bq-123 and Disease-Models--Animal

1. The aim of the present review is to summarize clinical observations and results of animal models that advance the knowledge of the attenuation of cerebrovascular dysfunction in the setting of heat stroke. It is a narrative review of selected published literature from Medline over the period 1959-2005. 2. All heat-stressed rodents, even under general anaesthesia, have hyperthermia, systemic inflammation, hypercoagulable state, arterial hypotension and tissue ischaemia and injury in multiple organs. These findings demonstrate that rodent heat stroke models can nearly mirror the full spectrum of human heat stroke. Experimental heat stroke fulfills the empirical triad used for the diagnosis of classical human heat stroke, namely hyperthermia, central nervous system alterations and a history of heat stress. 3. These physiological dysfunctions and survival during heat stroke can be improved by whole-body or brain cooling therapy adopted immediately after the onset of heat stroke. 4. However, in the absence of body or brain cooling, these heat stroke reactions can still be reduced by the following measures: (i) fluid replacement with 3% NaCl solution, 10% human albumin or hydroxyethyl starch; (ii) intravenous delivery of anti-inflammatory drugs, free radical scavengers or interleukin-1 receptor antagonists; (iii) hyperbaric oxygen therapy; or (iv) transplantation of human umbilical cord blood cells. 5. In addition, before initiation of heat stress, prior manipulations with one of the following measures was found to be able to protect against heat stroke reactions: (i) systemic delivery of alpha-tocopherol, mannitol, inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin ETA receptor antagonists, serotoninergic nerve depletors or receptor antagonists, or glutamate receptor antagonists; or (ii) heat shock protein 72 preconditioning. 6. There is compelling evidence that cerebrovascular dysfunction is an attractive target for therapy in heat stroke.

Topics: Animals; Antihypertensive Agents; Blood Coagulation; Brain; Brain Ischemia; Cerebrovascular Circulation; Cryotherapy; Disease Models, Animal; Endothelial Cells; Endothelin Receptor Antagonists; Enzyme Inhibitors; Fluid Therapy; Free Radical Scavengers; Heat Stroke; Humans; Hyperbaric Oxygenation; Nitric Oxide Synthase; Peptides, Cyclic; Receptors, Endothelin

The pulmonary endothelium modulates vascular tone by the release of endothelium-derived constricting (EDCF) and relaxing (EDRF) factors, among them endothelin-1, nitric oxide, prostacyclin, and putative endothelium-derived hyperpolarizing factors. Abnormalities in EDCF and EDRF generation have been demonstrated in a number of cardiopulmonary disease states, such as primary and secondary pulmonary hypertension, chronic obstructive lung disease, cardiopulmonary bypass, and congestive heart failure. An imbalance between EDCF and EDRF, termed "pulmonary endothelial dysfunction," may contribute to the alteration in vascular tone characteristic of pulmonary disease. The following review summarizes the present knowledge of the role of EDCF and EDRF in such processes with major focus on pulmonary endothelial dysfunction in hypoxia-induced pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Atrasentan; Bosentan; Controlled Clinical Trials as Topic; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Obstructive; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Pyrrolidines; Receptors, Endothelin; RNA, Messenger; Sulfonamides; Time Factors; Vasoconstriction; Vasodilation

Topics: Animals; Antibodies, Monoclonal; Aspartic Acid Endopeptidases; Disease Models, Animal; Drug Design; Endothelin Receptor Antagonists; Endothelin-Converting Enzymes; Endothelins; Humans; Metalloendopeptidases; Oligopeptides; Peptides, Cyclic; Pyrimidines; Receptors, Endothelin; Sulfonamides

Elevated levels of endothelin-1 (ET-1) were recorded in sera of scorpion sting patients. However, no studies focused on the mechanism of ET-1 involvement in the pathogenesis of scorpion envenomation, particularly in the cardiovascular system which is seriously affected in severe cases of scorpion stings. Inflammation induced by

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Inflammation Mediators; Male; Mice; Peptides, Cyclic; Receptor, Endothelin A; Scorpion Stings; Scorpion Venoms; Signal Transduction

Quercetin was reported to be crucial for a broad range of activities, including attenuating inflammation, platelet aggregation, capillary permeability, and lipid peroxidation. However, the effect of quercetin in hypertension during pregnancy, was not fully understood.. The model of hypertension in pregnancy was established in rats by reduced uterine perfusion pressure (RUPP). Quercetin was administrated by gavage. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using the CODA 6 BP system. Plasma concentrations of Endothelin-1 (ET-1), soluble fms-like tyrosine kinase-1 (sFlt-1), and vascular endothelial growth factor (VEGF) were detected using enzyme-linked immunosorbent assay kits. The mRNA and protein levels of ET-1 and endothelin-1 type A receptor (ET. In RUPP induced rats, quercetin treatment decreased SBP and DBP, fetal resorptions percentage, plasma ET-1 and sFlt-1 concentrations, ET-1 and ET. Quercetin attenuates RUPP induced hypertension in pregnant rats through the regulation of ET-1 and ET

Topics: Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Female; Fetal Weight; Hypertension, Pregnancy-Induced; Male; Peptides, Cyclic; Perfusion; Placenta; Pregnancy; Quercetin; Rats, Sprague-Dawley; Receptor, Endothelin A; Uterus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Endothelin alters central sympathetic responses, but the resultant effects on arrhythmogenesis are unknown. We examined ventricular tachyarrhythmias after endothelin receptor-A blockade in the brain of Wistar rats with acute myocardial infarction. For this aim, BQ-123 (n=6) or phosphate-buffered saline (n=6) were injected intracerebroventricularly. After 10 min, the left coronary artery was ligated, followed by implantation of telemetry transmitters. Electrocardiography and voluntary activity (as a surrogate of acute left ventricular failure) were continuously monitored for 24 h. Infarct-size was similar in the two groups. There were fewer episodes of ventricular tachyarrhythmias of shorter average duration in treated rats, leading to markedly shorter total duration (12.3+/-8.9 s), when compared to controls (546.2+/-130.3 s). Voluntary activity increased in treated rats during the last hours of recording, but bradyarrhythmic episodes were comparable between the two groups. Endothelin receptor-A blockade in the brain of rats decreases the incidence of ventricular tachyarrhythmias post-ligation, without affecting bradyarrhythmic episodes. These findings call for further research on the pathophysiologic role of endothelin during acute myocardial infarction.

Topics: Animals; Cerebral Ventricles; Disease Models, Animal; Endothelin A Receptor Antagonists; Injections, Intraventricular; Myocardial Infarction; Peptides, Cyclic; Rats, Wistar; Receptor, Endothelin A; Tachycardia, Ventricular; Ventricular Premature Complexes

To investigate the effect of Bosentan (non-selective endothelin receptor antagonist) and BQ123 (ET. Uveitis was induced by intravitreal injection of lipopolysaccharide (LPS). The animals were divided into 7 groups and there were six rabbits in each group (saline, saline and ethanol, bosentan, BQ123, lipopolysaccharide (LPS), bosentan and LPS, BQ123 and LPS-injected groups). Bosentan and BQ123 were applied before LPS injection. Aqueous humour was collected at 24th hour post-injections and enucleation was performed for the evaluation of histopathological changes.. BQ123 decreased clinical score, cell counts and protein amount more than bosentan and it was significant for cell counts (p = 0.018). Bosentan significantly diminished inflammatory reactions more than BQ123 as shown in histopathological specimens (p = 0.002).. ET

Topics: Animals; Aqueous Humor; Bosentan; Disease Models, Animal; Endothelin Receptor Antagonists; Eye; Eye Proteins; Intravitreal Injections; Leukocyte Count; Lipopolysaccharides; Male; Peptides, Cyclic; Rabbits; Sulfonamides; Uveitis

Under physiologic conditions, losartan showed a dose-dependent antagonistic effect to the endothelin-1 (ET-1)-mediated vasoconstriction. This reduced vasoconstriction was abolished after preincubation with an endothelin B

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensins; Animals; Basilar Artery; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Losartan; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; Subarachnoid Hemorrhage; Vasoconstriction; Vasodilation; Vasospasm, Intracranial

Oral ulcer is the most common oral disease and leads to pain during meals and speaking, reducing the quality of life of patients. Recent evidence using animal models suggests that oral ulcers induce cyclooxygenase-dependent spontaneous pain and cyclooxygenase-independent mechanical allodynia. Endothelin-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of endothelin-1 signaling with oral ulcer-induced pain using our proprietary assay system in conscious rats. Endothelin-1 was significantly upregulated in oral ulcers experimentally induced by topical acetic acid treatment, while endothelin-1 production was suppressed by antibacterial pretreatment. Spontaneous nociceptive behavior in oral ulcer model rats was inhibited by swab applications of BQ-788 (ET

Topics: Acetanilides; Anilides; Animals; Bridged Bicyclo Compounds; Caproates; Cinnamates; Disease Models, Animal; Endothelin-1; Male; Oligopeptides; Oral Ulcer; Pain; Peptides, Cyclic; Piperidines; Purines; Rats; Rats, Wistar; Signal Transduction; Sulfonamides; TRPV Cation Channels

Topics: Animals; Brain Ischemia; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide Synthase Type III; Peptides, Cyclic; Rats; Vasoconstriction

Testicular torsion is a well-known medical emergency that can lead to pathological changes in the testicular tissues and male infertility. This investigation was undertaken to gain insight into the effects of an endothelin type A receptor antagonist (BQ123) on torsion-induced germ cell loss. Twenty-eight male Wistar albino rats were divided into four groups. In group I (control group), a sham operation to the left testis was performed. In group II (I/R injury), I/R injury was created by rotating the left testis 720° in a clockwise direction for 2 h and detorsing the testis after 2 h. In group III (I/R injury+BQ123), the rats were subjected to I/R injury and BQ123 injection (1 mg/kg, intravenous). In group IV (control+BQ123), the sham operated rats were subjected to BQ123. The testes of the rats were removed in all groups. Torsion-induced apoptosis and the effects of BQ123 were examined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) technique, immunohistochemistry and western blotting. In group II, the number of TUNEL-positive cells increased after testicular torsion. Immunohistochemistry and western blotting showed that apoptotic proteins (active caspase 3 and Bax) were upregulated, and the anti-apoptotic protein Bcl2 was downregulated in I/R injury. The administration of BQ123 caused a significant decrease in the number of apoptotic cells and the expression of apoptotic proteins (p<0.05) when compared with the I/R injury group. No significant effect of BQ123 was observed in the testicular cells of group IV. This animal study provides evidence of the regulatory effects of BQ123 on torsion-induced testicular apoptosis.

Topics: Animals; Apoptosis; Blotting, Western; Disease Models, Animal; Endothelin A Receptor Antagonists; Immunohistochemistry; In Situ Nick-End Labeling; Male; Peptides, Cyclic; Rats; Rats, Wistar; Reperfusion Injury; Spermatic Cord Torsion

Cancer patients with bone metastases often suffer breakthrough pain. However, little progress has been made in the treatment of breakthrough pain and its associated mechanism(s) in the patient with cancer due to lacking of resembling and predictive animal models. We previously have demonstrated that endothelin-1 plays an important role in breakthrough cancer pain. In the present study, we have established an animal model of breakthrough cancer pain induced by endothelin-1. The animal model of breakthrough cancer pain is strictly followed the definition and meets the characteristics of breakthrough pain. The model is reliable, reproducible and easy to be produced. To our knowledge, this is the first report for establishing such an animal model. In addition, we also found that a selective ETA receptor antagonist BQ-123 could reverse endothelin-1 induced breakthrough pain. We further studied the characteristics of pain behaviors such as hind limb use score and voluntary wheel running as well as the electrophysiology of sciatic nerve fibers with the model. The murine model shows high resemblance compared to the breakthrough cancer pain in the patients with cancer clinically. It provides a platform for further study of the pathogenesis of breakthrough cancer pain and targeted intervention.

