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Introduction: The female gender is a risk factor for idiopathic pulmonary arterial hypertension. However, it is unknown whether females with rheumatic mitral valve disease are more predisposed to develop pulmonary hypertension compared to males. Aim: We aimed to investigate whether there was a difference in genotypic distribution of endothelin-1 (ET-1) and endothelin receptor A (ETA) genes between female and male patients of pulmonary hypertension associated with rheumatic mitral valve disease (PH-MVD). Methods: We compared prevalence of ET-1 gene (Lys198Asn) and ETA gene (His323His) polymorphisms according to gender in 123 PH-MVD subjects and 123 healthy controls. Results: The presence of mutant Asn/Asn and either mutant Asn/Asn or heterozygous Lys/Asn genotypes of Lys198Asn polymorphism when compared to Lys/Lys in females showed significant association with higher risk (odds ratio [OR] 4.5; p ¼0.007 and OR 2.39; p ¼0.02, respectively). The presence of heterozygous C/T and either mutant T/T or heterozygous C/T genotypes of His323His polymorphism when compared to wild C/C genotype in females showed a significant association with higher risk (OR 1.96; p ¼0.047 and OR 2.26; p ¼0.01, respectively). No significant difference was seen in genotypic frequencies in males between PH-MVD subjects and controls. Logistic regression analysis showed that mutant genotype Asn/Asn (p ¼0.007) and heterozygous genotype Lys/Asn of Lys198Asn polymorphism (p ¼0.018) were independent predictors of development of PH in females.
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AIM:To observe whether selective inhibition of endothelin receptor A(ETRA)improves white matter lesions(WMLs),and explore the mechanism.METHODS:Sprague-Dawley rats(n=33)were randomly divided into sham operation group(n=9),treatment group[stroke-prone renovascular hypertensive rats-modified 2 vessel occlu-sion(RHRSP-modified 2VO)+ambrisentan(n=12)]and placebo group[RHRSP-modified 2VO +vehicle(n =12)].Drug and vehicle administration was performed from 17th to 20th week and monitoring of systolic arterial pressure was performed weekly.Morris water maze test was conducted to evaluate the function of cognition.The protein levels of en-dothelin-1(ET-1)in the cortex,corpus callosum and caudate putamen were quantitatively analyzed respectively.The se-verity of WMLs and the relationship between ET-1 and vessels were observed by the method of histopathology.RESULTS:The difference of systolic arterial pressure between treatment group and placebo group was not significant.The animals in treatment group exhibited shorter escape latency(P<0.05),more times of crossing platform(P<0.05), lower level of ET-1 in corpus callosum and caudate putamen(P<0.05),respectively,improved WMLs severity(P<0.05)and lower binding level of ET-1 to vessels compared with the placebo group.CONCLUSION: Selective inhibition of endothelin receptor A improves the severity of WMLs and ameliorates the cognitive function.
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Aims: Endothelin-1 (ET-1) is a potent vasoconstrictive peptide, and its activity is mediated by the type A receptor (EDNRA). This action may play a significant role in the etiology of hypertension. There are different works that shows an association between certain polymorphisms of endothelin axis and clinical phenotype of hypertension. We describe the genetic variability +138/ex1 insertion/deletion (I/D) adenosine (A) in the ET-1 gene and polymorphism thymidine/cytosine (T/C) His323His in the EDNRA gene associated at the clinical variability in hypertensive patients. Study Design: Observational, transversal and analytical study. Place and Duration of Study: Hypertension Service at the Internal Medicine Department of Córdoba Hospital, and Biochemical and Molecular Biology Department in School of Medicine, National University of Cordoba, Argentine. Patients considered hypertensive between April 2009 and April 2010. Methodology: Were assessed 136 patients serum lipid profiles, renal and hepatic functions and were taken Thoracic X-rays, electrocardiograms, and echocardiographs. DNA extracted from circulating leukocyte were used to analyze the polymorphisms of genes by PCR-RFLP. Results: For the polymorphisms of Receptor A from Endothelin -1 studied the presence of cytosine homozygous genotype was less frequent in males (P = .02). For both genders, the same genotype was associated to low plasma alkaline phosphatase activity and cholesterol levels. The presence of thymidine nucleotide allele correlated with plasma alkaline phosphatase activity and cholesterol levels. The Thymidine allele correlated with the degree of cardiovascular compromise (r = 0.54, P= .002). For the genetic variant in the ET-1 gene, the homozygous adenine deletion was associated to normal plasma levels of glutamate/pyruvate transaminase enzyme activity, uric acid concentration, cholesterol, and Low Density Lipoprotein in hypertensive subjects without clinical risk. Conclusion: We observed a gender-specific protective effect for EDNRA gene variations, the subjects that carried the TT genotype presented more aggressive symptomatology. These results show an association between plasmatic biochemical parameters, the clinical condition, and polymorphisms in the endothelin axis genes.
