodies were performed to assess GCAD at POD 90.. Treatment with AS ODN and pressure significantly reduced ET-1 mRNA and protein expression. A significant reduction in GCAD was achieved with inhibition of ET-1 and was associated with attenuation of macrophages and SMCs in the neointima.. Peri-operative ex vivo inhibition of ET-1 expression results in a reduction of GCAD. This highly targeted therapy may be a clinically viable strategy for the prevention of ET-1-induced GCAD following cardiac transplantation.

Topics: Animals; Coronary Artery Disease; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Heart Transplantation; Immunohistochemistry; Male; Models, Cardiovascular; Muscle, Smooth, Vascular; Postoperative Complications; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The ET system is activated in cardiac surgical setting as evidenced by elevated systemic and myocardial ET-1 levels after coronary bypass grafting surgery which requires hypothermic cardioplegic arrest and cardiopulmonary bypass. Increased ET-1 may influence a number of clinical parameters in this setting. First, ET-1 may directly modulate myocardial contractile performance in the early postoperative period resulting in LV dysfunction and a complex postoperative course. Second, elevated ET-1 levels may exacerbate increased pulmonary vascular resistance and contribute to the development of transient pulmonary hypertension following bypass. Finally, augmented postoperative ET-1 levels could contribute to changes in the caliber and flow of vascular conduits used for coronary bypass. In this review, a current perspective on the ET system in the setting of cardiopulmonary bypass grafting surgery is provided and the potential use of ET receptor antagonists in this setting is discussed.

Topics: Animals; Cardiopulmonary Bypass; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Arrest, Induced; Humans; Myocardial Contraction; Postoperative Complications; Receptors, Endothelin; Ventricular Function, Left

The hepatorenal syndrome (HRS) is characterized by renal vasoconstriction leading to deterioration of renal function in patients with liver disease. A possible role of endothelin-1 (ET-1) in the pathogenesis of HRS has been suggested, but a correlation between ET-1 plasma levels and the development of HRS as well as the recovery from HRS following OLT has not been shown yet. We performed longitudinal measurements of ET-1 plasma levels in four groups of patients, 5 patients with HRS before and after orthotopic liver transplantation (OLT), 10 patients without HRS undergoing OLT, 20 patients with chronic renal failure but without liver disease, and 12 healthy controls. Before OLT, plasma levels of ET-1 were higher in patients with HRS (19.5 +/- 8.6 ng/l, P < 0.001; n = 5) compared to patients without HRS (4.9 +/- 1.1 ng/l; n = 10), normals (1.2 +/- 0.18 ng/l; n = 12), and patients with chronic renal failure (2.4 +/- 0.4 ng/l; n = 20). Patients with HRS compared to patients without HRS had higher levels for creatinine (2.42 +/- 0.6 vs. 0.89 +/- 0.05 mg/dl, P < 0.05), creatinine clearance (107 +/- 9 ml/min vs. 44.6 +/- 5.5 ml/ min, P < 0.001), and bilirubin (11.4 +/- 3.8 vs. 3.7 +/- 1 mg/dl, P < 0.05) before OLT. Within one week after OLT, there was a rapid decrease in ET-1 levels in patients with HRS while creatinine and bilirubin levels decreased slower. Regression analysis revealed a weak correlation between serum creatinine and ET-1 (r = 0.192, P = 0.04) and a significant correlation between serum bilirubin and ET-1 (r = 0.395, P < 0.001). The means of the ET-1 levels decreases rapidly with improvement of liver function after OLT. Levels of ET-1 correlate with excretory liver function assessed by bilirubin. The fall in ET-1 levels preceding improvement of renal function further strengthens the concept of ET-1 being a causative factor in HRS.

