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Objective To evaluate the effect of sitaxsentan on renal microcirculation in beagle dogs undergoing cardiopulmonary bypass(CPB)when ultrasound microbubble angiography was used to monitor renal microcirculation.Methods Eighteen male Beagle dogs,weighing 10-15kg,aged 2-4 yr,were allocated into 3 groups(n=6 each)using a random number table:sham operation group(Sham group),CPB group and sitaxsentan group(S group).Sitaxsentan 0.7 mg/kg was infused over 30min starting from 1 h before CPB in group S.Before CPB(T1),at 1 h of CPB(T2),at the end of CPB(T3)and at 2h after the end of CPB(T4),the time-intensity curve of renal parenchyma perfusion was obtained using ultrasound microbubble angiography,and quantitative parameters including the slope rate of ascending curve(A),area under curve(AUC),derived peak intensity(DPI)and time to peak(TTP)were fitted.Results Compared with Sham group,the value of A was significantly decreased at T2-4,AUC and TTP were increased at T3,4,DPI was decreased at T4 in renal cortex and medulla in CPB group,and the value of A was significantly decreased and TTP was increased at T2-4,AUC was increased at T3,4(P0.05).Compared with CPB group,the value of A was significantly increased and AUC and TTP were decreased at T3,4 in renal cortex and medulla(P0.05).Conclusion Sitaxsentan can improve renal microcirculation in beagle dogs undergoing CPB.
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Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. Originally considered to be a disorder of vasoconstriction and vasodilatation, it has become clear that the predominant characteristic of PAH is abnormal cellular proliferation leading to progressive obliteration of the pulmonary vasculature. Current PAH-specific therapies target one of three major pathways involved in development and progression of PAH: 1) The endothelin pathway targeted by the endothelin receptor antagonists (ERAs); 2) the prostacyclin pathway, targeted by prostacyclin analogs and 3) the nitric oxide (NO) pathway, targeted by the phosphodiesterase type 5 (PDE-5) inhibitors.
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Objective To determine the brain natriuretic peptide(BNP) levels and the effects of endothelin receptor antagonist(ERA) on BNP levels in patients with tetralogy of Fallot(TOF) recently surgical repaired.Methods During January 2010 to January 2012,32 cases of TOF after surgical repaired in hospital were selected.There are 20 males and 12 females,Aged 4 years to 18 years [mean age (7.64 ± 3.75) years] in age.All patients underwent enhanced CT to evaluate the pulmonary vessels and left ventricular before surgery arrangements.As the surgeries done,the patients were grouped randomly as either A or B.All 14 patients in group A started to follow the recommended dosage of bosentan within 3 days after surgery.Meanwhile,all 18 in group B had not taken bosentan or any other ERAs since the surgeries.Both group was evaluated and examined with echocardiography and blood test at the 10th day after surgery.Results None of the patients died within 10 days after surgery.BNP levels of group A was significantly lower than of group B.Inotropic score of group A was markedly lower,too.However,although group A showed mildly advantages in tricuspid regurgitation,pulmonary regurgitation,ratio of RV/LV end-systolic dimension and liver functions,there was no statistically significant difference.Conclusion For patients with tetralogy of Fallot,early use of ERAs after surgical repaired could reduce the use of inotropic agents and significantly decrease the BNP levels when discharged.
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La hipertensión arterial pulmonar (HAP) es consecuencia de una alteración aguda o crónica de la vasculatura pulmonar, que se caracteriza por el aumento de la presión arterial pulmonar como consecuencia del aumento de la resistencia vascular pulmonar. La fisiopatología de la HAP se caracteriza por la vasoconstricción pulmonar vascular, la proliferación de células musculares lisas, y la trombosis. Estos cambios son el resultado de un desequilibrio entre agentes vasodilatadores (prostaciclina, óxido nítrico, péptido intestinal vaso activo) y vasoconstrictores (tromboxano A2, endotelina, serotonina), los inhibidores de factores de crecimiento y mitógenos, y factores antitrombóticos y protrombóticos. Los recientes avances en el tratamiento están dirigidos a restablecer el equilibrio entre estos sistemas. Los antagonistas de los receptores de endotelina (bosentán, ambrisentán), inhibidores de la fosfodiesterasa tipo 5 (sildenafilo, tadalafilo), y prostaciclina (epoprostenol, iloprost, treprostinil, beraprost) representan las diferentes clases de medicamentos que se utilizan actualmente en monoterapia y en combinación para el tratamiento de la HAP. El propósito de esta revisión es proporcionar al lector una actualización del tratamiento de la HAP con antagonistas de los receptores de la endotelina.