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La familia de las endotelinas (ET), está constituida por tres isoformas de 21 aminoácidos: endotelina-1 (ET-1), endotelina-2 (ET-2) y endotelina-3 (ET-3). Las ET son potentes agentes presores endógenos, secretadas por diferentes tejidos y células del organismo. De las tres isoformas, la ET-1 es sintetizada predominantemente por el endotelio vascular. La ET- 1 induce vasoconstricción, es proinflamatoria, profibrosis y tiene acción potencialmente mitógena. Es un importante factor en la regulación del tono vascular y participa en la remodelación vascular. Estos efectos son mediados a través de dos tipos de receptores, ET A y ET B. Los receptores ET A están localizados principalmente en el músculo liso vascular y son responsables de inducir la proliferación celular y vasoconstricción. Los receptores ET B están presentes en las células endoteliales y son mediadores de la relajación vascular por activación de la producción de óxido nítrico y prostaciclina, además, intervienen en la depuración de la ET-1. El sistema endotelina está involucrado esencialmente con la hipertensión arterial sistémica, hipertensión pulmonar, aterosclerosis, reestenosis coronaria, falla cardíaca, cardiomiopatías e insuficiencia renal.
The endothelins (ET S) family consists of three 21 aminoacid isoforms: endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3). ET S are very potent endogenous pressor agents, secreted by various cells and tissues in the human body. Of the three, endothelin-1 is the predominant isoform produced by the vascular endothelium. ET-1 induces vasoconstriction, is proinflammatory, profibrosis, and has mitogenic potential; it is also an important factor in the regulation of vascular tone and arterial vascular remodeling. These effects are mediated via two receptor types, ET A and ET B. ET A receptor is located mainly on vascular smooth muscle and is responsible for mediating vasoconstriction and proliferation. The ET B receptor is present predominantly on endothelial cells and mediates vasorelaxation for NO and prostacyclin release and also ET-1 clearance. The ET system is activated in essential hypertension, pulmonary hypertension, atherosclerosis, coronary restenosis, heart failure, idiopathic cardiomyopathy and renal failure.
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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 CBDL 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 CBDL group than in Sham group (0. 58±0.16 vs 0.28±0.07, P＜0.05). The expression of ETRB in lung 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.
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Objective To detect the changes of Endothelin-A receptor mRNA in the cerebral basilar artery of rats with experimental subarachnoid hemorrhage-induced cerebral vessel spasm as well as its effect. Methods Fifty-six Wistar rats were randomly divided into normal, experimental,sham-operated and saline-control groups. The experimental group was subdivided into subarachnoid hemorrhage(SAH)2,3,7 and 14?d groups. Reverse transcription polymerse chain reaction was used to study the changes of Endothelin-A receptor mRNA level in the cerebral basilar artery of rats with experimental subarachnoid hemorrhage-induced cerebral vessel. Results ET-A receptor mRNA level of basilar artery in SAH2, 3?d and 7?d group was higher obviously than that of normal group,sham-operated and saline-control groups. That of 14?d group was approximate to normal group.Conclusion ET-A receptor may play an important role in pathogenesis of SAH-induced cerebral vessel spasm.