Topics: Action Potentials; Analgesics, Opioid; Animals; Breakthrough Pain; Cell Line, Tumor; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Hindlimb; Male; Mice, Inbred C57BL; Morphine; Motor Activity; Neoplasm Transplantation; Neoplasms; Nerve Fibers; Peptides, Cyclic; Sciatic Nerve

Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown.. The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes.. Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals.. Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Models, Animal; Endothelin A Receptor Antagonists; Hypoxia; Kidney; Male; Oxygen Consumption; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Renal Circulation

Endothelin-1 has been shown to increase neuronal activity and glutaminergic synaptic transmission by endothelin-A receptors (ETAR) in the nucleus tractus solitarius neurons that play an important role in epileptic seizures. Therefore, BQ-123 as an ETAR antagonist might attenuate neuronal excitability and glutaminergic synaptic transmission. The main purpose of the present study is to investigate the protective effect of acute BQ-123 treatment against pentylenetetrazole (PTZ)-induced tonic-clonic seizures. Wistar albino rats were divided into three groups: control, PTZ, and PTZ + BQ-123 groups. BQ-123 (3 mg/kg, intravenously) was administered for 15 min before injecting with PTZ (50 mg/kg, intraperitoneally). We determined a delay resulting from BQ-123 in "duration of the seizure onset." "Number of rats with major seizure" also decreased according to scoring with video camera in PTZ + BQ-123 group. In BQ-123-treated group, there were eight rats without a major seizure, but only one rat had a delayed major seizure. The brain tissue glutathione peroxidase activity was significantly decreased in the PTZ and PTZ + BQ-123 groups. According to the results of the control group, there was a significant increase in the protein carbonyl levels of the PTZ group and a significant increase in the nitric oxide levels of the PTZ + BQ-123 group. Histological examination showed an increase in the number of neuronal hyperchromatic nucleus especially in hippocampal gyrus dentatus region of BQ-123-treated group. We concluded that BQ-123 impeded the formation and spread of seizure to a great degree. The beneficial effects of BQ-123 were comparatively supported with biochemical parameters and histological examinations.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Endothelin A Receptor Antagonists; Epilepsy, Tonic-Clonic; Glutathione Peroxidase; Male; Nitric Oxide; Pentylenetetrazole; Peptides, Cyclic; Protein Carbonylation; Rats, Wistar; Receptor, Endothelin A; Time Factors; Video Recording

Retinopathy of prematurity adversely affects premature infants because of oxygen-induced damage of the immature retinal vasculature, resulting in pathological neovascularization (NV). Our pilot studies using the mouse model of oxygen-induced retinopathy (OIR) showed marked increases in angiogenic mediators, including endothelins and endothelin receptor (EDNR) A. We hypothesized that activation of the endothelin system via EDNRA plays a causal role in pathological angiogenesis and up-regulation of angiogenic mediators, including vascular endothelial growth factor A (VEGFA) in OIR. Mice were exposed to 75% oxygen from post-natal day P7 to P12, treated with either vehicle or EDNRA antagonist BQ-123 or EDNRB antagonist BQ-788 on P12, and kept at room air from P12 to P17 (ischemic phase). RT-PCR analysis revealed increased levels of EDN2 and EDNRA mRNA, and Western blot analysis revealed increased EDN2 expression during the ischemic phase. EDNRA inhibition significantly increased vessel sprouting, resulting in enhanced physiological angiogenesis and decreased pathological NV, whereas EDNRB inhibition modestly improved vascular repair. OIR triggered significant increases in VEGFA protein and mRNA for delta-like ligand 4, apelin, angiopoietin-2, and monocyte chemoattractant protein-1. BQ-123 treatment significantly reduced these alterations. EDN2 expression was localized to retinal glia and pathological NV tufts of the OIR retinas. EDN2 also induced VEGFA protein expression in cultured astrocytes. In conclusion, inhibition of the EDNRA during OIR suppresses pathological NV and promotes physiological angiogenesis.

Topics: Animals; Animals, Newborn; Astrocytes; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Mice; Oligopeptides; Peptides, Cyclic; Piperidines; Retina; Retinal Neovascularization; Retinopathy of Prematurity; Signal Transduction; Vascular Endothelial Growth Factor A

The contribution of endothelin-1 (ET-1) in a B2KO mouse model of a high salt-induced arterial hypertension was investigated.. Wild-type (WT) or B2KO mice receiving a normal diet (ND) or a high-salt diet (HSD) were monitored by radiotelemetry up to a maximum of 18 weeks. At the 12th week of diet, subgroups under ND or HSD received by gavage the ETA antagonist A127722 during 5 days. In addition, blood samples were collected and, following euthanasia, the lungs, heart and kidneys were extracted, homogenized and assayed for ET-1 by RIA. In a separate series of experiments, the ETA antagonist, BQ123 was tested against the pressor responses to a NOS inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) in anaesthetized WT and B2KO mice.. In B2KO, but not WT mice, 12 weeks of HSD triggered a maximal increase of the mean arterial pressure (MAP) of 19.1 ± 2.8 mmHg, which was corrected by A127722 to MAP levels found in B2KO mice under ND. Significant increases in immunoreactive ET-1 were detected only in the lungs of B2KO mice under HSD. On the other hand, metabolic studies showed that sodium urinary excretion was markedly reduced in B2KO compared with WT mice under ND. Finally, BQ123 (2 mg·kg(-1)) reduced by 50% the pressor response to L-NAME (2 mg·kg(-1)) in B2KO, but not WT mice under anaesthesia.. Our results support the concept that functional B2 receptors oppose high salt-induced increments in MAP, which are corrected by an ETA receptor antagonist in this mouse model of experimental hypertension.

Topics: Animals; Antihypertensive Agents; Arterial Pressure; Atrasentan; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NG-Nitroarginine Methyl Ester; Peptides, Cyclic; Pyrrolidines; Receptor, Bradykinin B2; Sodium; Sodium Chloride, Dietary; Telemetry

Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 (ET-1) signaling. Time-dated pregnant and nonpregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6-21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in nonpregnant rats but significantly increased blood pressure on day 12 (systolic blood pressure, 111.7 ± 6.1 versus 138.5 ± 3.5 mm Hg; P=0.004) and day 20 (systolic blood pressure, 103.4 ± 4.6 versus 125.1 ± 6.1 mm Hg; P=0.02) in pregnant rats and urine protein (μg/μL)/creatinine (nmol/μL) ratio on day 20 (0.10 ± 0.01 versus 0.20 ± 0.04; P=0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma ET-1 levels, as well as the abundance of prepro-ET-1 mRNA, ET-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the ET-1 type A receptor antagonist, BQ123, during the course of hypoxia exposure significantly attenuated the hypoxia-induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened ET-1 and ET-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Peptides, Cyclic; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction

The potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of plasma oxidative stress seen in sepsis. The selective endothelin receptor blockers BQ123 and BQ788 were used to investigate the importance of selective endothelin receptor blockage in modulating oxidative stress during endotoxemia.. The study was performed on male Wistar rats (n = 6 per group) divided into groups: (1) saline, (2) lipopolysaccharide (LPS) (15 mg/kg)-saline, (3) BQ123 (0.5 mg/kg)-LPS, (4) BQ123 (1 mg/kg)-LPS, (5) BQ788 (3 mg/kg)-LPS. The endothelin receptor type A(ETA-R) or type B (ETB-R) antagonist was injected intravenously 30 min before LPS administration. Blood pressure was monitored and blood was taken before, 90 min and 300 min after saline or LPS administration.. Injection of LPS alone resulted in a decrease in mean arterial pressure (MAP) (p < 0.05), a decrease in ferric reducing ability of plasma (FRAP) value (p < 0.01) and a marked increase in plasma tumor necrosis factor α (TNF-α) and thiobarbituric acid reactive substances (TBARS) (p < 0.001, p < 0.001, respectively). Administration of BQ123 before LPS administration deteriorated MAP in a dose dependent way. Moreover, BQ123 (1 mg/kg) decreased plasma level of TBARS and TNF-α (p < 0.01 and p < 0.05, respectively) and increased FRAP value (p < 0.001). On the contrary, BQ788 prevented LPS-induced decrease in MAP(p < 0.001) and led to a significant reduction in plasma TBARS concentration (p < 0.01).. Our study showed that blockage of ETB-R during endotoxemia improved blood hemodynamics and decreased plasma lipid peroxidation. Blockage of ETA-R improved plasma antioxidant status and decreased lipid peroxidation and TNF-α production, but it deteriorated hemodynamic conditions.

Topics: Animals; Antioxidants; Arterial Pressure; Disease Models, Animal; Drug Administration Schedule; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endotoxemia; Hemodynamics; Injections, Intravenous; Lipid Peroxidation; Lipopolysaccharides; Male; Oligopeptides; Oxidative Stress; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred WKY; Receptor, Endothelin A; Receptor, Endothelin B; Thiobarbituric Acid Reactive Substances; Time Factors; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents

To analyze gene expression profiles in an experimental pancreatitis and provide functional reversal of hypersensitivity with candidate gene endothelin-1 antagonists.. Dibutyltin dichloride (DBTC) is a chemical used as a polyvinyl carbonate stabilizer/catalyzer, biocide in agriculture, antifouling agent in paint and fabric. DBTC induces an acute pancreatitis flare through generation of reactive oxygen species. Lewis-inbred rats received a single i.v. injection with either DBTC or vehicle. Spinal cord and dorsal root ganglia (DRG) were taken at the peak of inflammation and processed for transcriptional profiling with a cDNA microarray biased for rat brain-specific genes. In a second study, groups of animals with DBTC-induced pancreatitis were treated with endothelin (ET) receptor antagonists [ET-A (BQ123) and ET-B BQ788)]. Spontaneous pain related mechanical and thermal hypersensitivity were measured. Immunohistochemical analysis was performed using anti-ET-A and ET-B antibodies on sections from pancreatic tissues and DRG of the T10-12 spinal segments.. Animals developed acute pancreatic inflammation persisting 7-10 d as confirmed by pathological studies (edema in parenchyma, loss of pancreatic architecture and islets, infiltration of inflammatory cells, neutrophil and mononuclear cells, degeneration, vacuolization and necrosis of acinar cells) and the pain-related behaviors (cutaneous secondary mechanical and thermal hypersensitivity). Gene expression profile was different in the spinal cord from animals with pancreatitis compared to the vehicle control group. Over 260 up-regulated and 60 down-regulated unique genes could be classified into 8 functional gene families: circulatory/acute phase/immunomodulatory; extracellular matrix; structural; channel/receptor/transporter; signaling transduction; transcription/translation-related; antioxidants/chaperones/heat shock; pancreatic and other enzymes. ET-1 was among the 52 candidate genes up-regulated greater than 2-fold in animals with pancreatic inflammation and visceral pain-related behavior. Treatments with the ET-A (BQ123) and ET-B (BQ-788) antagonists revealed significant protection against inflammatory pain related mechanical and thermal hypersensitivity behaviors in animals with pancreatitis (P < 0.05). Open field spontaneous behavioral activity (at baseline, day 6 and 30 min after drug treatments (BQ123, BQ788) showed overall stable activity levels indicating that the drugs produced no undesirable effects on normal exploratory behaviors, except for a trend toward reduction of the active time and increase in resting time at the highest dose (300 μmol/L). Immunocytochemical localization revealed that expression of ET-A and ET-B receptors increased in DRG from animals with pancreatitis. Endothelin receptor localization was combined in dual staining with neuronal marker NeuN, and glia marker, glial fibrillary acidic protein. ET-A was expressed in the cell bodies and occasional nuclei of DRG neurons in naïve animals. However, phenotypic expression of ET-A receptor was greatly increased in neurons of all sizes in animals with pancreatitis. Similarly, ET-B receptor was localized in neurons and in the satellite glia, as well as in the Schwann cell glial myelin sheaths surrounding the axons passing through the DRG.. Endothelin-receptor antagonists protect against inflammatory pain responses without interfering with normal exploratory behaviors. Candidate genes can serve as future biomarkers for diagnosis and/or targeted gene therapy.

Topics: Acute Disease; Animals; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression Profiling; Gene Expression Regulation; Hyperalgesia; Male; Oligopeptides; Organotin Compounds; Pancreas; Pancreatitis; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred Lew; Receptors, Endothelin; Spinal Cord

Endothelin-1 is known to be a potent vasoconstrictor. Administration of endothelin-1 to the central nervous system (CNS) induces antinociceptive effects. Nociceptive stimuli affect dorsal root ganglion (DRG) neurons and neurons/astrocytes/microglia in the dorsal horn of the spinal cord. Surgical incision in the plantar aspect of the rat hindpaw is a model for postoperative pain, and withdrawal thresholds reportedly decrease around the incision. We hypothesized that intrathecal endothelin-1 would have antinociceptive effects in this model, and affect DRG neurons and microglia/neurons in the dorsal horn. Intrathecal endothelin-1 partially restored the withdrawal threshold (which was decreased by plantar incision). BQ-123, and BQ-788 (specific endothelin ET(A)- and ET(B)-receptor antagonists, respectively) attenuated the increase in withdrawal threshold induced by endothelin-1. Phosphorylation of extracellular signal-regulated kinase (ERK) in DRG neurons and microglial activation/ERK phosphorylation in the dorsal horn were observed following the incision. Endothelin-1 decreased the incision-induced increase in the numbers of phosphorylated ERK-positive neurons in DRG and activated microglia in the dorsal horn, without affecting the numbers of phosphorylated ERK-positive neurons in the dorsal horn. BQ-123 or BQ-788 partially suppressed these endothelin-1-induced alterations. Our results show that the pain threshold, which is decreased by surgical stimuli, is partially restored by intrathecal endothelin-1 through both endothelin ET(A)- and ET(B)- receptors in DRG neurons and microglia in the spinal cord. Endothelin-1 administration to the CNS may be worth considering as a new candidate for the treatment of postoperative pain and to mitigate prolonged periods of pain.

