Endothelin receptor antagonists for the treatment of diabetic nephropathy:A meta-analysis and systematic review

BACKGROUND Diabetic nephropathy(DN)is the main cause of chronic kidney disease and endstage renal disease worldwide.Although available clinical trials have shown that endothelin receptor(ER)antagonists may be a novel and beneficial drug for DN,no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented.AIM To assess the effectiveness and safety of ER antagonists among patients with DN.METHODS The EMBASE,PubMed,MEDLINE,Cochrane,and ClinicalTrials.gov databases were searched without any language restrictions.Relative risks with 95%confidence intervals(CIs)for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software.Publication bias was assessed using Egger’s test with Stata/SE software.RESULTS We enrolled seven studies with six data sets and 5271 participants.The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40%reduction in urinary albumin-to-creatinine ratio than the control group(P<0.0001 and P=0.02,respectively).Subgroup analysis for reductions in estimated glomerular filtration rate(eGFR)showed that for the middle-dosage subgroup,the ER antagonists group exhibited lower eGFR reduction than the control group(P<0.00001;mean difference,0.7095%CI:0.66,0.74).Moreover,significant reductions in systolic and diastolic blood pressure were observed in the invention group.CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor/angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR.However,attention should be given to adverse events,including cardiac failure,anemia,and hypoglycemia,as well as serious adverse events.

Correlation between Pulmonary Endothelin Receptors and Alveolar-arterial Oxygen Gradient in Rats with Hepatopulmonary Syndrome

The correlation between pulmonary endothelin receptors and alveolar-arterial oxygen gradient （A aDO2） in rats with hepatopulmonary syndrome was investigated. Animals were divided into 2 groups： Sham operated （Sham） group and common bile duct ligation （CBDL） group. Arterial blood gas was evaluated by a blood gas analyzer. The concentrations of ET-1 in blood and lung tissue sample were evaluated by radioimmunoassay. The distribution and expression of two kinds of subtype receptor of ET-1, ETRA and ETRB were examined by in situ hybridization. The results showed that the level of A aDO2, was higher in CBDI. group than that in Sham group （P〈0.05）. The levels of plasma and pulmonary ET-1 in CBDL group were both higher than in Sham group （P〈0.05 ）. There was no significant difference in average A of ETRA between two groups by imaging analysis （0.21±0.06 vs 0.22±0.08, P〉0.05）, while that of ETRB was higher in CBDI. group than in Sham group （0.58±0.16 vs 0.28±0.07, P〈0.05）. The expression of ETRBinlung was positively correlated with A aDO2（P〈0.05）. It was concluded that the widened A-aDO2 may be related with enhancement of the expression of ETRB in lung.

The Expression of Endothelin Receptor B in Melanoma Cells A375 and Sk-mel-1 and the Proliferative Effects of Endothelin 3 on A375 Cells

In order to investigate the expression of endothelin receptor B （ETR-B） in human malignant melanoma （MM） cells A375 and SK-mel-1 and the proliferative effects of endothelin 3 （ET3） on A375 cells, RT-PCR was applied to detect the expression of ETR-B gene in human MM cells A375 and SK-mel-1. MTT method was used to evaluate the growth enhancing effects of ET3 on A375 cell line in vitro. The results showed that ETR-B gene was expressed in both MM A375 and SK-mel-1 cells. ET3 had stronger ability to enhance the proliferation of A375 cells in vitro in a concentration-dependent manner. It was suggested that ET3/ETR-B might play an important proliferative role in MM.