Topics: Acute Kidney Injury; Analysis of Variance; Bilirubin; Biomarkers; Creatinine; Endothelin-1; Hepatorenal Syndrome; Humans; Kidney Failure, Chronic; Liver Failure; Liver Transplantation; Postoperative Complications; Reference Values; Time Factors

Fetal cardiac bypass causes placental dysfunction, characterized by increased placental vascular resistance, decreased placental blood flow, hypoxia, and acidosis. Vasoactive factors produced by the vascular endothelium, such as nitric oxide and endothelin 1, are important regulators of placental vascular tone and may contribute to this placental dysfunction.. To investigate the role of the vascular endothelium in placental dysfunction related to fetal cardiac bypass, we studied 3 groups of fetal sheep. In the first group (n = 7) we determined placental hemodynamic responses before and after bypass to an endothelium-dependent vasodilator (acetylcholine), an endothelium-independent vasodilator (nitroprusside), and endothelin 1. In the second group (n = 8) a nonspecific endothelin receptor blocker (PD 145065) was administered and placental hemodynamic values were measured before and after bypass. In the third group (n = 5) endothelin 1 levels were measured before and after bypass.. Before fetal cardiac bypass exogenous endothelin 1 decreased placental blood flow by 9% and increased placental resistance by 9%. After bypass endothelin 1 decreased placental flow by 47% and increased resistance by 106%. There was also a significant attenuation of the placental vascular relaxation response to acetylcholine after bypass, whereas the response to nitroprusside was not significantly altered. In fetuses that received the PD 145065, placental vascular resistance increased significantly less than in control fetuses (28% versus 62%). Similarly, placental blood flow decreased significantly more (from 6. 3 +/- 3.1 to 28.3 +/- 10.4 pg/mL; P =.01) in control fetuses than in fetuses receiving PD 145065 (33% versus 20%). Umbilical venous endothelin 1 levels increased significantly in fetuses exposed to fetal bypass but did not change in control fetuses.. The basal endothelial regulatory mechanisms of placental vascular tone were deranged after fetal cardiac bypass. Endothelin receptor blockade, which substantially reduced postbypass placental dysfunction, and other interventions aimed at preserving endothelial function may be effective means of optimizing fetal outcome after cardiac bypass.

Topics: Acetylcholine; Analysis of Variance; Animals; Cardiac Surgical Procedures; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Fetal Heart; Hemodynamics; Nitroprusside; Oligopeptides; Placenta; Placenta Diseases; Postoperative Complications; Pregnancy; Sheep; Vasodilator Agents

Activation of polymorphonuclear neutrophils (PMN) and subsequent release of free oxygen radicals, including the superoxide anion (O2-) has been shown to result in postischaemic myocardial dysfunction during coronary artery bypass grafting (CABG). Several neutrophil-oriented stimuli are known to be released from myocardium during ischaemia and reperfusion. Release of endothelin-1 has been documented during CABG. The aim of the current study was to evaluate plasma-mediated neutrophil stimulation and to verify whether endothelin-1, known to be a stimulus for PMN, is involved in plasma-mediated stimulation of PMN during coronary artery bypass grafting.. Plasma samples from peripheral artery, peripheral vein, and coronary sinus were obtained from 21 patients undergoing CABG before aortic clamping (global ischaemia), immediately after beginning reperfusion, and 30 min after reperfusion as well as from healthy controls. Plasma was incubated with PMN isolated from healthy donors preincubated in the presence of saline or specific endothelin-1 receptor antagonist (ET-A). PMN O2- production was measured spectrophotometrically.. Plasma samples taken from the coronary sinus at the beginning of reperfusion were capable of higher stimulation of neutrophil superoxide anion production (24.2 +/- 2.0 nmol/5 x 10(6)PMN/30 min) than plasma obtained before reperfusion (15.6 +/- 1.5; p < 0.05) or plasma taken from peripheral artery (17.1 +/- 1.7; p < 0.05). Preincubation of PMN with endothelin-1 receptor antagonist decreased superoxide anion production by cells exposed to plasma taken from coronary sinus at the beginning of reperfusion (17.6 +/- 2.0, p < 0.05).. Transcardiac release of soluble stimuli for PMN occurs as a result of myocardial ischaemia during CABG. Endothelin-1 may be involved in the plasma-mediated stimulation of neutrophil superoxide anion production.