Topics: Analgesics; Animals; Behavior, Animal; Disease Models, Animal; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Ganglia, Spinal; Injections, Spinal; Male; Microglia; Oligopeptides; Pain Measurement; Pain Threshold; Pain, Postoperative; Peptides, Cyclic; Phosphorylation; Piperidines; Posterior Horn Cells; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors

The aim was to investigate effects of selective endothelin (ET) receptor antagonists on renal hemodynamics and dynamic renal blood flow autoregulation (RBFA) in angiotensin II (Ang II)-infused rats on a high NaCl intake.. Sprague-Dawley rats received Ang II (250 ng/kg/min, s.c.) and an 8% NaCl diet for 14 days after which renal clearance experiments were performed. After baseline measurements animals were administered either: (a) saline vehicle; (b) ETA receptor antagonist BQ-123 (30 nmol/kg/min); (c) ETB receptor antagonist BQ-788 (30 nmol/kg/min); or (d) BQ-123 + BQ-788, for six consecutive 20-minute clearance periods.. BQ-123 reduced arterial pressure (AP) and selectively increased outer medullary perfusion versus vehicle (p<0.05). These effects were attenuated or abolished by combined BQ-123 and BQ-788. BQ-788 reduced renal blood flow and increased renovascular resistance (p<0.05). Ang II-infused rats on high NaCl intake showed abnormalities in dynamic RBFA characterized by an impaired myogenic response that were not significantly affected by ET receptor antagonists.. In hypertensive Ang II-infused rats on a high-NaCl intake selective ETA antagonism with BQ-123 reduced AP and specifically increased OM perfusion and these effects were dependent on intact ETB receptor stimulation. Furthermore, ET receptor antagonists did not attenuate abnormalities in dynamic RBFA.

Topics: Angiotensin II; Animals; Blood Pressure; Disease Models, Animal; Endothelin Receptor Antagonists; Hemodynamics; Hypertension; Kidney; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sodium Chloride, Dietary

Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner.. Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system.. Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology.. BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management.

Topics: Animals; Anterior Cruciate Ligament; Arthralgia; Bradykinin; Bradykinin B1 Receptor Antagonists; Chronic Disease; Disease Models, Animal; Endothelin-1; Injections, Intra-Articular; Knee Joint; Male; Nociception; Osteoarthritis, Knee; Peptides, Cyclic; Rats; Rats, Inbred Lew; Weight-Bearing

While endothelin-1 and its receptors have traditionally been associated with mediating vasoreactivity, we have recently shown that the vast majority of endothelin receptor A expression following traumatic brain injury is localized within the neuron. While it has been suggested that endothelin receptor A plays a role in influencing neuronal integrity, the significance of neuronally expressed endothelin receptor A remains unclear. One report suggests that endothelin-1 signaling mediates diffuse axonal injury. Therefore, this work sought to determine whether treatment with BQ-123, a selective endothelin receptor A antagonist, diminishes the extent of diffuse axonal injury following trauma.. A total of 12 male Sprague-Dawley rats (350-400 g) were used in this study. Two groups (n = 6 per group) were generated as follows: sham operation and traumatic brain injury+1·0 mg/kg BQ-123 delivered intravenously 30 minutes prior to the injury. Trauma was induced using a weight acceleration impact device. Animals were terminated 24 or 48 hours after trauma, and a series of six coronal sections through the entire anterior-posterior extent of the corpus callosum were selected from each brain for quantification of diffuse axonal injury by beta-amyloid precursor protein immunostaining.. Our data indicated that animals treated with BQ-123 30 minutes prior to trauma showed a significant reduction in diffuse axonal injury in corpus callosum at both 24 and 48 hours post-injury.. The results show that endothelin receptor A antagonism reduced the extent of diffuse axonal injury, demonstrating a potential influence of the endothelin system on the intra-axonal cascade of molecular events underlying diffuse axonal injury.

Topics: Animals; Antihypertensive Agents; Axons; Brain Injuries; Diffuse Axonal Injury; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Injections, Intravenous; Male; Neuroprotective Agents; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Signal Transduction; Treatment Outcome

Purpose. To investigate the effect of the endothelin(A) receptor inhibitor BQ-123 on the retinal arteriolar vasculature in minipig retinas in normal eyes and eyes with acute branch retinal vein occlusion (BRVO). Methods. Seven healthy eyes of seven minipigs and six eyes of six minipigs with experimental BRVO were evaluated under systemic anesthesia. An intravitreal juxta-arteriolar microinjection of 30 microL BQ-123 0.61 microg/mL (pH 7.4) was performed in all but one eye from each group, into which the physiologic saline vehicle alone was injected. Vessel-diameter changes were measured with a retinal vessel analyzer. Results. In healthy minipig retinas (n = 6), arteriolar diameter (+/-SD) increased 6.19% +/- 3.55% (P < 0.05), 25.98% +/- 2.37% (P < 0.001), 23.65% +/- 1.2% (P < 0.001), and 16.84% +/- 1.95% (P < 0.001), at 1, 5, 10, and 15 minutes, respectively, after BQ-123 microinjection. Two hours after experimental BRVO (n = 5), the retinal arteriolar diameter had decreased (13.07% +/- 5.7%; P < 0.01). One, 5, 10, and 15 minutes after BQ-123 microinjection, retinal arteriolar diameter had increased by 7.14% +/- 3.3% (P < 0.01), 26.74% +/- 7.63% (P < 0.001), 23.67% +/- 6.4% (P < 0.001), and 16.09% +/- 3.41% (P < 0.001), respectively. Vehicle only injection had no vasoactive effect on physiologic or BRVO retinas. Conclusions. A significant increase in retinal arteriolar diameter was demonstrated after juxta-arteriolar BQ-123 microinjection in healthy and in acute BRVO minipig retinas. The results suggest a role for endothelin-1 in maintaining retinal basal arteriolar tone. Reversing the BRVO-related vasoconstriction by juxta-arteriolar BQ-123 microinjection could bring a new perspective to the management of BRVO.

Topics: Acute Disease; Animals; Arterioles; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Microinjections; Muscle, Smooth, Vascular; Peptides, Cyclic; Retinal Artery; Retinal Vein Occlusion; Swine; Swine, Miniature; Vasodilation

The peptide endothelin-1 (ET1), which was originally identified as a vasoconstrictor, has emerged as a critical regulator of a number of painful conditions, including inflammatory pain and tumor-associated pain. There is considerable pharmacological evidence supporting a role for endothelin A receptors (ET(A)) in mediating ET1-induced pro-algesic functions. ET(A) receptors are expressed in small-diameter nociceptive neurons, but also found in a variety of other cell types in peripheral tissues, including immune cells, keratinocytes, endothelial cells, which have the potential to modulate nociception. To elucidate the functional contribution of ET(A) receptors expressed in sensory neurons towards the functions of the ET1 axis in pathological pain states, we undertook a conditional gene deletion approach to selectively deplete expression of ET(A) in sensory nerves, preserving expression in non-neural peripheral tissues; the expression of ET(B) remained unchanged. Behavioural and pharmacological experiments showed that only late nociceptive hypersensitivity caused by ET1 is abrogated upon a loss of ET(A) receptors on nociceptors and further suggest that ET1-induced early nociceptive hypersensitivity involves activation of ET(A) as well as ET(B) receptors in non-neural peripheral cells. Furthermore, in the context of alleviation of cancer pain and chronic inflammatory pain by ET(A) receptor antagonists, we observed in corresponding mouse models that the contribution of ET(A) receptors expressed in nociceptors is most significant. These results help understand the role of ET(A) receptors in complex biological processes and peripheral cell-cell interactions involved in inflammatory and tumor-associated pain.

Topics: Analysis of Variance; Animals; Carcinoma; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Ganglia, Spinal; Hyperalgesia; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Transgenic; NAV1.8 Voltage-Gated Sodium Channel; Nociceptors; Pain; Pain Measurement; Peptides, Cyclic; Receptor, Endothelin A; RNA, Messenger; Sensory Receptor Cells; Sodium Channels; Time Factors; Tubulin

We previously reported that endothelin A (ET-A) receptor antagonism attenuates carcinoma-induced pain in a cancer pain mouse model. In this study, we investigated the mechanism of ET-A receptor-mediated antinociception and evaluated the role of endogenous opioid analgesia. Squamous cell carcinoma (SCC) cell culture treated with the ET-A receptor antagonist (BQ-123) at 10(-6) M and 10(-5) M significantly increased production and secretion of beta-endorphin and leu-enkephalin, respectively. Behavioral studies were performed by inducing tumors in the hind paw of female nude mice with local injection of cells derived from a human oral SCC. Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at 4 days after SCC inoculation and lasted to 18 days, the last day of measurement. Local administration of either naloxone methiodide (500 microg/kg), selective antagonists for mu-opioid receptor (CTOP, 500 microg/kg), or delta-opioid receptor (naltrindole, 11 mg/kg) but not kappa-opioid receptor (nor-BNI, 2.5 mg/kg) significantly reversed antinociception observed from ET-A receptor antagonism (BQ-123, 92 mg/kg) in cancer animals. These results demonstrate that antagonism of peripheral ET-A receptor attenuates carcinoma pain by modulating release of endogenous opioids to act on opioid receptors in the cancer microenvironment.. This article proposes a novel mechanism for ET-A receptor antagonist drugs in managing cancer-induced pain. An improved understanding of the role of innate opioid analgesia in ET-A receptor-mediated antinociception might provide novel alternatives to morphine therapy for the treatment of cancer pain.

Topics: Analgesics; Animals; Antihypertensive Agents; Carcinoma, Squamous Cell; Cells, Cultured; Disease Models, Animal; Endothelin A Receptor Antagonists; Female; Humans; Mice; Mice, Nude; Narcotic Antagonists; Neoplasm Transplantation; Neoplasms, Experimental; Opioid Peptides; Pain, Intractable; Peptides, Cyclic; Receptors, Opioid; Treatment Outcome; Tumor Cells, Cultured

Doxorubicin is an effective antineoplastic drug; however, its clinical benefit is limited by its cardiotoxicity. The inhibition of mitochondrial biogenesis is responsible for the pathogenesis of doxorubicin-induced cardiomyopathy. Endothelin-1 is a vasoconstrictive peptide produced from big endothelin-1 by endothelin-converting enzyme-1 (ECE-1) and a multifunctional peptide. Although plasma endothelin-1 levels are elevated in patients treated with doxorubicin, the effect of ECE-1 inhibition on doxorubicin-induced cardiomyopathy is not understood. Cardiomyopathy was induced by a single IP injection of doxorubicin (15 mg/kg). Five days after treatment, cardiac function, histological change, and mitochondrial biogenesis were assessed. Echocardiography revealed that cardiac systolic function was significantly deteriorated in doxorubicin-treated wild-type (ECE-1(+/+)) mice compared with ECE-1 heterozygous knockout (ECE-1(+/-)) mice. In histological analysis, cardiomyocyte size in ECE-1(+/-) mice was larger, and cardiomyocyte damage was less. In ECE-1(+/+) mice, tissue adenosine triphosphate content and mitochondrial superoxide dismutase were decreased, and reactive oxygen species generation was increased compared with ECE-1(+/-) mice. Cardiac mitochondrial deoxyribonucleic acid copy number and expressions of key regulators for mitochondrial biogenesis were decreased in ECE-1(+/+) mice. Cardiac cGMP content and serum atrial natriuretic peptide concentration were increased in ECE-1(+/-) mice. In conclusion, the inhibition of ECE-1 attenuated doxorubicin-induced cardiomyopathy by inhibiting the impairment of cardiac mitochondrial biogenesis. This was mainly induced by decreased endothelin-1 levels and an enhanced atrial natriuretic peptide-cGMP pathway. Thus, the inhibition of ECE-1 may be a new therapeutic strategy for doxorubicin-induced cardiomyopathy.

Topics: Animals; Antibiotics, Antineoplastic; Antihypertensive Agents; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathies; Cyclic GMP; Disease Models, Animal; Doxorubicin; Echocardiography; Endothelin-1; Endothelin-Converting Enzymes; Heart Rate; Male; Metalloendopeptidases; Mice; Mice, Knockout; Mitochondria; Myocardium; Peptides, Cyclic

Hepatic and circulating endothelin-1 (ET-1) are increased in patients with cirrhosis and in cirrhotic animals. However, the distinct roles of ET receptor subtypes ETA and ETB in cirrhosis and portal hypertension (PHT) have not been clearly elucidated. Thus, we studied the effects of selective ET-1 antagonists (ETA-ant or ETB-ant) and nonselective ET-1 antagonist (ETA/B-ant) on hepatic hemodynamics in cirrhotic rats. Liver fibrosis and PHT were induced by complete bile duct ligation (BDL) in rats. Two weeks after BDL or sham surgery, hemodynamic responses were measured during intraportal infusion of incremental doses of the following ET-ants: (i) BQ-123, (ii) BQ-788, and (iii) bosentan. After equilibration with vehicle, doses of ET-ants were infused for 30 min periods, and steady-state systemic and hepatic hemodynamics, portal venous pressure (PVP), and hepatic blood flow (HBF) were measured. BDL induced significant PHT and elevated concentrations of plasma ET-1 compared with sham. ETA-ant decreased PVP of cirrhotic rats but had no effect on sham, whereas ETB-ant increased PVP in sham but had no effect in BDL. Nonselective ETA/B-ant decreased PVP of BDL similarly to ETA-ant. Both ETA-ant and ETB-ant decreased local HBF, whereas a nonselective antagonist did not change HBF in sham; however no significant changes were observed in HBF of BDL rats with any of the antagonists. These findings suggest ETA activation contributes to PHT in cirrhotic rats, whereas ETB-mediated portal depressor effects are attenuated in cirrhotic rats compared with noncirrhotic rats.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Hemodynamics; Hepatic Stellate Cells; Hypertension, Portal; Liver; Liver Cirrhosis; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Portal Pressure; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Sulfonamides

Increasing renal pelvic pressure results in PGE2-mediated release of substance P, leading to increases in afferent renal nerve activity (ARNA) and natriuresis, that is, a renorenal reflex response. The renorenal reflexes are impaired in congestive heart failure (CHF). Impairment of the renorenal reflexes may contribute to the increased renal sympathetic nerve activity and sodium retention in CHF. Endothelin (ET)-1 contributes to the pathological changes in cardiac and renal function in CHF. Therefore, we examined whether the ETA receptor antagonist BQ123 altered the responsiveness of renal mechanosensory nerves in CHF. The ARNA responses to increasing renal pelvic pressure were suppressed in CHF but not in sham-CHF rats. In CHF, increasing renal pelvic pressure by 7.5 mm Hg before and during renal pelvic perfusion with BQ123 increased ARNA 12% +/- 3% and 21% +/- 3% (p < 0.05 vs. vehicle). In isolated renal pelvises from CHF rats, PGE2 increased substance P release from 5 +/- 0 to 7 +/- 1 pg/min without BQ123 and from 4 +/- 1 to 9 +/- 1 pg/min with BQ123 in the bath (p < 0.01 vs. vehicle). BQ123 had no effect on the ARNA responses or substance P release in sham-CHF. In conclusion, activation of ETA receptors contributes to the impaired responsiveness of renal mechanosensory nerves in CHF rats by a mechanism(s) at the renal sensory nerve endings.