MUTATION OF THE ENDOTHELIN-B RECEPTOR AND THE ENDOTHELIN-3 GENE IN CHINESE SPORADIC CASES OF HIRSCHSPRUNG'S DISEASE

Objective To investigate the mutation of endothelin receptor B (EDNRB) gene and endothelin 3 (EDN 3) gene in sporadic Hirschsprungs disease (HD) in Chinese population. Methods Genomic DNA was extracted from bowel tissues of 34 unrelated HD patients which were removed by surgery. Exon 3, 4, 6 of EDNRB gene and Exon 1, 2 of EDN 3 gene were amplified by polymerase chain reaction (PCR) and analyzed by single strand conformation polymorphism (SSCP).Results EDNRB mutations were detected in 2 of the 13 short segment HDs. One mutant was in the exon 3; the other one was in the exon 6. EDN 3 mutation was detected in 1 of the 13 short segment HDs and in the exon 2. Both EDNRB mutation and EDN 3 mutation were detected in one short segment HD. No mutations were detected in the ordinary or long segment HD. Conclusion The mutations of EDNRB gene and EDN 3 gene are found in the short segment HD of sporadic Hirschsprung's disease in Chinese population, which suggests that the EDNRB gene and EDN 3 gene play important roles in the pathogenesis of HD. the mutations of EDNRB and EDN 3 lead to the maldevelopment of the enteric nervous system.

EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit＋ bosentan group and Nit＋ losartan group. Nitroglycerin tolerance was induced by 2- day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg－ 1· d－ 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg－ 1· d－ 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit＋ losartan group and Nit＋ bosentan group compared with Nit group [(31.95± 4.45 )％ vs (21.00± 3.69 )％ , P< 0.01 and (33.18± 6.16 )％ vs (21.00± 3.69 )％ , P< 0.01 ,respectively]. The maximal vessel relaxation induced by SNP was the same in 4 different groups but the highest EC50 (concentration which produces 50％ of the maximal response to SNP) was found in tolerant group[(34± 10) nmol/ L,P < 0.01 .The ET- 1 amounts in plasma and vascular tissue were markedly increased by 54％ and 60％ in Nit group compared with those in control group(P< 0.01).The ET- 1 amounts in plasma and vascular tissue were decreased by 30％ and 37％ in Nit＋ losartan group compared with those in Nit group (P< 0.01). Conclusion. Endothelin receptor antagonist and angiotensinⅡ receptor antagonist could prevent against the Nit tolerance .

Effects of endotoxin on endothelin receptor in hepatic and intestinal tissues after endotoxemia in rats

INTRODUCTIONEndothelins(ETs) has a potent and sustainedvasoconstrictive effect on a variety of blood vessels.The vascular smooth muscle cell (VSMC)is thetarget for ETs.VSMC of the whole body containsendothelin receptor (ETR).A great number ofexperiments have shown that three distinctcomplementary DNAs of ETR have been identifiedi.e.,endothelin A receptor(ET_A receptor),endothelin B receptor(ET_B receptor)

Increased endothelin receptor B and G protein coupled kinase-2 in the mesentery of portal hypertensive rats

AIM: To elucidate the mechanisms of mesenteric vasodilation in portal hypertension (PHT), with a focus on endothelin signaling. METHODS: PHT was induced in rats by common bile duct ligation (CBDL). Portal pressure (PP) was measured directly via catheters placed in the portal vein tract. The level of endothelin-1 (ET-1) in the mesenteric circulation was determined by radioimmunoassay, and the expression of the endothelin A receptor (ETAR) and endothelin B receptor (ETBR) was assessed by immunofluorescence and Western blot. Additionally, expression of G protein coupled kinase-2 (GRK2) and β-arrestin 2, which influence endothelin receptor sensitivity, were also studied by Western blot. RESULTS: PP of CBDL rats increased significantly (11.89 ± 1.38 mmHg vs 16.34 ± 1.63 mmHg). ET-1 expression decreased in the mesenteric circulation 2 and 4 wk after CBDL. ET-1 levels in the systemic circulation of CBDL rats were increased at 2 wk and decreased at 4 wk. There was no change in ETAR expression in response to CBDL; however, increased expression of ETBR in the endothelial cells of mesenteric arterioles and capillaries was observed. In sham-operated rats, ETBR was mainly expressed in the CD31+ endothelial cells of the arterioles. With development of PHT, in addition to the endothelial cells, ETBR expression was noticeably detectable in the SMA+ smooth muscle cells of arterioles and in the CD31+ capillaries. Following CBDL, increased expression of GRK2 was also found in mesenteric tissue, though there was no change in the level of β-arrestin 2. CONCLUSION: Decreased levels of ET-1 and increased ETBR expression in the mesenteric circulation following CBDL in rats may underlie mesenteric vasodilation in individuals with PHT. Mechanistically, increased GRK2 expression may lead to desensitization of ETAR, as well as other vasoconstrictors, promoting this vasodilatory effect.

