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Cerebral autoregulation is a main mechanism of brain tissue maintains constant brain blood flow,which has important significance for the occurrence,development,and outcome of ischemic stroke.This article reviews the roles and mechanisms of endothelin system in cerebral blood flow regulation after ischemic stroke.
ABSTRACT
Cerebral autoregulation is a main mechanism of brain tissue maintains constant brain blood flow,which has important significance for the occurrence,development,and outcome of ischemic stroke.This article reviews the roles and mechanisms of endothelin system in cerebral blood flow regulation after ischemic stroke.
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The myocardial protective effects of endothelin antagonist in ischemic cardiomyopathy (ICMP), doxorubicin-induced cardiomyopathy (DOX) and pressure-overload hypertrophy by transverse aortic constriction (TAC) models have been predicted to be different. The objective of this experiment, therefore, is to evaluate the myocardial protective effect of tezosentan, an endothelin receptor antagonist, in various experimental heart failure models. Sprague-Dawley rats (6-8 weeks old, 200-300 g) were randomized to three experimental groups (n=30 each): ICMP; DOX; and TAC group. Each of these groups was randomly assigned further to the following subgroups (n=10 each): sham-operated ischemia-reperfusion subgroup (SHAM); tezosentan treated ischemia-reperfusion subgroup (Tezo); and tezosentan non-treated ischemia-reperfusion subgroup (N-Tezo). Total circulatory arrest was induced for 1 hr, followed by 2 hr of reperfusion. The left ventricular developed pressure, peak positive and negative first derivatives, and coronary blood flow were significantly different (P<0.05) among the SHAM, Tezo, and N-Tezo subgroups of the ICMP group at 30 min of reperfusion, but there were no statistically significant differences among the subgroups of the DOX and TAC groups. In conclusion, tezosentan, an endothelin receptor antagonist, showed myocardial protection effects only on the ischemic cardiomyopathy rat model, but not in the non-ischemic heart failure rat models.
Subject(s)
Animals , Male , Rats , Cardiomyopathies/chemically induced , Coronary Vessels/physiology , Disease Models, Animal , Doxorubicin/toxicity , Heart Failure/drug therapy , Hypertrophy/drug therapy , Pressure , Pyridines/therapeutic use , Rats, Sprague-Dawley , Receptors, Endothelin/antagonists & inhibitors , Reperfusion Injury/drug therapy , Tetrazoles/therapeutic use , Vasodilator Agents/therapeutic use , Ventricular Function, Left/physiologyABSTRACT
A doença veno-oclusiva pulmonar (DVOP) é uma causa rara de hipertensão pulmonar. A biópsia cirúrgica era usualmente necessária para seu diagnóstico; entretanto, sua morbidade, mortalidade e seu impacto limitado levantou a discussão sobre o diagnóstico não-invasivo. Apresentamos um caso de uma paciente com dispnéia progressiva, hipoxemia e hipertensão pulmonar no cateterismo. A tomografia computadorizada revelou espessamento septal e micronódulos difusos. O lavado broncoalveolar revelou hemorragia alveolar oculta. Iniciou-se tratamento com antagonista da endotelina, que resultou em melhora clínica e funcional. A hemorragia alveolar oculta é uma característica da DVOP capaz de diferenciá-la da hipertensão pulmonar idiopática. Acreditamos que sua presença, associada à tomografia característica, seja suficiente para o diagnóstico de DVOP.
Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Surgical biopsy was usually required for diagnostic confirmation. However, the morbidity, mortality and limited benefit of this procedure have generated discussion regarding noninvasive diagnostic techniques. We present the case of a female patient with progressive dyspnea, hypoxemia and pulmonary hypertension, the last diagnosed via catheterization. Computed tomography revealed septal thickening and diffuse micronodules. Bronchoalveolar lavage revealed occult alveolar hemorrhage. Treatment with an endothelin antagonist was started, resulting in symptomatic and functional improvement. Occult alveolar hemorrhage differentiates PVOD from idiopathic pulmonary hypertension. We believe that this finding, in combination with characteristic tomographic findings, is sufficient to establish a diagnosis of PVOD.