Topics: Afferent Pathways; Animals; Antihypertensive Agents; Dinoprostone; Disease Models, Animal; Endothelin A Receptor Antagonists; Heart Failure; Hydrostatic Pressure; Kidney; Kidney Pelvis; Male; Mechanoreceptors; Myocardium; Organ Size; Peptides, Cyclic; Perfusion; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sodium; Substance P; Ventricular Dysfunction, Left

Endothelin antagonists are being investigated to prevent neuronal loss after cerebral ischemia. Acetaminophen has been tried in stroke patients to produce hypothermia so that injury following cerebral ischemia can be reduced. The aim of this study was to assess the effect of BQ123, an endothelin-A receptor antagonist, alone and in combination with acetaminophen on neurological outcome, oxidative stress and infarct volume in rats subjected to focal ischemia by occlusion of the middle cerebral artery. In normal rats, acetaminophen decreased, while BQ123 did not produce any change in body temperature, but rats treated with BQ123 and acetaminophen produced a significantly greater (41%) hypothermic response compared to acetaminophen group. In rats subjected to middle cerebral artery occlusion, neurologic deficit was observed; acetaminophen alone did not improve, but BQ123 alone and in combination with acetaminophen produced a significant improvement in neurological deficit. The level of malondialdehyde (MDA) increased and reduced glutathione (GSH) decreased in the brain following ischemia; acetaminophen did not but BQ123 alone and in combination with acetaminophen decreased MDA and increased GSH levels in ischemic rats. Cerebral ischemia produced significant infarction, the infarct volume decreased in response to BQ123 and its combination with acetaminophen. The infarct volume, MDA level and neurological deficit in ischemic rats significantly improved in rats treated with both BQ123 and acetaminophen compared to BQ123 alone. The results demonstrate that a combination of acetaminophen and BQ123 is more effective in reducing the neuronal damage following cerebral ischemia, and this combination may be worth investigating in stroke patients.

Topics: Acetaminophen; Animals; Antipyretics; Brain Ischemia; Disease Models, Animal; Drug Synergism; Endothelin A Receptor Antagonists; Glutathione; Hypothermia, Induced; Infarction, Middle Cerebral Artery; Male; Malondialdehyde; Oxidative Stress; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Stroke

Chronic post-ischemic pain (CPIP) is an animal model of CRPS-I developed using a 3-h ischemia-reperfusion injury of the rodent hind paw. The contribution of local endothelin to nociception has been evaluated in CPIP mice by measuring sustained nociceptive behaviors (SNBs) following intraplantar injection of endothelin-1 or -2 (ET-1, ET-2). The effects of local BQ-123 (ETA-R antagonist), BQ-788 (ETB-R antagonist), IRL-1620 (ETB-R agonist) and naloxone (opioid antagonist) were assessed on ET-induced SNBs and/or mechanical and cold allodynia in CPIP mice. ETA-R and ETB-R expression was assessed using immunohistochemistry and Western blot analysis. Compared to shams, CPIP mice exhibited hypersensitivity to local ET-1 and ET-2. BQ-123 reduced ET-1- and ET-2-induced SNBs in both sham and CPIP animals, but not mechanical or cold allodynia. BQ-788 enhanced ET-1- and ET-2-induced SNBs in both sham and CPIP mice, and cold allodynia in CPIP mice. IRL-1620 displayed a non-opioid anti-nociceptive effect on ET-1- and ET-2-induced SNBs and mechanical allodynia in CPIP mice. The distribution of ETA-R and ETB-R was similar in plantar skin of sham and CPIP mice, but both receptors were over-expressed in plantar muscles of CPIP mice. This study shows that ETA-R and ETB-R have differing roles in nociception for sham and CPIP mice. CPIP mice exhibit more local endothelin-induced SNBs, develop a novel local ETB-R agonist-induced (non-opioid) analgesia, and exhibit over-expression of both receptors in plantar muscles, but not skin. The effectiveness of local ETB-R agonists as anti-allodynic treatments in CPIP mice holds promise for novel therapies in CRPS-I patients.

Topics: Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelins; Hyperalgesia; Keratinocytes; Male; Mice; Muscle, Skeletal; Naloxone; Narcotic Antagonists; Oligopeptides; Pain Measurement; Pain Threshold; Peptide Fragments; Peptides, Cyclic; Peripheral Nervous System; Physical Stimulation; Piperidines; Receptors, Endothelin; Reflex Sympathetic Dystrophy; Skin

We investigated the effect of BQ-123, a selective endothelin-A (ET(A)) receptor antagonist in ischemia-reperfusion (IR) induced myocardial infarction (MI) with and without endothelin-1 (ET-1) challenge. MI was produced in rats by occlusion of left anterior descending coronary artery for 40 min and reperfusion for 120 min. ET-1 was administered immediately prior to coronary occlusion whereas vehicle or BQ-123 was administered 20 min after the occlusion. IR control group exhibited marked hemodynamic changes along with significant impairment of left ventricular functions. In addition, oxidative stress was increased, as evidenced by marked reduction in the activities of antioxidants and cardiac injury markers in myocardium. Furthermore, light microscopic and ultrastructural changes revealed myocardial necrosis, edema and inflammation. Prior administration of ET-1 acts synergistically with IR injury and further aggravates the impairment of ventricular functions, increased percent infarct area and decreased antioxidant levels. However, treatment with BQ-123 (1 mg/kg, IV) with or without ET-1 caused significant improvement in cardiac functions, percent infarct area, decreased malonaldehyde level, restored myocardial enzymes activities and maintained the redox status of the myocardium as compared to IR control group. Further, histopathological and ultrastructural studies reconfirmed the protective action of BQ-123. The results of present study suggest that ET-1 acting via ET(A) receptor may exaggerate myocardial damage produced by IR injury and selective blockade of ET(A) receptor by BQ-123 might offer potential cardioprotective action.

Topics: Animals; Antioxidants; Cardiotonic Agents; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Hemodynamics; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Peptides, Cyclic; Rats; Rats, Wistar; Receptor, Endothelin A; Ventricular Function, Left

Endothelin-1 (ET-1) is thought to play a pivotal role in pulmonary edema formation. The underlying mechanisms remain uncertain but may include alterations in capillary pressure and vascular permeability. There are no studies investigating whether ET-1 also affects alveolar fluid clearance which is the primary mechanism for the resolution of pulmonary edema. Therefore, we performed this study to clarify effects of ET-1 on alveolar reabsorption and fluid balance in the rat lung.. Alveolar fluid clearance was measured in fluid instilled rat lungs using a 5% albumin solution with or without ET-1 (10(-7) M) and/or amiloride (100 microM). Net alveolar fluid balance, time course of edema formation, pulmonary capillary pressure, and alveolar permeability to albumin were measured in the isolated, ventilated, constant pressure perfused rat lung with or without ET-1 (0.8 nM) added to the perfusate.. In the fluid-instilled lung, ET-1 reduced alveolar fluid clearance by about 65%, an effect that was related to a decrease in amiloride-sensitive transepithelial Na(+) transport (P < 0.001). The ET-1-induced inhibition was completely prevented by the endothelin B receptor antagonist BQ788 (P = 0.006), whereas the endothelin A receptor antagonist BQ123 had no effect (P = 0.663). In the isolated, ventilated, perfused rat lung ET-1 caused a net accumulation of alveolar fluid by about 20% (P = 0.011 vs control), whereas lungs of control rats cleared about 20% of the instilled fluid. ET-1 increased pulmonary capillary pressure (+9.4 cm H(2)O), decreased perfusate flow (-81%), accelerated lung weight gain and reduced lung survival time (P < 0.001). Permeability to albumin was not significantly affected by ET-1 (P = 0.24).. ET-1 inhibits alveolar fluid clearance of anesthetized rats by inhibition of amiloride-sensitive epithelial Na(+) channels. The inhibitory effect of ET-1 results from activation of the endothelin B receptor. These findings suggest a mechanism by which ET-1, in addition to increasing capillary pressure, contributes to pulmonary edema formation.

Topics: Albumins; Amiloride; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Capillaries; Capillary Permeability; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epithelial Sodium Channel Blockers; Epithelial Sodium Channels; Extravascular Lung Water; Hydrostatic Pressure; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Alveoli; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sodium Channel Blockers; Time Factors; Vasoconstriction

Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. However, no abnormalities in the vascular responsiveness to ET-1 have been identified in the chronic stage of type 2 diabetes. Our goal was to look for abnormalities in the roles played by ET receptors (ET(A) and ET(B)) in the mesenteric artery of the type 2 diabetic Goto-Kakizaki (GK) rat and to identify the molecular mechanisms involved. Using mesenteric arteries from later-stage (32-38 wk old) individuals, we compared the ET-1-induced contraction and the relaxation induced by the selective ET(B) receptor agonist IRL1620 between GK rats and control Wistar rats. Mesenteric artery ERK activity and the protein expressions for ET receptors and MEK were also measured. In GK rats (vs. age-matched Wistar rats), we found as follows. 1) The ET-1-induced contraction was greater and was attenuated by BQ-123 (ET(A) antagonist) but not by BQ-788 (ET(B) antagonist). In the controls, BQ-788 augmented this contraction. 2) Both the relaxation and nitric oxide (NO) production induced by IRL1620 were reduced. 3) ET-1-induced contraction was enhanced by N(G)-nitro-l-arginine (l-NNA; NO synthase inhibitor) but suppressed by sodium nitroprusside (NO donor). 4) The enhanced ET-1-induced contraction was reduced by MEK/ERK pathway inhibitors (PD-98059 or U0126). 5) ET-1-stimulated ERK activation was increased, as were the ET(A) and MEK1/2 protein expressions. 6) Mesenteric ET-1 content was increased. These results suggest that upregulation of ET(A), a defect in ET(B)-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism mediating the hyperreactivity to ET-1 examined in this study.

Topics: Angiotensin II; Animals; Arginine Vasopressin; Butadienes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Male; MAP Kinase Kinase Kinases; Mesenteric Arteries; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitriles; Nitroarginine; Nitroprusside; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction; Vasoconstriction; Vasodilation

We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ET(A)) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 +/- 2 to 137 +/- 4 mmHg; P < 0.005) but did not change in sham-exposed rats. The ET(A) receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol.kg(-1).day(-1) sc for 14 days) prevented E-IH-induced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ET(A) receptor antagonist BQ-123 (10 microM) but not by the ET type B (ET(B)) receptor antagonist BQ-788 (100 microM). ET(A) receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ET(B) receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ET(A) receptors appears to elevate blood pressure in E-IH-exposed rats.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension; Hypoxia; Infusions, Parenteral; Male; Mesenteric Arteries; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renal Artery; Time Factors; Vasoconstriction

In this study, we investigated the effects of the selective ET(A) (BQ-123) and ET(B) (BQ-788) receptor antagonists for endothelin-1 (ET-1) against several flogistic agent-induced paw edema formation and ovalbumin-induced allergic lung inflammation in mice. The intraplantar injection of BQ-123, but not BQ-788, significantly inhibited carrageenan-, PAF-, ET-1- and bradykinin-induced paw edema formation. The obtained inhibitions (1h after the inflammatory stimulus) were 79+/-5%, 55+/-4%, 55+/-6% and 74+/-4%, respectively. In carrageenan-induced paw edema, the mean ID(50) value for BQ-123 was 0.77 (0.27-2.23)nmol/paw. The neutrophil influx induced by carrageenan or PAF was reduced by BQ-123, with inhibitions of 55+/-2% and 72+/-4%, respectively. BQ-123 also inhibited the indirect macrophage influx induced by carrageenan (55+/-6%). However, BQ-788 failed to block the cell influx caused by either of these flogistic agents. When assessed in the bronchoalveolar lavage fluid in a murine model of asthma, both BQ-123 and BQ-788 significantly inhibited ovalbumin-induced eosinophil recruitment (78+/-6% and 71+/-8%), respectively. Neither neutrophil nor mononuclear cell counts were significantly affected by these drugs. Our findings indicate that ET(A), but not ET(B), selective ET-1 antagonists are capable of preventing the acute inflammatory responses induced by carrageenan, PAF, BK and ET-1. However, both ET(A) and ET(B) receptor antagonists were found to be effective in inhibiting the allergic response in a murine model of asthma.