Study of the Effect of Leeching on Plasma Endothelin and Soluble Interleukin-2 Receptor in Patients with Systemic Lupus Erythematosus

Objective: to explore the mechanism of leeching in treating systemic lupus erythematosus (SLE). Methods: Forty-four patients with SLE were randomly divided into conventional corticosteroid treated group (control group, n =20) and conventional treatment group with leeching intervention added (leeching group, n =24). Before and after treatment the concentration of plasma endothelin (ET) and soluble interleukin-2 receptor (sIL-2R) were determined. Results: Before treatment the level of plasma ET and sIL-2R in the SLE patients were all higher than those in the normal healthy group, ( P <0.01). But after treatment the level of these in both groups were significantly improved than those of before treatment ( P <0.05), and comparison between these two treated groups showed that the difference between them was significant ( P <0.05). Conclusion: Leeching added to conventional treatment of SLE could be more effective in improving the level of plasma ET and sIL-2R, and ameliorating the impairment of renal tissues.

Correlation of calcitonin gene-related peptide and endothelin receptor A with subarachnoid hemorrhage

Numerous studies have demonstrated that endothelin-1 combines with endothelin receptor A, resulting in intense vasoconstriction. Although calcitonin gene-related peptide （CGRP） suppresses endothelin-1, CGRP and endothelin receptor A exhibit direct biological effects on brain tissue. The present study analyzed CGRP and endothelin receptor A expression following subarachnoid hemorrhage in rabbits using immunohistochemistry. CGRP expression was significant at 5 days after model establishment, and endothelin receptor A expression was significant at 3 days after model induction. The perimeter of the basilar artery was measured to determine the amount of cerebral vasospasm. Analytical results revealed a significantly shortened basilar artery perimeter following subarachnoid hemorrhage. Changes in the basilar artery perimeter were negatively associated with endothelin receptor A expression, but positively correlated with CGRP expression in vessels. These results suggest that following subarachnoid hemorrhage, CGRP and endothelin receptor A expressions dynamically changed in brain vessels and tissues, although these changes were not synchronous. Changes in endothelin receptor A expression exhibited a significant effect on the occurrence and development of delayed cerebral vasospasm and delayed neuronal death, while CGRP relaxed vessels and protected nerves.

Increased Expression of Endothelin Receptors in Human Cirrhosis—— Relationship with Splanchnic Hemodynamics

The purpose of the present study was to assess the correlation that likely exists among increased portal pressure (P p), portal blood flow quantity (Q p) and ET A and ET B receptor mRNA expression in human cirrhosis. In situ hybridization and reverse transcription polymerase chain reactions (RT PCR) were performed to determine the expression of ET A and ET B receptor mRNA in liver tissues from traumatic subjects ( n =10) and cirrhotic patients ( n =15) in whom hepatic hemodynamic values were measured. The expression of the two transcripts was significantly higher in liver samples of cirrhotic patients than in those obtained from traumatic subjects. It has shown that ET A receptor mRNA predominantly located in hepatic stellate cells (HSCs) and vascular smooth muscle cells of intrahepatic arteries and portal veins, ET B receptor mRNA in HSCs, sinusoidal endothelial cells and Kuppfer cells. There was a highly significant direct relationship between ET A and ET B receptor mRNA and P p and Q p in cirrhotic patients. It suggests that liver paracrine endothelin system may be overactivated in human cirrhosis accompanied with increased expression of ET A and ET B receptor mRNA which may play an important role in the pathogenesis and maintenance of splanchnic hyperdynamics.