Subject(s)
Female , Humans , Middle Aged , Hypertension, Pulmonary/etiology , Lung/pathology , Pulmonary Veno-Occlusive Disease/pathology , Biopsy , Bronchoalveolar Lavage , Bronchoscopy , Pulmonary Veno-Occlusive Disease/complications , Pulmonary Veno-Occlusive Disease/drug therapy , Receptors, Endothelin/antagonists & inhibitors , Receptors, Endothelin/therapeutic useABSTRACT
Endothelin (ET) receptor antagonists have been developed to produce a reduction of ET related effects in various diseases, as well as in animal models of airway inflammation. We aimed to investigate the anti-inflammatory potential of bosentan on a rat model of emphysema. Thirty Wistar male rats were classified as control group (group 1), intratracheally (i.t.) instilled with saline, treated with vehicle solution; elastase group (group 2), i.t. instilled with porcine pancreatic elastase (PPE), treated with vehicle solution; and PPE+bosentan group (group 3), i.t. instilled with PPE, treated with bosentan. The levels of TNF-alpha, IL-1beta, IL-6, and IL-8 in bronchoalveolar lavage fluid (BALF) and lung tissue, cell counts in BALF, and histologic analysis of all groups were evaluated. Neutrophile granulocytes (NG) and alveolar macrophages (AM) were increased more in group 2 than in group 1 (P<0.001, P=0.04, respectively). Compared with group 2, neutrophil granulocyte (NG) and alveolar macrophages (AM) counts were decreased in group 3 (P< 0.001). Histological examination confirmed a diffuse neutrophilic inflammation and irregular alveolar air space enlargement in group 2. Treatment with bosentan partially reduced the enlarged lung volumes. Compared with group 1, the BALF levels of TNF-alpha and IL-6, and the lung tissue levels of IL-1beta, IL-6, and IL-8 were increased in group 2 (P=0.028, P=0.005, P=0.001, P=0.019, P<0.001, respectively). The TNF-alpha and IL-8 levels of BALF (P=0.007, P=0.001, respectively), and the TNF-alpha, IL-1beta, IL-6, and the IL-8 levels of lung tissue (P=0.031, P=0.017, P=0.007, P<0.001) were decreased in group 3 compared to group 2. In conclusion, bosentan decreased the inflammatory response by reducing numbers of inflammatory cells and proinflammatory cytokines.
Subject(s)
Animals , Male , Rats , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bronchoalveolar Lavage Fluid/cytology , Cytokines/biosynthesis , Disease Models, Animal , Emphysema/drug therapy , Inflammation Mediators/metabolism , Lung/drug effects , Pancreatic Elastase/administration & dosage , Rats, Wistar , Receptors, Endothelin/antagonists & inhibitors , Sulfonamides/pharmacologyABSTRACT
Objective To explore the expression of high selective A receptor of endothelin-1 (ETA-R) in melanocytes from normal human beings. Methods Normal human melanocytes were cultured and mR-NA expression of ETA-R in melanocytes was measured by reverse transcription-polymerase chain reaction. Results The mRNA expression of ETA-R was seen in melanocytes. Conclusion This study combined with other experiments suggests that endothelin-1 may affect melanocytes by high selective ETA-R which may con-tribute to the pathogenesis of vitiligo.
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Objective: To investigate changes of the endothelin-1(ET-1) and its receptor (endothelin receptor subtype A, ET AR ) mRNA expression in some organs(kidney, lung and small intestinal mucous membrane) in the sepsis and septic shock rats. Methods: Twenty-four male rats randomized into sepsis group, septic shock group, control and normal group was infused with endotoxin(LPS) via indwelling right atria catheters except normal and control group. RT-PCR was used to detect kidney, lung and small intestinal mucous membrane tissue mRNA expression of the ET-1 , ET AR and glucose-6-phospho dehydrogenase(G-6-PD) in every group.Serum BUN, Cr, ALT and A were determined. The arterial oxygen tension (PaO 2) and arterial carbon dioxide partial pressure(PaCO 2)were measured in every group. Results: ET-1 mRNA and ET AR mRNA expression in the sepsis group and septic shock group were significantly higher than in normal group. There were significant differences between the normal/control group and sepsis/shock group in BUN,Cr,ALT,PaO 2 and PaCO 2. Conclusion: A higher expression of ET-1 mRNA and ET AR mRNA may be one of the startup factors on multiple organ dysfunction syndrome (MODS) and may play an important role on pathogenesis in sepsis and septic shock.