Topics: Animals; Anti-Allergic Agents; Antihypertensive Agents; Asthma; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Female; Inflammation; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Peptides, Cyclic; Piperidines

Levels of endothelins are particularly high in the lung, and there is evidence that these peptides are involved in asthma. Asthma is a chronic inflammatory disease associated with lymphocyte infiltration. In the present study, we used a murine model of asthma to investigate the role of endothelins in lymphocyte and eosinophil infiltration into the airway hyperreactivity and mucus secretion. Sensitized C57Bl/6 mice were treated with endothelin ETA receptor antagonist (BQ123) or endothelin ETB receptor antagonist (BQ788) 30 min before an antigen aerosol challenge. After 24 h, dose response curves to methacholine were performed in isolated lungs, FACS analysis of lymphocytes and eosinophil counts were performed in bronchoalveolar lavage fluid and mucus index was determined by histopathology. In sensitized and antigen-challenged mice there is a marked increase in the T CD4+, T CD8+, B220+, Tgammadelta+ and NK1.1+ lymphocyte subsets. Treatment with BQ123 further increased these cell populations. The number of eosinophils, airway hyperreactivity and mucus were all reduced by BQ123 treatment. The BQ 788 had no significant effect on the parameters analyzed. Treatment with BQ123 reduced the endothelin concentration in lung homogenates, suggesting that endothelins exert a positive feedback on their synthesis. We show here that in murine asthma the ETA receptor antagonist up-regulates lymphocyte infiltration and reduces eosinophils, hyperreactivity and mucus.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelin A Receptor Antagonists; Eosinophils; Lung; Lymphocyte Subsets; Male; Methacholine Chloride; Mice; Mice, Inbred C57BL; Mucus; Ovalbumin; Peptides, Cyclic

The aim was to investigate the role of endothelin 1 receptor subtypes in the early renal response to lipopolysaccharide (LPS) during normotensive endotoxemia with acute kidney dysfunction. Endotoxemia was induced in thiobutabarbital-anesthetized rats (n = 9 per group) by infusion of LPS (dosage, 1 mg/kg per hour i.v.). The study groups (1) sham-saline, (2) LPS-saline, (3) LPS-BQ123, (4) LPS-BQ788 and (5) LPS-BQ123 + BQ788 received isotonic saline, the ETA receptor antagonist BQ-123 (dosage, 30 nmol/kg per minute i.v.), and/or the ETB receptor antagonist BQ-788 (dosage, 30 nmol/kg per minute i.v.) before and during 2 h of LPS infusion. Renal clearance measurements, renal blood flow (RBF), and cortical and outer medullary perfusion (laser-Doppler flowmetry) and oxygen tension (Clark-type microelectrodes) were analyzed throughout. Before LPS administration, there were no significant differences between groups in glomerular filtration rate (GFR), RBF, or in cortical (CLDF) and outer medullary perfusion. However, mean arterial pressure (MAP) was elevated in LPS-BQ788 group compared with LPS-BQ123 + BQ788 group (P < 0.05). In saline-treated rats, endotoxin induced an approximate 35% reduction in GFR (P < 0.05), without significant effects on MAP, RBF, or on CLDF and cortical PO2. In addition, LPS increased outer medullary perfusion and PO2 (P < 0.05). The fractional urinary excretion rates of sodium, potassium, and water were not significantly different in LPS-saline group compared with sham-saline group. Neither selective nor combined ETA and ETB receptor blockade improved GFR. In BQ-788-infused rats, endotoxin produced marked reductions in RBF (-18% +/- 4% [P < 0.05]) and CLDF (-18% +/- 2% [P < 0.05]). Similarly, endotoxin decreased RBF (-14% +/- 3% [P < 0.05]) and CLDF (-10% +/- 2% [P < 0.05]) in LPS-BQ123 + BQ788 group. Endotoxin reduced MAP (-22% +/- 4% [P < 0.05]) in BQ-123-treated rats but did not significantly influence MAP in other groups. We conclude that in early normotensive endotoxemia, ETB receptors exert a renal vasodilator influence and contribute to maintain normal RBF.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Disease Models, Animal; Endothelin B Receptor Antagonists; Endothelin-1; Endotoxins; Glomerular Filtration Rate; Lipopolysaccharides; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Renal Circulation; Vasodilation

Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents, results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric oxide-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ETA; atrasentan; 5 mg x kg(-1) x day(-1)) or type B (ET(B); A-192621; 15 or 30 mg x kg(-1) x day(-1)) receptors for 4 wk. Third-order mesenteric arteries were isolated, and vascular function was assessed with a wire myograph. Maximum response to ET-1 was increased in diabetes and attenuated by ETA antagonism. ETB blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls, whereas it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ETA-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ETB antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ETA receptor blockade attenuates vascular dysfunction and that ETB receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state.

Topics: Acetylcholine; Animals; Atrasentan; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Male; Mesenteric Arteries; Microcirculation; Myography; Peptides, Cyclic; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Viper Venoms

Vascular remodeling, rather than vasoconstriction, is believed to account for high vascular resistance in severe pulmonary arterial hypertension (PAH). We have found previously that acute Rho kinase inhibition nearly normalizes PAH in chronically hypoxic rats that have no occlusive neointimal lesions. Here we examined whether Rho kinase-mediated vasoconstriction was also important in a rat model of severe occlusive PAH. Adult rats were exposed to chronic hypoxia ( approximately 10% O(2)) after subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SUGEN 5416. Hemodynamic measurements were made in anesthetized rats after 2 weeks of hypoxia (early group) and 3 weeks of hypoxia plus 2 weeks of normoxia (late group). Both groups developed PAH, with greater severity in the late group. In the early group, intravenous fasudil was more effective than intravenous bradykinin, inhaled NO, or intravenous iloprost in reducing right ventricular systolic pressure. Despite more occlusive vascular lesions, fasudil also markedly reduced right ventricular systolic pressure in late-stage rats. Blood-perfused lungs from late-stage rats showed spontaneous vasoconstriction, which was reversed partially by the endothelin A receptor blocker BQ123 and completely by fasudil or Y-27632. Phosphorylation of MYPT1, a downstream target of Rho kinase, was increased in lungs from both groups of rats, and fasudil (intravenous) reversed the increased phosphorylation in the late group. Thus, in addition to structural occlusion, Rho kinase-mediated vasoconstriction is an important component of severe PAH in SUGEN 5416/hypoxia-exposed rats, and PAH can be significantly reduced in the setting of a severely remodeled lung circulation if an unconventional vasodilator is used.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Disease Models, Animal; Disease Progression; Endothelin A Receptor Antagonists; Hypertension, Pulmonary; Hypoxia; Indoles; Intracellular Signaling Peptides and Proteins; Male; Myosin-Light-Chain Phosphatase; Organ Culture Techniques; Peptides, Cyclic; Phosphorylation; Protein Serine-Threonine Kinases; Pulmonary Artery; Pyrroles; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Vascular Endothelial Growth Factor Receptor-2; Vasoconstriction; Vasodilator Agents

The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ET(A)), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Post-incisional mechanical hyperesthesia was evaluated by cutaneous trunci muscle reflexes (CTMR) of subcutaneous muscles responding to stimulation with von Frey filaments near the wound (primary responses) and at a distance, especially on the contralateral dorsum (secondary responses, involving spinal circuits). The role of ET(A) was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24h before surgery. Control incisions showed both primary tactile allodynia and hyperalgesia, and a weaker secondary hyperesthesia, peaking 3-4h after surgery and lasting at least 24h. Primary allodynia, but not hyperalgesia, was dose-dependently suppressed by 15 min pre-incisional BQ-123. In contrast, both secondary allodynia and hyperalgesia were inhibited by local BQ-123. The suppression of primary allodynia by local antagonist disappeared in 24h, but that of secondary hyperesthesia remained strong for at least 24h. Systemically delivered BQ-123 was without effect on any post-incisional hyperesthesia, and if the antagonist was locally injected 24h before surgery there was no difference on hyperesthesia compared to vehicle injected at that time. We conclude that ET-1, released from skin by incision, activates nociceptors to cause primary allodynia and to sensitize spinal circuits through central sensitization. Blockade of ET(A) in the immediate peri-operative period prevents the later development of central sensitization.

Topics: Animals; Disease Models, Animal; Endothelin A Receptor Antagonists; Functional Laterality; Hyperesthesia; Male; Pain Measurement; Pain Threshold; Pain, Postoperative; Peptides, Cyclic; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Skin; Time Factors

Heart failure (HF) is a multifactorial and progressive disease that has been associated with multiple systemic and vascular alterations. Previous reports from our laboratory showed that in 2-month-old Bio-To2 Syrian cardiomyopathic hamsters (SCH) that have not yet developed the clinical manifestations of HF, the vascular contractility induced by 0.1 microM angiotensin II was approximately 35% greater than in control animals. This finding was observed concomitantly with an increased aortic ACE activity. To further evaluate the mechanisms underlying angiotensin II-enhanced vascular contraction, concentration-response curves for angiotensin II (0.01 nM-10 microM) were constructed before and after the addition of prazosin (alpha-1 blocker), NS-398 (selective COX-2 blocker) and BQ-123 (ET-1A-receptor antagonist) in aortic rings from 2-month-old SCH. The binding capacity and affinity of the AT-1 receptors were also evaluated in aortic homogenates using 125I-angiotensin II. Age-matched golden hamsters were used as controls (CT). Our results indicate that incubation with either 10 microM prazosin or 10 microM NS-398 did not modify EC50 or Emax values for angiotensin II indicating that norepinephrine and prostaglandins are not involved in the enhanced contractile action of angiotensin II. However, 10 microM BQ-123 reduced by 40% the contraction induced by 1.0 microM angiotensin II (from 1.05+/-0.04 to 0.6475+/-0.06 g/mg tissue, n = 5, P < 0.05), suggesting that in cardiomyopathic hamsters, the action of angiotensin II is mediated in part by ET-1. At lower angiotensin II concentration (0.1 microM), the ET-1-dependent contraction decreases to 29%. In addition, although dissociation constants for labeled angiotensin II were found to be similar in the aorta of SCH and control animals (K(D): CT = 7.8 nM and SCH = 5.1 nM), 125I-angiotensin II binding capacity was about 2-fold greater in SCH than in controls (Bmax: SCH = 1113 and CT = 605 fmol/mg protein). Altogether these results suggest that in 2-month-old SCH the enhanced response of angiotensin II in the vasculature is mediated both by an increased binding capacity for the hormone and facilitation of the ET-1 action.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Binding, Competitive; Cardiomyopathies; Cricetinae; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; In Vitro Techniques; Losartan; Male; Mesocricetus; Peptides, Cyclic; Protein Binding; Receptor, Angiotensin, Type 1; Receptor, Endothelin A; Vasoconstriction; Vasoconstrictor Agents

The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 microg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4+/-1.3, carrageenan 21.2+/-3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ET(A) or ET(B) receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3+/-1.8, CION 32.4+/-5.3s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ET(A) (atrasentan, 3-10 mg/kg) or ET(B) (A-192621, 5-20 mg/kg) receptors caused significant inhibitions lasting 1-2.5h (peaks approximately 65-90%). Bosentan (dual ET(A)/ET(B) receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ET(A) and/or ET(B) receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atrasentan; Bosentan; Carrageenan; Celecoxib; Cold Temperature; Dexamethasone; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelin-1; Endothelins; Grooming; Hyperalgesia; Indomethacin; Male; Maxillary Nerve; Nerve Compression Syndromes; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Pyrazoles; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Trigeminal Neuralgia

Regardless of proximal cause, photoreceptor injury or disease almost invariably leads to the activation of Muller cells, the principal glial cells in the retina. This observation implies the existence of signaling systems that inform Muller cells of the health status of photoreceptors. It further suggests that diverse types of photoreceptor damage elicit a limited range of biochemical responses. Using the mouse retina, we show by microarray, RNA blot, and in situ hybridization that the genomic responses to both light damage and inherited photoreceptor degeneration involve a relatively small number of genes and that the genes activated by these two insults overlap substantially with one another and with the genes activated by retinal detachment. Among the induced transcripts, those coding for endothelin2 (Edn2) are unusual in that they are localized to photoreceptors and are also highly induced in all of the tested models of photoreceptor disease or injury. Acute light damage also leads to a >10-fold increase in endothelin receptor B (Ednrb) in Muller cells 24 h after injury. These observations suggest that photoreceptor-derived EDN2 functions as a general stress signal, that EDN2 signals to Muller cells by binding to EDNRB, and that Muller cells can increase their sensitivity to EDN2 as part of the injury response.