Topics: Adult; Aged; Coronary Artery Bypass; Endothelin-1; Female; Free Radicals; Humans; Male; Middle Aged; Myocardial Reperfusion Injury; Neutrophil Activation; Neutrophils; Plasma; Postoperative Complications; Superoxides

Plasma thromboxane B2 (TXB2), leukotriene B4 (LTB4), and endothelin-1 (ET-1) levels increase on cardiopulmonary bypass (CPB). Elevated levels of TXB2 and ET-1 have been correlated with postoperative pulmonary hypertension in infants undergoing repair of congenital heart defects. LTB4 is a potent chemotactic cytokine whose levels correlate with leukocyte-mediated injury. Modified ultrafiltration (MUF) has been associated with improved hemodynamics and pulmonary function, in addition to its beneficial effects on fluid balance and blood conservation. Recent investigations have suggested that removal of cytokines may be the cause of the improved cardiopulmonary function seen with MUF.. Plasma TXB2, ET-1, and LTB4 levels were measured in 34 infants undergoing CPB: 22 underwent MUF (group 1), and 12 did not (group 2). Samples were obtained at various time points. All patients underwent conventional ultrafiltration during the rewarming phase of cardiopulmonary bypass.. In group 1, mean end-CPB TXB2 level was 101.2 pg/mL versus 46.9 pg/mL post-MUF (p < 0.05). The mean TXB2 level 1 hour post-CPB (54.1 pg/mL) was not significantly different from the post-MUF level. In group 2, the mean end-CPB TXB2 level was 123.6 pg/mL versus 53.2 pg/mL 1 hour post-CPB. Hence, TXB2 levels decreased by similar amounts and to similar levels by 1 hour post-CPB in both groups. ET-1 levels increased after CPB and were unaffected by MUF: 1.45, 1.80, 2.55 pg/mL at end-CPB, post-MUF, and 1 hour post-CPB, respectively, in group 1; and 1.51, and 2.73 pg/mL at end-CPB and 1 hour post-CPB in group 2. LTB4 levels post-MUF were 119% of pre-MUF values, and were similar at 1 hour post-CPB in both groups.. Despite reduction in TXB2 by MUF, values were similar and approached baseline 1 hour post-CPB in both groups. LTB4 levels increased slightly with MUF. ET-1 levels increased during and post-CPB and were unaffected by MUF. MUF does not appear to have a significant effect on post-CPB levels of TXB2, ET-1, and LTB4. Therefore, the improved hemodynamics observed with MUF do not appear to be related to removal of these cytokines.

Topics: Cardiopulmonary Bypass; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Leukotriene B4; Male; Postoperative Complications; Risk Factors; Thromboxane B2; Treatment Outcome

After cardiopulmonary bypass (CPB), pulmonary hypertension and its associated increased vascular reactivity are a major source of morbidity, particularly for children with increased pulmonary blood flow. Although post-CPB pulmonary hypertension is well described, its mechanisms remain incompletely understood. Plasma levels of endothelin 1. a potent vasoactive substance implicated in pulmonary hypertension, are increased after CPB. The purpose of the present study was threefold: to characterize the changes in pulmonary vascular resistance and vascular reactivity induced by hypothermic CPB; to investigate the effects of preexisting increased pulmonary blood flow on these changes; and to better define the role of endothelin 1 in the pathogenesis of post-CPB pulmonary hypertension.. Vascular pressures and blood flows were monitored in 14 1-month-old lambs with increased pulmonary blood flow (after in utero placement of an aortopulmonary shunt) and 6 age-matched control lambs. During the 2-hour study period after 105.3 +/- 20.6 minutes of hypothermic CPB the increase in pulmonary vascular resistance was significantly augmented in lambs with increased pulmonary blood flow compared with control lambs (P < .05). Pretreatment with PD 145065 (a nonselective endothelin receptor blocker; 50 micrograms.kg-1.min-1) completely blocked this increase in pulmonary vascular resistance and blocked the increase in pulmonary vascular resistance in response to acute alveolar hypoxia after CPB (96.3 +/- 88.5% versus -9.7 +/- 16.4%; P < .05). Plasma endothelin 1 levels increased after CPB in all lambs.. Preexisting increased pulmonary blood flow alters the response of the pulmonary circulation to hypothermic CPB; the increase in pulmonary vascular resistance induced by CPB is augmented in lambs with increased pulmonary blood flow. Pretreatment with endothelin 1 receptor blockers eliminated the increase in pulmonary vascular resistance and the pulmonary vasoconstricting response to alveolar hypoxia, suggesting a role for endothelin 1 in post-CPB pulmonary hypertension. Endothelin 1 receptor blockers may decrease morbidity in children at risk for pulmonary hypertension after surgical repair with CPB and warrants further study.