Therapeutic Trial of an Endothelin Receptor Agonist for the Highly Pathogenic Avian Influenza A/H5N1 Virus Infection in Chicks

The rapid spread of the highly pathogenic A/H5N1 avian influenza virus among domestic birds and its transmission to humans has induced world-wide fears of a new influenza pandemic. A/H5N1 has infected over 300 people since 1997, and has shown a mortality rate of over 50%. The high mortality in human cases is thought to be enhanced by the excessive secretion of various endogenous factors, including cytokines and interleukins, stimulated by viral infections. Chickens infected with A/H5N1 viruses experience sudden death without showing severe clinical symptoms or inflammation. However, severe hemorrhage and congestion are seen in various tissues in sporadic chicken cases of A/H5N1-infections, especially in the pulmonary tissues, thus indicating that there is ischemia due to vascular abnormalities. Our previous studies have focused on the expression pattern of endothelin-1, which modulates the vascular tone via endothelin receptors. An Indonesian sporadic strain of A/H5N1 virus was intranasally administered to 10-day-old chicks, and the expression of endothelin was examined in the infected birds. All birds died within five days of inoculation, and had moderate inflammation accompanied by severe hemorrhage and congestion in the lungs. Immunohistochemical studies showed enhanced expression of endothelin-1 in the infected lungs. In addition, the real-time PCR analyses revealed that endothelin-1 and endothelin receptor A mRNA were significantly elevated in the birds with A/H5N1 infections. Subsequently, H5N1-infected birds were inoculated with bosentan hydrate, a competitive antagonist of endothelin receptors. Interestingly, the mortality rate of the infected birds was dramatically decreased in a dose-dependent manner by the administration of bosentan hydrate. The pathological lesions, including congestion and hemorrhage in the pulmonary tissues, were clearly inhibited. These findings are promising, and suggest that endothelin receptor antagonists are a potential treatment for the highly pathogenic avian flu.

Effect of endothelin-1 receptor antagonists on histological and ultrastructural changes in the pancreas and trypsinogen activation in the early course of caerulein-induced acute pancreatitis in rats

AIM: To assess the effect of non-selective ETA/B (LU 302872)and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.METHODS: Male Wistar rats with caerulein-induced AP,lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w.of each antagonist. Edema, inflammatory infiltration,necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase,and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.RESULTS: In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P＜0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82±0.06 at higher dose (P＜0.05) vs 0.58±0.06 in untreated AP. The nonselective antagonist increased slightly the vacuolization score to 2.41±0.07 at higher dose (P＜0.01) vs 1.88±0.08in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum,autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups.%FAT/TPT in untreated AP increased about four times (18.4±3.8 vs4.8±1.3 in control group without AP, P＜0.001).Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.CONCLUSION: The treatment with endothelin-1 receptors (non-selective ETA/B and selective ETA) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired effects in caerulein-induced AP at investigated doses.

Synthesis and Crystal Structure of an Endothelin Receptor Antagonist Ambrisentan

The title compound was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. The crystal is of orthorhombic system （C22H22N2O4, Mr = 378.42）, space group P2121 with a = 6.8786（12）, b = 14.259（2）, c = 19.712（3） A, V= 1933.5（6） A3, Z = 4, Dc = 1.300 g/cm3, f（000） = 800, μ= 0.090 mm-1, the final R = 0.0324 and wR = 0.0775 for 2410 observed reflections （I 〉 2σ（I））. The structure, especially the absolute configuration, of the title compound ambrisentan, an important endothelin receptor antagonist, was confirmed by single- crystal X-ray diffraction. The three aromatic rings in the lattice are basically orthogonal to one another. There is an intermolecular hydrogen bond in the crystal, which helps to further stabilize the crystal. One of the two non-classical intramolecular hydrogen bonds can help to stabilize the molecular conformation in the lattice.