Topics: Animals; Annexin A2; Aspartate Carbamoyltransferase; Blotting, Northern; Blotting, Western; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); Ceruloplasmin; Dihydroorotase; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-2; Endothelins; Fluorescent Antibody Technique; Gene Expression Regulation; Genomics; Glial Fibrillary Acidic Protein; Immunohistochemistry; In Situ Hybridization; Intermediate Filament Proteins; Light; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Nerve Tissue Proteins; Neuroglia; Oligonucleotide Array Sequence Analysis; Peptides, Cyclic; Peripherins; Photoreceptor Cells; Protein Binding; Receptors, Endothelin; Retinal Diseases; Signal Transduction; Time Factors

Despite obvious participation of endothelins in pathogenesis of heart failure therapeutic approaches to the use of endothelin receptor antagonists remain to be elucidated. Experimental heart failure caused by prolonged infusion of norepinephrine is associated with diminished endothelin induced coronary constricting effect of stimulation of ET(A) receptors and inversion of coronary dilating effect of stimulation of these receptors. The latter effect is mediated by smooth muscle ET(B)-receptors and is indicative of functional derangement of vascular control by endothelial cells. The use of selective ET(A)-antagonist is effective on early stages of heart failure while on later stages administration of nonselective ET(AB)-antagonist produces more pronounced effect.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Coronary Vessels; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelium, Vascular; Heart Failure; In Vitro Techniques; Norepinephrine; Oligopeptides; Peptides, Cyclic; Rats; Vasoconstriction; Ventricular Function, Left

Evidence has indicated that endothelin-1 is related to the pathogenesis of hypertension. To characterize the role of endothelin-1 (ET-1) in the development of pulmonary hypertension syndrome in broilers, the blockade effect of ETA receptor (ET(A)) antagonist, BQ123, on blood pressure in experimental models of pulmonary hypertension was examined. Birds were locally anesthetized and instrumented with venous catheters for pulmonary arterial pressure (PAP) and right ventricular pressure (RVP), followed by packed cell volume (PCV) and Ascites heart index (AHI) measured, after exposed to low ambient temperature for 7 or 14 d. In treated groups, BQ123 (0.4 or 2.0 microg each time, 2 times a day), administered in abdominal cavities for 7 or 14 d during birds kept in low ambient temperature, prevented both PAP and RVP increasing, especially the high dose BQ123 lowered PAP and RVP to normotensive levels as that in control under normal temperature, whereas significant increases (p<0.05) were found in the two parameters of broilers in both untreated and saline treated group under low ambient temperature compared with those of birds in control. Furthermore, there was also a reduction in low ambient temperature-induced right ventricular hypertrophy in the groups administered BQ123. The preventive effect of BQ123 suggests that ET-1 is associated with the development of broilers' pulmonary hypertension, which leads to the development of ascites, and BQ123 can prevent the occurrence of pulmonary hypertension.

Topics: Age Factors; Animals; Antihypertensive Agents; Blood Pressure Determination; Chickens; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelin A Receptor Antagonists; Environmental Exposure; Hematocrit; Hypertension, Pulmonary; Male; Peptides, Cyclic; Pulmonary Artery; Temperature; Time Factors; Ventricular Function, Right

Endothelin receptors have been involved in inflammatory, neuropathic and tumoral pain. In the case of inflammatory hyperalgesia, some previous papers have pointed towards the involvement of ETB receptors, although the stimulation of ETA receptors seems to participate in the development of the inflammatory reaction. We have studied the effect of ETA and ETB receptor antagonists in the thermal and mechanical hyperalgesia induced in a model of acute (induced by carrageenan) and chronic (induced by complete Freund's adjuvant, CFA) inflammation in mice. The i.pl. administration of the selective ETA antagonist BQ-123 (1-10 nmol) antagonized the thermal hyperalgesia detected by the unilateral hot plate test, observed in both inflammatory models, whereas the i.pl. administration of the ETB selective antagonist BQ-788 (17.7 nmol) failed to modify this. In contrast, both BQ-123 (3-17.7 nmol) and BQ-788 (3-17.7 nmol) antagonized the mechanical hyperalgesia, as assessed by the Randall-Selitto test in carrageenan- and CFA-treated mice. Both BQ-123 and BQ-788 were able to antagonize the mechanical hyperalgesia induced by ET-1 (200 pmol; i.pl.) in the same dose range. Thus, ETA receptors are involved in both thermal and mechanical hyperalgesia whereas ETB receptors are only involved in mechanical hyperalgesia in these inflammatory models. In conclusion, the role of ETB receptors in inflammatory pain is further supported and new insights into the participation of ETA receptors in inflammatory hyperalgesia are given.

Topics: Animals; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Inflammation; Male; Mice; Oligopeptides; Pain Measurement; Peptides, Cyclic; Physical Stimulation; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors

Endothelin peptides play active roles in different aspects of inflammation. This study investigates the contribution of endogenous endothelins to lipopolysaccharide (LPS) pulmonary inflammation by assessing the influence of ET(A) receptor antagonism on leukocyte accumulation, granulocyte adhesion molecule expression, and chemokine/cytokine modulation. Local pretreatment with BQ-123 or A-127722 (150 pmol), two selective and chemically unrelated endothelin ET(A) receptor antagonists, inhibits neutrophil and eosinophil accumulation in LPS-induced pleurisy at 24 h but not neutrophil migration at 4 h. The effect of endothelin antagonism on neutrophil accumulation at 24 h was concomitant with inhibition of eosinophil and CD4 and CD8 T lymphocyte influx. It is surprising that the ET(A) receptor blockade did not inhibit the accumulation of gammadelta T lymphocytes, cells that are important for granulocyte recruitment in this model. Blockade of ET(A) receptors did not influence the expression of adhesion molecules (CD11b, CD49d) on granulocytes but abrogated the increase in tumor necrosis factor alpha levels 4 h after LPS stimulation and also markedly inhibited increases in levels of interleukin-6 and keratinocyte-derived chemokine/CXC chemokine ligand 1 but not eotaxin/chemokine ligand 11. Thus, acting via ET(A) receptors, endogenous endothelins play an important role in early cytokine/chemokine production and on granulocyte and lymphocyte mobilization in LPS-induced pleurisy.

Topics: Animals; Antihypertensive Agents; Atrasentan; Cell Adhesion Molecules; Chemokines; Chemotaxis, Leukocyte; Disease Models, Animal; Endothelin A Receptor Antagonists; Granulocytes; Inflammation; Lipopolysaccharides; Lung; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Peptides, Cyclic; Pleurisy; Pyrrolidines

Several neurotransmitter mechanisms have been proposed as playing a role in the development of morphine tolerance. We provide evidence for the first time that endothelin antagonists can restore morphine analgesia in morphine-tolerant rats and prevent the development of tolerance to morphine. Studies were carried out in rats and mice treated with implanted placebo or implanted morphine pellet. The maximal tail-flick latency in morphine pellet + vehicle-treated rats (7.54 seconds) was significantly lower when compared with placebo pellet + vehicle-treated rats (10 seconds), indicating that tolerance developed to the analgesic effect of morphine. BQ123 potentiated tail-flick latency by 30.0% in placebo-tolerant rats and 94.5% in morphine-tolerant rats compared with respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo-tolerant rats and 66.7% in morphine-tolerant rats. The enhanced analgesic effect of morphine after treatment with endothelin antagonists could be blocked by naloxone, indicating an opiate-mediated effect; but naloxone binding to brain membranes was not affected by BQ123. Guanosine triphosphate binding was stimulated by morphine and endothelin-1 in non-tolerant mice and not in morphine-tolerant mice; however, guanosine triphosphate binding was stimulated by BQ123 in morphine-tolerant mice and was unaffected in non-tolerant mice. These results suggest that uncoupling of G-protein occurs in morphine tolerance and endothelin antagonist restores the coupling of G-protein to its receptors. A combination use of endothelin antagonist and opiates could provide a novel approach in improving analgesia and eliminating tolerance.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dansyl Compounds; Disease Models, Animal; Drug Therapy, Combination; Drug Tolerance; Endothelin A Receptor Antagonists; Guanosine 5'-O-(3-Thiotriphosphate); Injections, Intraventricular; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Opioid, mu; Sulfur Radioisotopes; Time Factors

Endothelin-1 (ET-1) in the central nervous system has been suggested to produce suppressive effects on pain transmission. We investigated the manner by which ET-1 exerts this action. ET-1 administered intracerebroventricularly produced a dose-dependent antinociceptive effect in a thermal pain test that utilized a spinal reflex to determine nociceptive thresholds. This suggested that the antinociceptive effect of ET-1 involved a descending pain inhibitory system. The antinociceptive effect was blocked by an ETA receptor antagonist but not by an ETB receptor antagonist, indicating that the action was mediated through the ETA receptor. Antagonists of opioid receptors, serotonin receptors, alpha-2 adrenergic receptors, oxytocin receptors, and dopamine receptors did not block the antinociceptive effect of ET-1. Thus, major descending inhibitory systems were probably not involved. The antinociceptive effect was blocked by intracerebroventricular administration of an alpha-1 adrenergic receptor antagonist. This indicated that the antinociceptive effect involved the activation of a supraspinal noradrenergic pathway, which in turn may activate a still unknown descending pain inhibitory system.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Analgesics, Non-Narcotic; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Neural Inhibition; Neural Pathways; Oligopeptides; Pain; Pain Measurement; Pain Threshold; Peptides, Cyclic; Piperidines; Prazosin; Reaction Time; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Adrenergic, alpha-1; Yohimbine

Renal vasoconstriction with resultant tissue hypoxia, especially in the renal medulla, has been suggested to play a role in contrast media (CM)-induced nephropathy. Endothelin (ET) is released into the blood stream following CM injection and has been proposed as a potential mediator through its vasoconstrictive properties.. To investigate the possible protective influence of ET-receptor antagonists against CM-induced reduction in renal function, we studied the effects of injection of iopromide with and without pretreatment with BQ123 (ET-A antagonist) or BQ788 (ET-B antagonist) on renal superficial cortical flow (CBF), outer medullary blood flow (OMBF) and outer medullary oxygen tension (pO2) in normal rats.. Administration of CM (1600 mg I/kg b.w.) did not affect CBF in any of the groups. However, a transient decrease in OMBF occurred, which was unaffected by both BQ123 and BQ788. Also a transient decrease in outer medullary pO2 was induced by CM administration. The pO2 reduction was significantly smaller after pretreatment with BQ123, than after injection of CM alone or together with BQ788, and pO2 returned more rapidly to the control level. Neither receptor antagonist had an effect on CM-mediated increases in electrolyte excretion.. In the normal rat, activation of ET-A receptors is partly involved in the depression of outer medullary pO2 caused by injection of iopromide. However, the decrease in OMBF after iopromide injection is not mediated by ET receptors. The beneficial effects of the ET-A receptor antagonist on CM-induced changes in outer medullary pO2 seem therefore not primarily mediated on the hemodynamic level but may rather involve tubular transport mechanisms.

Topics: Animals; Antihypertensive Agents; Contrast Media; Disease Models, Animal; Endothelin Receptor Antagonists; Hypoxia; Iohexol; Kidney Diseases; Kidney Medulla; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Renal Circulation

Subarachnoid hemorrhage (SAH) leads to the development of vasospasm in which endothelin-1 plays a very important role. The effect of its vasoconstricting action is hypoxia of the nervous tissue, which stimulates the release of growth factors. Vascular endothelial growth factor (VEGF) released in excessive amounts from hypoxically altered cerebrovascular endothelial cells is the most potent angiogenic factor and may enhance angiogenesis after SAH. If endothelin-1 is mainly responsible for vasospasm after SAH, it is possible that early administration of endothelin converting enzyme inhibitor or endothelin receptor antagonist may protect neurons against. The aim of the study was to establish whether prolonged vasospasm and endothelial cell hypoxia stimulate VEGF expression and, in consequence, promote angiogenesis in the central nervous system after subarachnoid hemorrhage. Investigations were also performed to determine whether the administration of phosphoramidon, an endothelin-converting enzyme (ECE) inhibitor, and BQ-123, an endothelin receptor ET(A) antagonist, suppresses angiogenesis and VEGF expression. Experiments were carried out in male Wistar rats injected with phosphoramidon or BQ-123 into the cisterna magna following the induction of subarachnoid hemorrhage. The brains were removed 48 h after the hemorrhage for histopathological and immunohistochemical examinations of VEGF expression and angiogenesis in the cerebral hemispheres, brainstem, and cerebellum. Statistical analysis was performed using nonparametric Wilcoxon test (P<0.05). The results obtained have shown for the first time a close correlation between endothelial hypoxia after SAH in cerebral microvessels and enhanced angiogenesis. There is also an increase in VEGF expression in cerebral vessels and neurons within the cerebral hemispheres, brainstem, and cerebellum. The administration of phosphoramidon or BQ-123 has been found to inhibit angiogenesis. Angiogenesis in the chronic phase of SAH-induced vasospasm is the result of prolonged narrowing of vessels due to excessive secretion of endothelin by damaged endothelial cells. Present results obtained indicate that it is possible to reduce or prevent the late effects of SAH, i.e., neuronal hypoxia and cerebral edema, through the inhibition of endothelin-1 induced vasospasm.