Topics: Animals; Blood Pressure; Cardiopulmonary Bypass; Child; Endothelin-1; Female; Fetus; Heart Rate; Hemodynamics; Humans; Hypertension, Pulmonary; Oligopeptides; Postoperative Complications; Pregnancy; Pulmonary Artery; Pulmonary Circulation; Sheep; Vascular Resistance

Renal insufficiency is a significant complication that occurs after surgical procedures, requiring cross-clamping of the aorta. The mechanism for this renal dysfunction is currently not known, but studies suggest a potential role of endothelin in mediating the insufficiency. Accordingly, the role of endothelin was assessed using the nonpeptidyl, dual ETA/ETB endothelin antagonist L-754,142 in a model of renal insufficiency in the anesthetized dog induced by cross-clamping the suprarenal aorta for 60 min, followed by 2 h of reperfusion. In vehicle-treated animals (saline, n = 8) after 2 h of reperfusion, plasma [ET-1] increased 66% and renal blood flow (RBF) was reduced by 38% compared with baseline. This decline was associated with an 84% increase in renal vascular resistance and a 54% reduction in GFR (baseline, 46 +/- 5 ml/min; 21 +/- 3 ml/min at 2 h; P < 0.01) and sodium reabsorption (baseline, 6.7 +/- 0.7 microEq/min; 3.0 +/- 0.5 microEq/min at 2 h, P < 0.01). After baseline measurements, pretreatment with L-754,142 at 0.3 mg/kg bolus + 0.1 mg/kg per h continuous infusion (low dose; n = 8) or 3.0 mg/kg bolus + 1 mg/kg per h infusion (high dose; n = 8) initiated 45 min before aortic cross-clamp led to a dose-dependent normalization of RBF and renal vascular resistance within 2 h of cross-clamp removal. GFR was also improved and returned to within 75% of baseline (P < 0.01 versus vehicle) by 2 h of reperfusion with L-754,142 (baseline, 55 +/- 5 ml/min; 42 +/- 5 ml/min at 2 h with the high dose). The improvement of GFR with L-754,142 treatment was associated with a preservation of sodium reabsorption compared with vehicle-treated animals. This study supports a role of endothelin in the pathogenesis of renal insufficiency after aortic cross-clamping and demonstrates that pretreatment with the dual ETA/ETB endothelin antagonist L-754,142 preserves RBF and sodium reabsorption, leading to a significant improvement in GFR.

Topics: Acetamides; Acute Kidney Injury; Animals; Aorta; Constriction; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Female; Glomerular Filtration Rate; Hemodynamics; Ischemia; Kidney; Male; Postoperative Complications; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Renal Circulation; Vascular Resistance