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Objective To analyze the relationship between polymorphisms of EDNRB gene and Hubei provincial patients of Han ethnicity with sporadic Hirschsprung disease(sHD). Methods Peripheral blood samples from 104 patients with sHD and 84 parents of 42 patients, and 120 normal children(as controls) were collected. PCR-SSCP and direct DNA sequencing were used to detect mutations and polymorphisms of exon-4 in EDNRB gene. The differences of allele frequencies and genotype distribution in polymorphic sites were further analyzed between the three groups. Allele frequencies of SNPs in forty-two sHD trios were analyzed by transmission disequilibrium test(TDT), and the association between phenotype of HD and SNPs was analyzed. Results No mutant site was detected and one polymorphic site of c831 G→A(L277L) was observed in Hubei provincial patients of Han ethnicity with sHD. The allele frequency of A(68% vs 53%) and genotype frequency of AA(49% vs 30%) were significantly higher in sHD group than that in control group(P
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Objective To investigate the alteration of protein kinase C (PKC) and endothelin system in early diabetic rats, and the effect of specific PKC inhibitor on the expression of retinal endothelin-1 (ET-1). Methods The rats model with streptozotocin(STZ)-induced diabetes were set up. The expression of retinal PKC was detected by enzyme-linked immunoabsorbent assay (ELISA). The expression of retinal ET-1, ET-3, ET-A and ET-B receptor mRNA was determined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The alteration of retinal ET-1 mRNA after intravitreal injection of PKC inhibitor GF109203X in diabetic rats was also observed. Results The activities of membranous PKC were significantly increased in 2-week diabetic rats compared with that in normal rats(t=3.296, P=0 008), while activities of cytosolic PKC were unchangeable(t=0 138, P=0 894). The expression of retinal ET-1 mRNA was significantly increased(P=0 008), while no change was found in expression of ET-3, ET-A and ET-B mRNA(P=0 918,P=0 889,P=0 500). After intravitreal injection of 10 -5、10 -6、10 -7 mol/L PKC inhibitor GF109203X in diabetic rats, the expression of retinal ET-1 mRNA was decreased in a dose-dependent manner compared with the control rats. Conclusion Activation of PKC and increased expression of ET-1 could be found in the retina of early diabetic rats, and PKC inhibitor could inhibit the expression of retinal ET-1.
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AIM: To study the changes of endothelin system during chronic heart failure (CHF) and imply the relationship between endothelin system and the course of CHF by observing the mRNA expression of endothelin receptors (ET_AR and ET_BR) and PreproET_1 in early stage and later stage of CHF caused by left coronary artery ligation. METHODS: The mRNA expression of ET_A, ET_B receptors and PreproET_1 were detected by RT-PCR technique. The plasma concentrations of ET_1 and ANP were determined by RIA method. RESULTS: The plasma concentrations of ET_1 and ANP, and the mRNA expression of ET receptors and PreproET_1 in the lefe ventricle increased significantly in early stage (myocardial infarction 10 d). While the plasma concentrations of ET_1 and ANP in later stage (myocardial infarction 70 d) were higher than those in the early stage. However, the mRNA expression of ET_AR, ET_BR and PreproET_1 decreased significantly. The mRNA expression of ET_AR in myocardial infarction (MI) 70 d rats had no difference with those in sham-operated rats, and the mRNA expression of ET_BR and PreproET_1 in MI 70 d rats was lower significantly than those in MI 10 d rats, but significantly higher than those in sham-operated rats. CONCLUSION: The changes of ET receptors and PreproET_1 mRNA expression are involved in the cardiac function modulation during the different stages in chronic heart failure. [
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AIM: To study the effect of BQ123 on voltage-gated K+ current in pulmonary artery smooth muscle cells(PASMCs) from chronic hypoxic rats.METHODS: Twelve age and body weight matched Wistar rats were randomly divided into control and chronic hypoxic group.Single PASMCs were obtained with acute enzyme(collagnaseⅠ plus papain) dispersing method.Using the whole cell patch-clamp technique in freshly isolated PASMCs from normorxic and hypoxic rats,the effects of ET-1 and BQ123,a selective ETA receptor antagonist,on voltage-gated K+ current were recorded.RESULTS:(1) ET-1(10-8 mol?L-1) caused inhibition of K+ current in PASMCs from normoxic and hypoxic rats.The effect of ET-1 on K+ current in PASMCs from hypoxic rats was greater than that from normoxic rats [+50 mV,percent inhibition were(71.04?6.58)% and(60.21?5.32)%,respectively,P0.05,n=5),nor ETA receptor blockade had change of ET-1 mediated IKV inhibition.(3) In chronic hypoxic PASMCs,BQ123 significantly reduced the effect of ET-1 mediated IKV inhibition,from(28.49?6.69) pA/pF to(74.19?9.74) pA/pF at +50 mV(P
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AIM: To elucidate the effect of ET-1 on the expression of voltage-gated K~+ channel ? subunits Kv2.1, Kv9.3 in pulmonary artery smooth muscle cells in rats. METHODS: The mRNA expression of Kv2.1, Kv9.3 in the 2nd, 3rd, 4th subculture of intrapulmonary artery smooth muscle cells isolated from Wistar rats, which exposed to either normoxia or chronic hypoxia, were detected with reverse transcription-PCR (RT-PCR). At the same time, PASMCs were treated with BQ123, an ET_A receptor antagonist. RESULTS: The expression of Kv2.1 and Kv9.3 gene were found in the subculture PASMCs of rats exposed either to normoxia or chronic hypoxia. Chronic hypoxia decreased mRNA expressions of Kv channel subunit Kv2.1, Kv9.3 in PASMCs from 0.827?0.126 and 0.388?0.026 to 0.378?0.015 and 0.184?0.009, respectively (P