Topics: Animals; Antihypertensive Agents; Cell Count; Cerebral Cortex; Disease Models, Animal; Endothelial Growth Factors; Glycopeptides; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Neovascularization, Physiologic; Peptides, Cyclic; Protease Inhibitors; Rats; Rats, Wistar; Subarachnoid Hemorrhage; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

In the present study, we examined cardiac and regional haemodynamic effects of endothelin-1 (ET-1), a potent vasoconstrictive factor, in a rat model of pressure-controlled irreversible haemorrhagic shock resulting in the death of all control animals within 30 min. Experiments were carried out in male ethylurethane-anaesthetised Wistar rats subjected to hypotension of 20-25 mmHg, which resulted in bradycardia, an extreme decrease in cardiac index (CI) and an increase in total peripheral resistance index (TPRI), with reductions in renal (RBF), hindquarters (HBF) and mesenteric blood flow (MBF). ET-1 (50, 200 pmol/kg) administered intravenously at 5 min of critical hypotension produced increases in mean arterial pressure (MAP) and heart rate (HR), which were significantly higher than those in normotensive animals, and a 100% survival at 2 h after treatment. The effects were accompanied by a rise in CI, a decrease in TPRI, with increases in RBF and HBF and persistently lowered MBF, and an increase in circulating blood volume 20 min after treatment. The cardiovascular effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 (1 mg/kg), while the ETB receptor antagonist BQ-788 (3 mg/kg) had no effect. In conclusion, ET-1 acting via ETA receptors produces reversal of haemorrhagic hypotension in rats due to the mobilisation of blood from venous reservoirs, with the improvements in cardiac function and the perfusion of peripheral tissues.

Topics: Animals; Blood Pressure; Bradycardia; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Hemorrhage; Hindlimb; Hypotension; Injections, Intravenous; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Renal Circulation; Shock, Hemorrhagic; Sodium Chloride; Splanchnic Circulation; Time Factors; Vascular Resistance

The role of endothelin-1 (ET-1) in the development of experimental autoimmune encephalomyelitis (EAE) was studied by the blocking the action of ET-1 with a receptor antagonist, BQ-123. Intrathecal administration of BQ-123 significantly ameliorated EAE progression at the peak stage of EAE (p<0.05). By immunohistochemistry, ED-1-positive macrophages in EAE lesions were identified as major producers of ET-1, whereas the immunoreactivity of ET-1 on brain cells, such as astrocytes, was dramatically increased in accordance with the progression of EAE. This study points to a putative pro-1nflammatory role for ET-1 in the pathogenesis of EAE. One possible application for the ET-1 receptor antagonist might be helpful in the therapy of autoimmune neurological disorders.

Topics: Animals; Antihypertensive Agents; Astrocytes; Blood Vessels; Demyelinating Diseases; Disease Models, Animal; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Endothelin Receptor Antagonists; Endothelin-1; Female; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Spinal; Male; Nerve Degeneration; Peptides, Cyclic; Rats; Rats, Inbred Lew; Receptors, Endothelin; Spinal Cord; Treatment Outcome

The aim of this study was to assess the role of nitric oxide (NO) and endothelin (ET)-1 in the pathophysiology of persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created congenital diaphragmatic hernia (CDH). The pulmonary vascular response to various agonists and antagonists was assessed in vivo between 128 and 132 days gestation. Age-matched fetal lambs served as control animals. Control and CDH lambs had similar pulmonary vasodilator responses to acetylcholine, sodium nitroprusside, zaprinast, and dipyridamole. The ET(A)-receptor antagonist BQ-123 caused a significantly greater pulmonary vasodilatation in CDH than in control animals. The ET(B)-receptor agonist sarafotoxin 6c induced a biphasic response, with a sustained pulmonary vasoconstriction after a transient pulmonary vasodilatation that was not seen in CDH animals. We conclude that the NO signaling pathway in vivo is intact in experimental CDH. In contrast, ET(A)-receptor blockade and ET(B)-receptor stimulation significantly differed in CDH animals compared with control animals. Imbalance of ET-1-receptor activation favoring pulmonary vasoconstriction rather than altered NO-mediated pulmonary vasodilatation is likely to account for persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created CDH.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Cyclic GMP; Dipyridamole; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Nitric Oxide; Nitroprusside; Peptides, Cyclic; Phosphodiesterase Inhibitors; Pregnancy; Pulmonary Circulation; Purinones; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep; Vasoconstrictor Agents; Vasodilator Agents; Viper Venoms

The study was designed to investigate the effects of acetylcholine (ACh) on pulmonary circulation with special regard to mediators that could be involved in the mediation of ACh-induced effects. ACh has been reported to induce either vasodilation or vasoconstriction in the pulmonary circulation of different species.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. Sixty-six adult rabbits of either sex.. The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. ACh was injected in various concentrations after pulmonary artery preconstriction and in untreated lungs.. Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. Perfusate samples were taken intermittently to determine endothelin-1 (ET-1), thromboxane A2 (TXA2), and prostacyclin (PGI2) concentrations. ACh in final dosages from 10(-5) to 10(-2) M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10(-5) M) was administered in additional experiments after pretreatment with either ETA receptor antagonist BQ123 (10(-6) M; n = 6) or the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). In preconstricted pulmonary vessels, ACh (10(-3) and 10(-2) M) initially induced a PAP rise for 10 mins followed by a sustained decrease. In untreated lungs, ACh induced an immediate dose-dependent increase in PAP, requiring as long as 30 mins to return to predrug levels. Simultaneously, significantly elevated TXA2 and PGI2 levels were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10(-5) M)-induced PAP increase and the release of TXA2 and PGI2. At 5 mins, the PAP maximum was reduced from 18.5 +/- 3.2 mm Hg to 9.9 +/- 0.65 mm Hg by BQ123 pretreatment (p < .01). An inhibition of PAP increase was also observed after diclofenac pretreatment (11.6 +/- 0.4 mm Hg at 5 mins; p < .05). Inhibitory effects at 5 mins were significantly more pronounced in the BQ123 group compared with the diclofenac group.. The effects of ACh on the pulmonary circulation of isolated rabbit lungs depend on ACh concentration and the basal tone of the arterial vasculature. In lungs with a normal pulmonary vascular resistance, ACh administration causes vasoconstriction via the release of ET-1 and TXA2, whereas vasodilation is induced in preconstricted pulmonary vessels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Female; Hypertension, Pulmonary; In Vitro Techniques; Male; Peptides, Cyclic; Pulmonary Circulation; Pulmonary Wedge Pressure; Rabbits; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

We attempted to determine the role of endothelin in a previously characterized animal model of preeclampsia by studying the effect of a specific endothelin antagonist, BQ123, on blood pressure.. A preeclampsia-like condition was induced by infusing pregnant rats with the nitric oxide synthase inhibitor N(G)-nitro-L -arginine methyl ester. Osmotic minipumps were inserted subcutaneously into timed pregnant Harlan-Sprague-Dawley rats on day 17 of pregnancy (term, 22 days). The pumps were loaded to continuously deliver either vehicle (control group) or N(G)-nitro-L -arginine methyl ester 50 mg/d, either alone or with BQ123 at 0.5 mg/d. In a similar but separate experiment, the dose of BQ123 was increased to 1 mg/d. Blood pressure was measured with the tail-cuff method before pump insertion and then daily until postpartum day 2.. Except for a decrease on the day after pump insertion, BQ123 0.5 mg/d had no significant effect on the hypertension induced by N(G)-nitro-L -arginine methyl ester. At the higher dose, however, BQ123 significantly attenuated the increase in blood pressure induced by N(G)-nitro-L -arginine methyl ester during most of the study period.. The effect of nitric oxide inhibition can be successfully attenuated by the use of an endothelin antagonist, thereby supporting the role of endothelin in the hypertension described with the preeclampsialike condition seen in pregnant rats.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelins; Enzyme Inhibitors; Female; Gestational Age; Hypertension; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Peptides, Cyclic; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley

Endothelin (ET)-1 is a potent vasoconstrictor peptide that modulates basal pulmonary vascular resistance (PVR) in the normal ovine fetus and contributes to high PVR after chronic intrauterine pulmonary hypertension. Although high PVR is present in premature lambs with severe hyaline membrane disease (HMD), whether ET-1 plays a role in the pathophysiology of experimental HMD is unknown. To test the hypothesis that ET-1 activity contributes to high PVR in the premature lamb with HMD, we studied the hemodynamic effects of a selective ET(A) receptor antagonist, BQ 123, in 10 animals (gestational age 125 d; 147 d=term). After baseline measurements, animals were intubated, treated with surfactant (Infasurf), and mechanically ventilated with a fraction of inspired oxygen of 1.00 for 8 h. Animals were treated with continuous infusions of either BQ 123 (1 mg/h; treatment group, n=5) or 1% DMSO (control; n=5). Plasma ET-1 levels progressively increased during prolonged ventilation with hyperoxia (0.8+/-0.1 pg/mL, baseline to 6.8+/-2.5 pg/mL, 8 h, p < 0.05). In comparison with control lambs, BQ 123 treatment caused a sustained reduction in pulmonary vascular resistance (0.55+/-0.04 mm Hg mL-(-1) min(-1), control versus 0.18+/-0.04 mm Hg mL(-1) min(-1), BQ 123, p < 0.05), increased left pulmonary artery blood flow (70+/-12 mL/min, control versus 194+/-28 mL/min, BQ 123, p < 0.05), and increased arterial PaO2 (53+/-14 mm Hg, control versus 174+/-71 mm Hg, BQ 123, p < 0.05) 8 h after the onset of ventilation. We conclude that circulating levels of ET-1 increase after delivery of premature lambs with severe HMD, and that selective ET(A) receptor blockade causes sustained improvement in hemodynamics in severe experimental HMD. These studies suggest that ET-1 contributes to the hemodynamic abnormalities in this model of pulmonary hypertension and severe HMD.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Gestational Age; Hemodynamics; Humans; Hyaline Membrane Disease; Infant, Newborn; Oxygen; Peptides, Cyclic; Pulmonary Circulation; Pulmonary Gas Exchange; Receptor, Endothelin A; Respiration, Artificial; Sheep; Vascular Resistance

This study was designed to investigate the effects of the selective endothelin-A receptor antagonist BQ123 on myocardial and endothelial function after reversible deep hypothermic ischemia and reperfusion.. Isogenic intra-abdominal heterotopic heart transplantation was performed in Lewis rats. After one hour of cold ischemic preservation reperfusion was started after application of either saline vehicle or BQ123 (1 micromol/L). Left-ventricular pressure-volume relations and myocardial blood flow were assessed after one and 24 hours of reperfusion. Responses to endothelium-dependent vasodilator acetylcholine and endothelium-independent vasodilator sodium nitroprusside were also determined.. BQ123 significantly improved myocardial contractility, as indicated by the leftward shift of the systolic pressure-volume relation and significantly increased myocardial blood flow during early reperfusion (p < 0.05). Although myocardial function and baseline myocardial blood flow were similar in both groups after 24 hours of reperfusion, endothelium-dependent vasodilatation was still significantly higher in the BQ123 group (p < 0.05).. These results suggest that endothelin-A receptor antagonists may be useful in reducing ischemia/reperfusion injury after heart transplantation by preservation of myocardial and endothelial function.