Pulmonary arterial hypertension (PAH) is a consequence of acute or chronic disorder of the pulmonary vasculature, which is characterized by increased pulmonary artery pressure as a result of increased pulmonary vascular resistance. The pathophysiology of PAH is characterized by pulmonary vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. These changes are a result of an imbalance between vasodilators (prostacyclin, nitric oxide, vasoactive intestinal peptide) and vasoconstrictors (thromboxane A2, endothelin, serotonin), growth inhibitors and mitogenic factors, and antithrombotic and prothrombotic factors. Recent advances in treatment are directed at restoring the balance between these systems. Endothelin receptor antagonists (bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), and prostacylin (epoprostenol, iloprost, treprostinil, beraprost) represent the different classes of medications that are currently used in monotherapy and in combination to treat PAH. The purpose of this review is to provide the reader with an update on the treatment of PAH with antagonists of endothelin receptors.
A hipertensão arterial pulmonar (HAP) é uma consequência da doença aguda ou crônica da vasculatura pulmonar, o que é caracterizado pelo aumento da pressão da artéria pulmonar, como um resultado da resistência vascular pulmonar aumentada. A fisiopatologia de HAP é caracterizada pela vasoconstrição pulmonar vascular, proliferação de células de músculo liso, e trombose. Estas alterações são um resultado de um desequilíbrio entre os vasodilatadores (prostaciclina, o óxido nítrico, o péptido intestinal vasoativo) e vasoconstritores (tromboxano A2, endotelina, serotonina), e inibidores de crescimento de fatores miogênicos, e fatores antitrombóticos e pró-trombóticos. Avanços recentes no tratamento são dirigidos para o restabelecimento do equilíbrio entre estes sistemas. Antagonistas do receptor da endotelina (bosentan, ambrisentan), inibidores da fosfodiesterasa tipo 5 (sildenafilo, tadalafilo) e prostaciclina (epoprostenol, iloprost, treprostinil, beraprost) representam as diferentes classes de medicamentos que são usados atualmente em monoterapia e em combinação para tratar HAP. O objetivo desta revisão é fornecer ao leitor uma atualização sobre o tratamento da HAP com os antagonistas dos receptores de endotelina.
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The efficacy of endothelin receptor antagonists in protecting against myocardial ischemia/reperfusion (I/R) injury is controversial, and the mechanisms remain unclear. The aim of this study was to investigate the effects of CPU0123, a novel endothelin type A and type B receptor antagonist, on myocardial I/R injury and to explore the mechanisms involved. Male Sprague-Dawley rats weighing 200-250 g were randomized to three groups (6-7 per group): group 1, Sham; group 2, I/R + vehicle. Rats were subjected to in vivo myocardial I/R injury by ligation of the left anterior descending coronary artery and 0.5 percent sodium carboxymethyl cellulose (1 mL/kg) was injected intraperitoneally immediately prior to coronary occlusion. Group 3, I/R + CPU0213. Rats were subjected to identical surgical procedures and CPU0213 (30 mg/kg) was injected intraperitoneally immediately prior to coronary occlusion. Infarct size, cardiac function and biochemical changes were measured. CPU0213 pretreatment reduced infarct size as a percentage of the ischemic area by 44.5 percent (I/R + vehicle: 61.3 ± 3.2 vs I/R + CPU0213: 34.0 ± 5.5 percent, P < 0.05) and improved ejection fraction by 17.2 percent (I/R + vehicle: 58.4 ± 2.8 vs I/R + CPU0213: 68.5 ± 2.2 percent, P < 0.05) compared to vehicle-treated animals. This protection was associated with inhibition of myocardial inflammation and oxidative stress. Moreover, reduction in Akt (protein kinase B) and endothelial nitric oxide synthase (eNOS) phosphorylation induced by myocardial I/R injury was limited by CPU0213 (P < 0.05). These data suggest that CPU0123, a non-selective antagonist, has protective effects against myocardial I/R injury in rats, which may be related to the Akt/eNOS pathway.