Pulmonary hypertension causes major morbidity and mortality after congenital heart surgery, but its mechanism remains unclear.. Plasma endothelin-1 (ET-1), nitric oxide (NO), and cyclic GMP (cGMP) were assayed at 6 intervals in 50 children undergoing cardiopulmonary bypass (CPB): before CPB, 10 minutes into CPB, and 0, 3, 6, and 12 hours after CPB. Three groups based on pulmonary flow and pressure were analyzed: low flow (LF, n=21), high flow/low pressure (systolic pulmonary pressure/systemic pressure ratio, Pp/Ps<50%, HF-LP, n=11), and high flow/high pressure (Pp/Ps> or =50%, HF-HP, n=19). HF-HP and HF-LP received alpha-blockers (chlorpromazine and/or prazosin). HF-HP patients received nitric oxide donors (nitroglycerin/sodium nitroprusside). ET-1 peaked at 6 hours, with its highest level in the HF-HP group (P<.01, by ANOVA). ET-1 correlated significantly with Pp/Ps at 6 hours (r2=.43, P<.005). In the HF-HP group, ET-1 remained above the other groups at 12 hours (12.7+/-2.5 pg/mL versus 6.4+/-1.1 pg/mL versus 6.5+/-3.8 pg/mL P<.05 by ANOVA). NO metabolites were elevated equivalently for the HF-HP and HF-LP groups (5.7+/-2.6 micromol/L versus 0.3.5+/-2.5 micromol/L at 12 hours, P=NS) despite nitric oxide donors and the excess ET-1 in HF-HP patients. Levels of cGMP were similarly elevated in HF-HP and HF-LP patients during this study.. Endogenous NO may decrease vascular tone and maintain low pulmonary pressure in HF-LP patients. High levels of ET-1, inadequate NO production, and/or impaired responses to NO may increase pulmonary pressure in HF-HP patients.

Topics: Blood Pressure; Cardiopulmonary Bypass; Child, Preschool; Cyclic GMP; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Postoperative Complications

Topics: Aged; Aged, 80 and over; Constriction, Pathologic; Endothelin-1; Female; Humans; Postoperative Complications; RNA, Messenger; Saphenous Vein

Experiments were designed to compare perioperative blood loss, early thrombogenicity and morphologic and functional characteristics of the neointima of three types of prosthetic materials used for carotid artery patch angioplasty. Bilateral carotid patch angioplasties were performed in 20 dogs, using 20 gelatin-impregnated fluoropassivated Dacron (GIF), 10 untreated knitted Dacron and 10 expanded polytetrafluoroethylene (PTFE) patches (5 cm2). Intraoperative blood loss, platelet deposition at 24 h and neointimal morphology at 6 weeks after the operation were assessed. Bioassay of the neointima was performed at 6 weeks in 16 patches. Mean (s.e.m.) blood loss was significantly less in GIF patches (14.7 (2.7) ml) compared with either PTFE (75.6 (24) ml) or untreated Dacron (64.3 (9.5)) (P < 0.005). Mean (s.e.m.) platelet deposition in GIF patches (1380 (328) platelets/cm2) was approximately 50% less at 24 h than in untreated Dacron (2562 (1035) platelets/cm2) or PTFE (2140 (998( platelets/cm2) patches (P < 0.05). Neointimal coverage was greater in PTFE (94 (1.3%)) compared with GIF (79 (2.7%)) or untreated Dacron (86 (2.4%)) patches (P < 0.05). The thickness of the neointimal layer of PTFE (0.5 (0.01) mm) patches was greater than other patch types; GIF (0.2 (0.01) mm) or untreated Dacron (0.3 (0.01) mm) (P < 0.50). Under bioassay conditions, acetylcholine caused release of vasoactive relaxing factor(s) from all patches. However, relaxations from baseline were less with GIF patches (-37.9 (11.7)% versus -54.5(9.6( for untreated Dacron; -50.2 (15.2)% for PTFE) (P = n.s.). Endothelin-1 release occurred from all patches and was increased with the extent of neointimal coverage. These data demonstrate that GIF patches caused the least perioperative bleeding, were the least thrombogenic at 24 h and developed the thinnest neointima at 6 weeks. All patch materials developed a functioning neointima.

Topics: Angioplasty; Animals; Biocompatible Materials; Blood Vessel Prosthesis; Carotid Arteries; Dogs; Endothelin-1; Evaluation Studies as Topic; Gelatin; Platelet Aggregation; Polyethylene Terephthalates; Polytetrafluoroethylene; Postoperative Complications; Postoperative Hemorrhage; Thrombosis; Tunica Intima; Vascular Patency

Topics: Endothelin-1; Endothelins; Graft Rejection; Graft Survival; Humans; Liver Function Tests; Liver Transplantation; Postoperative Complications; Protein Precursors; Surgical Wound Infection