INTRACELLULAR REDISTRIBUTION OF CARDIAC ENDOTHELIN- 1 RECEPTOR IN RAT DURING MYOCARDIAL HYPERTROPHY

Objective. In a model of rat cardiac hypertrophy, the changes in the distribution of ET- 1 receptors in two subcellular fractions, the sarcolemma and the light vesicles during myocardial hypertrophy were studied. Methods. Cardiac hypertrophy was produced by placing a constricting clip around the suprarenal abdominal aorta of rats, and ET- 1 receptor was assayed with radioactive analysis method. Results. It was found that plasma and ventricular ET- 1 levels increased significantly on week 2 and week 4 of pressure overload. ET- 1 binding studies showed that during myocardial hypertrophy, the maximum binding capacity (Bmax) was increased by 41％ (P< 0.01) and 65％ (P< 0.01) in sarcolemma in H- 2 week and H- 4 week groups, but was decreased by 24％ (P< 0.01) and 21％ (P< 0.01) in light vesicles. The sum of Bmax of sarcolemmal and light vesicle fractions was increased by 33％ (P< 0.01) and 57％ (P< 0.01) in group H- 2 week and H- 4 week, respectively. Conclusion. ET- 1 receptors in rat heart were externalized from light vesicles to sarcolemma, which may contribute to the development of myocardial hypertrophy.

Antifibrotic effects of ambrisentan,an endothelin-A receptor antagonist,in a non-alcoholic steatohepatitis mouse model

AIM: To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model.METHODS: Fatty liver shionogi(FLS) FLS-ob/ob mice(male, 12 wk old) received ambrisentan(2.5 mg/kg orally per day; n = 8) or water as a control(n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver.RESULTS: In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group(18.0 μg/g ± 6.1 μg/g vs 33.9 μg/g ± 13.5 μg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group(0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1(TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related m RNA expression in the liver were not significantly different between the groups.CONCLUSION: Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis.

EXTERNALIZATION AND INTERNALIZATION OF CARDIAC ENDOTHELIN RECEPTORS DURING DIFFERENT PHASES OF SEPSIS IN RAT

To study the redistribution of endothelin- 1 (ET- 1) receptors in two subcellular organelles , the sarcolemmal membrane and the light vesicle, of rat heart during the progression of sepsis. Methods. Sepsis was induced by cecal ligation and puncture (CLP). ET1 receptor was assayed by using [125I]- ET1 binding. Marker enzyme activities, protein yield, and dry- to- wet weight ratio of cardiac membranes were measured. Results. Septic rat heart exhibited two distinct phases: an initial hyperdynamic phase( 9h after CLP; early stage of sepsis) followed by a hypodynamic (18h after CLP, late stage of sepsis) phase. [125I]- ET1 binding study showed that during early stage of sepsis, the Bmax of ET1 receptors was increased by 30％ in sarcolemma but decreased by 19％ in light vesicles, while during late stage of sepsis, the Bmax was decreased by 24％ in sarcolemma but increased by 38％ in light vesicles.The total binding of sarcolemma and light vesicles was increased by 25％ during early stage of sepsis but decreased by 17％ during late stage of sepsis. Conclusions. These data indicated that ET1 receptors in the rat heart were externalized from light vesicles to sarcolemmal membranes during early hyperdynamic phase while internalized from surface membranes to intracellular compartment during late hypodynamic phase of sepsis.

Effect of Lycium barbarum Polysaccharides on the expression of endothelin-1 and its receptors in an ocular hypertension model of rat glaucoma