Subject(s)
Animals , Male , Rats , Cardiotonic Agents/pharmacology , Myocardial Reperfusion Injury/prevention & control , Pyrazoles/pharmacology , Receptor, Endothelin A/antagonists & inhibitors , Receptor, Endothelin B/antagonists & inhibitors , Analysis of Variance , Disease Models, Animal , Myocardial Reperfusion Injury/drug therapy , Nitric Oxide Synthase Type III/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Random Allocation , Rats, Sprague-Dawley , Signal Transduction/drug effectsABSTRACT
PURPOSE: To examine the effect of bosentan, a dual endothelin receptor (ER) antagonist, on the development of monocrotaline (MCT)-induced pulmonary hypertension in rats by especially focusing on the pulmonary vascular morphology changes. METHODS: Sprague-Dawley rats were treated as follows: controls received a subcutaneous saline injection, MCT-treated rats received a subcutaneous MCT injection, and bosentan-treated rats received a MCT injection followed by treatment with bosentan (20 mg/kg/day). To assess the effects of ER blockade on the time course, the animals were exsanguinated, and their hearts and lungs were dissected after 7, 14, or 28 days. RESULTS: The mean body weights of the MCT- and bosentan-treated rats were significantly lower than that of the control rats on days 7, 14, and 28. Bosentan administration significantly inhibited the progression of right ventricular hypertrophy on day 28 (right ventricle/[left ventricle+septum]: 0.71+/-0.10 in MCT-treated rats vs. 0.49+/-0.09 in bosentan-treated rats; P<0.05). Quantitative analysis of peripheral pulmonary arteries revealed that the increase in medial wall thickness after MCT injection was significantly attenuated in the bosentan-treated rats on day 28 (49.96+/-10.06% in MCT-treated rats vs. 47.09+/-10.48% in bosentan-treated rats; P<0.05). In addition, the increase in the number of intra-acinar muscular arteries after MCT injection was reduced by bosentan on days 14 and 28. CONCLUSION: Bosentan administration in intermediate doses exerts inhibitory effects on lung vascular hypertrophy and right ventricular hypertrophy during the development of MCT-induced pulmonary hypertension in rats.
Subject(s)
Animals , Rats , Arteries , Body Weight , Endothelins , Heart , Hypertension, Pulmonary , Hypertrophy , Hypertrophy, Right Ventricular , Lung , Monocrotaline , Pulmonary Artery , Rats, Sprague-Dawley , Receptors, Endothelin , SulfonamidesABSTRACT
Objective To observe the inhibitory effect of endothelin receptor antagonist on increased vascular endothelial growth factor(VEGF) level of retina in diabetic rats. Methods Male Wistar rats were randomly divided into three groups: normal control group,diabetic group(diabetes without treatment) and treated group(diabetes treated with endothelin receptor antagonist).The rats were killed after 24 weeks.Levels of VEGF in retina of rats were detected by ELISA. Results Levels of VEGF were significantly lower in treated group than diabetic group(P
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BACKGROUND: Endothelin (ET) is the most potent vasoconstrictor and bronchoconstrictor. In patients with acute pulmonary thromboembolism (APTE), (delete) The plasma ET-1 level is elevated in patients with acute pulmonary thromboembolism (APTE). These findings suggest the possibility of ET-1 as an important mediator This finding suggest that ET-1 may be an important mediator in the cardiopulmonary derangement of APTE. But whether ET-1 is a pathogenic mediator or a simple marker of APTE is not known. We investigated the The role of ET-1 in the pathogenesis of cardiopulmonary dysfunction in APTE through evaluating (delete) was investigated through an evaluation of the effects of ETA-receptor antagonist on APTE. We also demonstrated that increased The increase in local levels of preproET-1 mRNA and ET-1 peptide in the embolized lung was also demonstrated. METHODS : In a canine autologous blood clot pulmonary embolism model, ETA-receptor antagonist (10 mg/kg intravenously, n = 6) was administered one hour after the onset of the embolism. Hemodynamic measurements, blood gas tensions and plasma levels of ET-1 immunoreactivity in this treatment group were compared with those in the control group (n = 5). After the experiment, preproET-1 mRNA expression (using Northern blot analysis) and the distribution of ET-1 (by immunohistochemical analysis) in the lung tissues were examined. RESULTS: Increase The increases in pulmonary arterial pressure and pulmonary vascular resistance were smaller in treatment group compared with of the treatment group were less than those of the control group. Decrease in cardiac output was also less in the treatment group. Complications such as systemic arterial hypotension and hypoxemia did not occur with the administration of ETA-receptor antagonist. While the The plasma level of ET-1 like (ED: what does 'like' mean?) immunoreactivity was increased after embolization in both the groups groups, it but was significantly higher in the treatment group. The preproET-1 mRNA and ET-1 peptide expressions were increased in the embolized lung. CONCLUSION: ET-1 synthesis increases with embolization in the lung and may plays play an important role in the pathophys iology of cardiopulmonary derangement of APTE. Also Furthermore, ETA-receptor antagonist attenuates cardiopulmonary alterations seen in APTE, suggesting a potentially beneficial effect a potential benefit of this therapy.