Topics: Animals; Disease Models, Animal; Endothelin Receptor Antagonists; Heart; Heart Arrest, Induced; Heart Transplantation; Hypothermia, Induced; Myocardial Reperfusion Injury; Peptides, Cyclic; Rats; Rats, Inbred Lew; Transplantation, Heterologous; Ventricular Function, Left

Endothelin-1, unlike the selective endothelin ETB receptor agonist sarafotoxin S6c, causes nociception in the rat when injected intraarticularly into the naive knee-joint. By using selective antagonists, the present study further characterizes the receptors underlying the articular nociceptive actions of endothelin-1, as well as the possible contribution of endogenous endothelins towards nociception induced by carrageenan or E. coli lipopolysaccharide (LPS) in this tissue. Nociception was evaluated by placing the animal for 1 min each hour on a revolving (3 rpm) cylinder and measuring the increase in time the hindpaw of the limb affected by the intra-articular (i.a.) injection of the nociceptive agent, failed to touch its metallic surface (i.e. paw elevation time, PET). In naive joints, endothelin-1 (120 pmol) increased the area under the PET curve (AUC 0-6 h, in arbitrary units) from 61+/-3 (control) to 156+/-12. This nociceptive effect was reduced by prior intravenous (i.v.) injection of the mixed ET(A)/ET(B)receptor antagonist bosentan (by 54 and 73% with 10 and 30 mg/kg) or i.a. administration of the selective ETA receptor antagonist BQ-123 (cyclo [D-Asp-Pro-D-Val-Leu]; by approximately/= 45% with 10 or 30 nmol), but was unaffected by the selective ET(B) receptor antagonist BQ-788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-gamma-methoxycarbonyl- tryptophanil-D-norleucine; 10 nmol). Prior joint challenge with carrageenan (300 microg) 72 h beforehand (i.e. priming) rendered the joint more sensitive to nociception induced by either endothelin-1 or sarafotoxin S6c (15, 30 and 60 pmol). Responses elicited by endothelin (30 pmol) in the primed joint were sensitive to inhibition by either BQ-123 or BQ-788 (each causing approximately/= 80% inhibition at 10 nmol). Priming also enhanced PET responses to carrageenan itself and to LPS (1 microg) markedly and persistently, increasing the area under the curve (AUC 0-12 h, in arbitrary units) from 241+/-19 to 409+/-50 and from 312+/-40 to 466+/-25, respectively (P < 0.05), without changing that measured following vehicle injection (from 121+/-3 to 117+/-4). Bosentan (up to 30 mg/kg, i.v.) failed to modify nociception caused by carrageenan or LPS in naive joints, by carrageenan in the primed joint, or control PET responses. LPS-induced nociception in the primed joint, however, was inhibited by 52 to 56% by bosentan (3 or 10 mg/kg) or 59% by local injection of the selective endothelin ET(B) receptor antagonist BQ-788 (1

Topics: Animals; Antihypertensive Agents; Arthritis, Reactive; Bosentan; Carrageenan; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Excipients; Knee Joint; Lipopolysaccharides; Male; Nociceptors; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Sulfonamides; Vasoconstrictor Agents; Viper Venoms

1. The aim of the study was to visualize endothelin-1 (ET-1)-mediated constriction in renal vessels of cortical and juxtamedullary glomeruli in the split hydronephrotic rat kidney in vivo and to functionally characterize the ET receptor subtypes involved. 2. ET-1 (10(-9) M) constricted preglomerular vessels (by 6-18%) and efferent arterioles (by 11-13%), and decreased glomerular blood flow (GBF, by 55%) of cortical and juxtamedullary glomeruli. 3. The ETA antagonist BQ-123 (10(-6) M), as well as the ETB antagonist BQ-788 (2 x 10(-7) M) and IRL 1038 (10(-6) M), shifted the concentration-response curve of GBF for ET-1 to the right by one order of magnitude. While BQ-123 antagonized ET-1 constriction only in preglomerular vessels, BQ-788 and IRL 1038 were effective both in preglomerular vessels and efferent arterioles. 4. The ETB agonist IRL 1620 (10(-8) M) reduced GBF by 50% and constricted efferent arterioles (by 20-33%) about two times more than preglomerular vessels (by 6-14%). 5. Our results suggest that in renal cortical and juxtamedullary vessels of rats, ET-1-induced preglomerular vasoconstriction is mediated by ETA and ETB receptors, while efferent vasoconstriction is predominantly mediated by ETB receptors, which might have important consequences for the regulation of glomerular filtration pressure by ET.

Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Glomerular Filtration Rate; Kidney; Kidney Glomerulus; Microcirculation; Nephrosis; Peptide Fragments; Peptides, Cyclic; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstriction

Endothelin-1, a 21-residue peptide isolated from vascular endothelial cells, has a broad spectrum of actions. To clarify the involvement of endothelin-1 in acute pancreatitis, we examined the effects of endothelin-1 and its receptor antagonist BQ-123 on cerulein-induced pancreatitis in rats. Rats were infused intravenously with heparin-saline (control), endothelin-1 (100 pmol/kg/hr), cerulein (5 micrograms/kg/hr), or cerulein plus endothelin-1 for 3.5 hr. In another experiment, cerulein or cerulein plus BQ-123 (3 mg/kg/hr) was infused. Infusion of cerulein caused hyperamylasemia and pancreatic edema. Endothelin-1, when infused with cerulein, decreased the extent of pancreatic edema with a significant increase in the pancreatic dry- to wet-weight ratio. Histological changes induced by cerulein were markedly attenuated when endothelin-1 was given with cerulein. In contrast, endothelin-receptor blockade with BQ-123 further augmented pancreatic edema caused by cerulein. The extent of inflammatory cell infiltration was greater than BQ-123 was given with cerulein. Endothelin-1 or BQ-123 had no influence on hyperamylasemia. This study suggests that endothelin-1 has protective effects on experimental acute pancreatitis.

Topics: Acute Disease; Amylases; Analysis of Variance; Animals; Ceruletide; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelin Receptor Antagonists; Endothelins; Male; Pancreas; Pancreatitis; Peptides, Cyclic; Rats; Rats, Wistar

To investigate the roles of endothelin and nitric oxide (NO) in the regulation of cerebral vascular tone under basal conditions and in cerebral vasospasm following subarachnoid hemorrhage in dogs, we used BQ-123 (cyclo(-D-Trp-D-Asp-L-Pro-D-Val-L-Leu-) sodium salt), an endothelin ETA receptor antagonist, L-arginine, a substrate for the formation of NO, and NG-nitro-L-arginine methyl ester, an NO synthesis inhibitor, and measured the angiographic diameter of the basilar artery in vivo. In normal dogs, intracisternal (i.c.) injection of BQ-123 (0.6 mg/kg) produced a 29.4 +/- 6.11% (P < 0.01) increase in the basal diameter 24 h after injection. NG-nitro-L-arginine methyl ester (0.6 mg/kg i.c.) produced a 19.3 +/- 2.93% (P < 0.05) decrease in the basal diameter 2 h after injection. This decrease was significantly attenuated by both BQ-123 (0.06-0.6 mg/kg i.c.) and L-arginine (6 mg/kg i.c.), but not by D-arginine. In the two-hemorrhage canine model, BQ-123 significantly inhibited the development of cerebral vasospasm (36.9 +/- 4.11% decrease on day 5 and 42.0 +/- 4.54% decrease on day 6 in controls vs 21.7 +/- 4.75% decrease (P < 0.05) on day 5 and 20.8 +/- 4.14% decrease (P < 0.05) on day 6 for 0.6 mg/kg i.c.) significantly attenuated the cerebral vasospasm on day 4 from a mg/kg i.c.). Furthermore, in this model, L-arginine (6 30.9 +/- 5.78% decrease (before)) to a 12.6 +/- 5.99% decrease (after). The immunoreactive endothelin-1 levels in the endothelial layer and the adventitia of the basilar artery were much higher on days 3 and 7 after the injection of autologous blood than on day 0 before blood injection. These results suggest that endogenous endothelin and NO both participate in regulating the basal tone of cerebral arteries, and, therefore, the development of cerebral vasospasm following subarachnoid hemorrhage may be at least partially attributed to an impairment of the balanced action of endothelin and NO. Furthermore, endothelin ETA antagonists or NO products may be useful in the treatment of cerebral vasospasm following subarachnoid hemorrhage.

Topics: Amino Acid Sequence; Animals; Arginine; Basilar Artery; Cisterna Magna; Disease Models, Animal; Dogs; Endothelins; Female; Immunohistochemistry; Ischemic Attack, Transient; Male; Molecular Sequence Data; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptides, Cyclic; Radiography; Subarachnoid Hemorrhage

Topics: Acute Disease; Animals; Blood Flow Velocity; Ceruletide; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Hemorrhage; Male; Pancreatitis; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Stress, Physiological

Topics: Animals; Basilar Artery; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Infusion Pumps, Implantable; Ischemic Attack, Transient; Male; Peptides, Cyclic; Rabbits; Subarachnoid Hemorrhage

The authors investigated the roles of endothelin (ET)-1 and the ETA receptor in the pathogenesis of delayed cerebral vasospasm following subarachnoid hemorrhage (SAH). A study was made of the preventive effect of a novel ETA receptor antagonist, BQ-123, on vasospasm and the expression of the ETA receptor messenger ribonucleic acid (mRNA) using a canine two-hemorrhage SAH model. Continuous intrathecal administration of BQ-123 (5 x 10(-6) mol/day) prevented narrowing of the basilar artery on Day 7 after SAH in 97.6% of cases in the study group versus 70.7% of cases in the control group (p < 0.05). While expression of the mRNA-coding ETA receptor was not detected in the control animals, it markedly increased on Day 3 after SAH and was also detected on Day 7. The results suggest that endothelin-1 and the ETA receptor participate in the pathogenesis of delayed cerebral vasospasm following SAH.

Topics: Animals; Basilar Artery; Blotting, Northern; Coronary Vasospasm; Disease Models, Animal; DNA Probes; DNA, Complementary; Dogs; Endothelin Receptor Antagonists; Endothelins; Gene Expression Regulation; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Subarachnoid Hemorrhage

The two endothelin (ET) receptor subtypes (ETA and ETB) have been characterized in rat kidney from normal rats and rats with acute renal failure induced by hypertonic glycerol administration. In control rats, the total number of ET receptors in kidney cortex and medulla was 155 and 386 fmol/mg of protein, respectively. The ratio of ETA to ETB receptors was 54:46 in renal cortex and 35:65 in renal medulla. Treatment of rats with 10 ml/kg glycerol (50%, w/v) intramuscularly resulted in severe renal dysfunction; the serum urea concentration increased from 0.46 to 2.65 g/liter and the creatinine clearance decreased from 1.06 to 0.30 ml/min. Ligand binding studies showed that glycerol-induced acute renal failure was associated with a marked up-regulation of ETA and ETB receptor subtypes in both cortex and medulla. In glycerol-treated rats, the total ET receptor density in kidney cortex and medulla was increased to 294 and 1172 fmol/mg of protein, with ETA/ETB ratios of 52:48 and 31:69, respectively. The upregulatory effect of glycerol treatment was significantly more pronounced in renal medulla than renal cortex and affected ETB receptors preferentially, compared with ETA receptors. Subsequently, ETA and ETB receptor mRNA levels were markedly increased by glycerol administration in both kidney cortex and medulla, as assessed by polymerase chain reaction coupled to reverse transcription. These results suggest that up-regulation of renal ET receptors, particularly ETB receptors in kidney medulla, may account for or contribute to renal function impairment induced by glycerol, and they support a pathophysiological role for ET in acute renal failure.

Topics: Acute Kidney Injury; Animals; Base Sequence; Binding, Competitive; Disease Models, Animal; Endothelin Receptor Antagonists; Glycerol; Kidney Cortex; Kidney Medulla; Male; Molecular Sequence Data; Peptides, Cyclic; Polymerase Chain Reaction; Rats; Rats, Wistar; Receptors, Endothelin; Up-Regulation; Vasoconstrictor Agents; Viper Venoms

The aim was to determine the effect of the endothelin-1 receptor antagonist, BQ-123, on infarct size in anaesthetised dogs subjected to 90 min of left circumflex coronary artery occlusion and 5 h of reperfusion.. BQ-123 was given directly into the left circumflex coronary artery at 0.03 or 10 micrograms.kg-1 x min-1 starting 15 min before coronary occlusion and continuing throughout occlusion and reperfusion. Regional myocardial blood flow was determined before, during, and after ischaemia. At the end of the study, infarct size was determined using triphenyltetrazolium chloride staining.. Myocardial infarct size was significantly reduced by BQ-123 (40% reduction from vehicle infarct size) at both doses used. This cardioprotection occurred despite a lack of effect of BQ-123 on peripheral haemodynamic status. BQ-123 also had no effect on regional myocardial blood flow in ischaemic and non-ischaemic tissue. Both cardioprotective doses of BQ-123 were found to completely abolish the coronary constrictor effect of intracoronary endothelin-1 administration.. These data indicate that endothelin-1 release during ischaemia may be involved in the pathogenesis of myocardial ischaemia and infarction.

Topics: Animals; Coronary Vessels; Disease Models, Animal; Dogs; Drug Administration Schedule; Endothelin Receptor Antagonists; Endothelins; Female; Male; Myocardial Infarction; Myocardium; Peptides, Cyclic

The current study was undertaken to define a biological role for the endothelin-A receptor in a clinically relevant model of altered systemic and renal function produced by suprarenal aortic cross-clamping. This model is associated with profound systemic and renal vasoconstriction, acute renal failure, and a significant increase in circulating endothelin. Studies were performed in three groups of anesthetized mongrel dogs. Group 1 (n = 5) underwent aortic cross-clamping for 1 hour; group 2 (n = 5) underwent aortic cross-clamping for 1 hour in the presence of BQ-123, a specific antagonist of the endothelin-A receptor; group 3 (n = 4) received BQ-123 alone. The marked systemic and renal vasoconstriction associated with aortic cross-clamping in group 1 was markedly attenuated in group 2 in the presence of BQ-123. Unlike the vasoconstrictor response, BQ-123 did not attenuate the decrease in glomerular filtration rate associated with this model. Under unstimulated conditions in group 3, BQ-123 had no actions on systemic or renal hemodynamics. In conclusion, the current study demonstrates that the systemic and renal vasoconstriction associated with aortic cross-clamping are in part mediated through the interaction of endothelin and the endothelin-A receptor. This study demonstrates the functional importance of increased endogenous endothelin in the regulation of vascular tone in this pathophysiological state.

Topics: Animals; Aorta; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Endothelins; Heart Rate; Hemodynamics; Ischemia; Kidney; Myocardial Ischemia; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Vascular Resistance; Vasoconstriction