Lycium barbarum, a traditional Chinese anti-aging herb, has been shown to protect retinal ganglion cells （RGCs） in a rat chronic ocular hypertension （COH） model. Here, we investigated the expression of endothelin-1 （ET-1）, a strong vasoconstrictor, and its receptors, ETA and ETB, in the COH model and assessed the effects of Lycium barbarum on the ET-1 axis. Elevated intraocular pressure （IOP） was induced in the right eye of SD rats using argon laser photocoagulation. （1） The expression of ET-1, ETA and ETB in normal and COH retinas was studied. （2） Some COH rats were fed daily with Lycium barbarum Polysaccharides （LBP） using 1 mg/kg or phosphate-buffered saline （PBS） for 3 weeks （started 1 week before photocoagulation）. The effects of LBP on the expression of ET-1 and its receptors, ETA and ETB, in COH retina were evaluated. A semi-quantitative analysis of staining intensity was used to evaluate the expression levels of ET-1, ETA and ETB in retinal vasculature. We found that （1） Under COH condition, the immunoreactivity of ET-1 was increased in retina associated with an increase of ETB receptor immunoreactivity and a decrease of ETA receptor immunoreactivity. （2） After feeding COH rats with LBP, the expression of ET-1 was decreased with an increase of ETA expression and a decrease of ETB expression in the retina, especially in RGCs. （3） By comparing the staining intensity in the vasculature of COH retina in LBP-fed group with PBS-fed group, there was a decrease in the expression of ET-1 and ETA and an increase in ETB. In summary, ET-1 expression was up-regulated in the retina in COH model. LBP could decrease the expression of ET-1 and modulate the expression of its receptors, ETA and ETB, under the condition of COH. The neuroprotective effect of LBP on RGCs might be related to its ability to regulate the ET-1-mediated biological effects on RGCs and retinal vasculature.

Endothelin A-receptors and the coronary circulation

We review the role of endothelin (ET) A-receptors (R) on the coronary circulation. ET-1 maintains the normal coronary artery tone. ET-1 plasma levels are increased during and after coronary angioplasty and this increase is related to myocardial ischaemia rather than to mechanical artery injury. ETAR antagonists inhibit coronary artery vasoconstriction induced by ET release after coronary angioplasty in humans. ET promotes neointimal formation and ETAR antagonism has been shown to inhibit restenosis after angioplasty in the animal model but not in humans. ETAR blockade increases coronary blood flow, dilates distal coronary arterial segments and decreases coronary vascular resistance. Coronary collaterals are less sensitive than other coronary vessels to ET-1. ETAR blockade decreases collateral blood flow and, consequently, perfusion of the ischemic myocardium.

Olfactory receptors in neural regeneration in the central nervous system

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.

Effect of ETA receptor antagonist BQ-123 on cardiac function and endothelin system after coronary microembolization in rats

Objective To evaluate the effects of BQ-123 on cardiac function and ventricular remodelling after coronary microembolization (CME) in rats. Methods We created a rat model of CME by injecting a suspension of autogenic microthrombotic particles into left ventricle. Three days after the procedure, the 30 surviving rats were randomly divided into 3 groups, each consisted of 10 rats: sham-operation group(SO), CME model group(CM) and BQ-123 intervention group(BQ). Rats in the BQ group received BQ-123 (400μg/kg per day, intraperitoneally) for 4 weeks. Plasma and myocardial endothelin-1 (ET-1) were measured by radioimmunoassay. And serial echocardiography was performed to monitor alterations of left ventricular end-systolic and end-diastolic diameter (LVESD, LVEED), and left ventricular short-axis fraction shortening(LVFS) and ejection fraction (LVEF), and physiologicography to document the changes of left ventricular systolic pressure (LVSP) and end-diastolic pressure pressure(LVEDP), and left ventricular maximum positive and negative dp/dt (±LVdp/dtmax). Results Compared with sham-operated group, both LVEDD and LVESD were increased (P【0.01), whereas LVFS and LVEF were significantly decreased (P【0.01) in CME group; LVEDP was markedly increased, while LVSP and±LVdp/ dtmax markedly reduced in CME group (P【0.01); plasma and tissue ET-1 levels increased in CME group (P【0.01). BQ-123 intervention significantly decreased both the plasma and tissue ET-1 levels (P【0.01), and markedly increased LVFS and LVEF, with significant improvement of LVSP and±LVdp/ dtmax (P【0.01). Conclusions Treatment with BQ-123 prevents ventricular remodeling after CME due to suppression of the endothelin system.