Subject(s)
Humans , Hypoxia , Arterial Pressure , Blotting, Northern , Cardiac Output , Embolism , Endothelin-1 , Endothelins , Hemodynamics , Hypotension , Lung , Plasma , Pulmonary Embolism , Receptors, Endothelin , Respiratory Mechanics , RNA, Messenger , Vascular ResistanceABSTRACT
AIM To determine the antagonistic activities of new endothelin receptor antagonist CPU0214 on the left ventricle membranes and the aorta ring contraction in normal rat and its reduction effect on the mean arterial pressure in conscious DOCA salt hypertensive rats. METHODS Left ventricle membranes of normal rat hearts achieved for competition binding assay was used to investigate the antagonistic effects of CPU0214. Aorta ring contraction induced by ET 1 in normal rat was used to investigate the antagonistic activity of CPU0214. DOCA salt hypertensive rats were induced by injection of deoxycorticosterone acetate (DOCA, sc) following with 1% NaCl as drinking for 4 wk. A multiple physiological recorder was used to record the mean arterial pressure of femoral artery. The endothelin receptor change in the left ventricle membranes of DOCA salt hypertensive rat was measured by binding assays. Intraperitoneal injection of CPU0214 was used to investigate its effect on reduction of mean arterial pressure. RESULTS In the left ventricle the IC 50 of endothelin receptor antagonist CPU0214 is 16 nmol?L -1 and CPU0214 (10 ?mol?L -1 ) inhibited the ET 1 induced isolated aorta rings contraction in normal rats. Mean arterial pressure as well as B max and K d of left ventricle were increased significantly in DOCA salt hypertensive rat. CPU0214 (60 mg?kg -1 ip) significantly reduced the mean arterial pressure of conscious DOCA salt hypertensive rats especially during 60～90 min after administration. CONCLUSIONS CPU0214 has significantly antagonistic effects on the left ventricle membrane and the isolated aorta ring contraction in normal rat, which is verified by CPU0214 as a strong endothelin receptor antagonist. Furthermore its effect on the mean blood pressure reduction in conscious DOCA salt hypertensive rats, which is manifested as an abnormal endothelin system, shows its prosperity of drug development value as a new endothelin receptor antagonist.
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Objective To study the effects of ETP-508,a novel endothelin receptor antagonist,on the proliferation of pulmonary arterial smooth muscle cells(PASMCs) of rat cultured in hypoxia environment.Methods Primary culture of rat PASMCs was prepared by the method of tissue block anchorage,and they were assigned into four groups: normoxia group(21% O2),hypoxia group(2% O2),hypoxia+BQ-485 group(10-6,10-7,10-8,10-9mol/L) and hypoxia + ETP-508 group(10-6,10-7,10-8,10-9mol/L).MTT(492nm) assay was used to detect the A value of the four groups after cells were cultured for 24,48 and 72h.Flow cytometry and radioimmunoassay were respectively used to detect the cell cycle and ET-1 content at 48h time point.Results MTT assay demonstrated that A value of each group did not significantly differ at 24h time point.At 28h time point,A value of hypoxia group was markedly increased(P