Arg16 homozygosity of the β2-adrenergic receptor improves the outcome after β2-agonist tocolysis for preterm labor&ast (original) (raw)
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Clinical pharmacology and therapeutics, 2005
Beta(2)-adrenergic receptor (beta(2)AR) agonists are not consistently successful when administered as tocolytic therapy. The beta(2)AR displays genetic variability; an arginine-to-glycine substitution at codon 16 (Arg16Gly) has been shown to increase receptor desensitization in response to agonist exposure, whereas a substitution of glutamate for glutamine at codon 27 (Gln27Glu) decreases down-regulation. We have demonstrated that homozygosity for Arg16 protects against preterm delivery. Our goal was to determine whether beta(2)-agonists are more effective in women with the Arg16 genotype and preterm labor. Sixty white women with preterm labor between 24 and 34 weeks' gestation were treated for 48 hours with intravenous hexoprenaline. The effect of tocolysis and outcome of pregnancy were recorded. The beta(2)AR genotypes at codons 16 and 27 of ADRB2 were determined. A control group of 116 women delivered at term was also genotyped. Preterm labor was not associated with beta(2)AR...
β2-Adrenergic receptor genotype and preterm delivery
American Journal of Obstetrics and Gynecology, 2002
Our purpose was to determine whether the functional genetic polymorphisms of the β 2-adrenergic receptor (β 2 AR) that result in changes in amino acid residues 16 and 27 are associated with preterm delivery. STUDY DESIGN: A case-control study comparing the distribution of β 2 AR genotype between 251 Hispanic women delivered at term and 28 Hispanic women delivered preterm. Preterm delivery was defined as spontaneous onset of labor resulting in delivery before 37 weeks of gestation, in a singleton pregnancy, with no apparent etiology for preterm labor and delivery. Genomic DNA was isolated from peripheral blood, and β 2 AR alleles were identified by established techniques. RESULTS: Only one woman (4%) with preterm labor was homozygous for Arg16 versus 79 (31%) in the control group (P = .01, odds ratio 0.08). There was no association of preterm labor with genotype at position 27. CONCLUSION: Our data demonstrate that homozygosity for Arg16, which in vitro is associated with decreased down-regulation of the β 2 AR, protects from preterm delivery.
Association of the Gln27Glu polymorphism of the beta-2-adrenergic receptor with preterm labor
International Journal of …, 2002
Objectives: To investigate a potential association between the beta-2-adrenergic receptor (B2AR) polymorphisms occurring at amino acid positions 16 (Arg16Gly) and 27 (Gln27Glu) and preterm labor. Methods: Eighty patients with preterm labor and 76 control subjects were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: A significant association was found between Gln27Glu substitution and preterm labor (Ps0.001). The frequency of Gly16 and Glu27 alleles were found to be higher in patients than in control women (0.54 vs. 0.48 and 0.42 vs. 0.26, respectively), and the odds ratio for the occurrence of preterm labor was 2.14 (95% CI, 1.32-3.46; Ps0.002) for the Glu 27 allele. An early delivery was noted in 52.5% of patients. Conclusion: The Gln27Glu polymorphism of the B2AR gene may have a role in molecular pathogenesis of preterm labor. Glu27 allele in patients with preterm labor might be a risk factor for deliveries before 37 weeks of gestation.
Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?
BMC Pregnancy and Childbirth, 2007
The management of premature birth still remains unsatisfactory. Since the relative lack of efficiency and/or safety of current tocolytic agents have been highlighted, it is necessary to develop new uterorelaxant drugs deprived of important maternal and foetal side effects. Our work reported in this review focuses on a potential new target for tocolytic drugs, the β 3 -adrenoceptor (ADRB3). This third type of ADRB is shown to be present and functional in human myometrium. We demonstrated that ADRB3 agonists are able to inhibit in-vitro spontaneous contractions of myometrial strips, via a cyclic AMP-mediated pathway. Furthermore, we established that ADRB3 is the predominant subtype over the ADRB2 in human myometrium and that its expression is increased in near-term myometrium, compared to non-pregnant myometrium. Finally, we reported that contrary to ADRB2, the human myometrial ADRB3 is resistant to long-term agonist-induced desensitisation. These compelling data confirm the clinical potential interest of ADRB3 agonists in the pharmacological management of preterm labour.
β2-Adrenergic Receptor Genotype and Other Variables that Contribute to Labor Pain and Progress
Anesthesiology, 2011
Background-Beta-2-adrenergic receptor (β2AR) activity influences labor and its genotype affects the incidence of preterm delivery. We determined the effect of β2AR genotype on term labor progress and pain. Methods-We prospectively enrolled 150 nulliparous parturients in the third trimester and obtained sensory thresholds, demographic information and DNA. Cervical dilation, pain scores and labor management data were extracted with associated times. The association of genetic and demographic factors with labor was tested with mixed effects models. Results-Parturients who express Gln at the 27 position of the β2AR had slower labor (P<0.03).
American Journal of Reproductive Immunology, 2012
We investigated genetic polymorphisms to understand the etiology of preterm delivery, which involves inflammatory cytokines and uterine contraction. Maternal polymorphisms of ADRB2, iNOS, and eNOS were examined, and associations between these and the risk of preterm delivery were sought. Method of Study This study was performed on 166 Korean women who underwent preterm delivery and 289 normal controls. Logistic regression analyses were carried out to identify single genes and haplotypes that affect the risk of preterm delivery. Results The G/G haplotype of ADRB2-rs1042713 and-rs1042714 was found to be associated with the risk of preterm delivery (OR = 1.90, 95% CI = 1.08-3.33, P-value = 0.0252). The genotype frequency of G allele in ADRB2-rs1042714 was associated with increased the risk of preterm delivery. However, after the adjustment of multiple comparison corrections, the association with preterm delivery was not remained significantly. Conclusion These findings possibly aid our understanding of the pathogenesis of preterm delivery and suggest that a haplotype with variants in maternal genes involved in adrenergic activation may lead to the dysregulation of uterine contractility and increase the risk of preterm delivery.
American Journal of Obstetrics and Gynecology, 1986
Iodine 125-labeled iodocyanopindolol, a radioactive l3-adrenergic antagonist, bound to particulate preparations of pregnant human myometrium in a manner compatible with binding to the l3-adrenergic receptor. Studies with a specific 132-antagonist, IPS 339, indicated that 72% of receptors present were of the 132-subtype. Quantitative studies of l3-receptor concentrations in myometrium from women at term indicated no change in receptor concentration during labor. Similarly, there was no difference in l3-receptor concentration in myometrium from women in labor or before labor between 28 and 34 weeks of gestation. Concentrations of the l3-receptor were not different at any stage of gestation assayed. Isoproterenol competition for iodocyanopindolol binding was used to examine efficacy of receptor agonist interactions in myometrium from women at term, in labor, or before labor and from women in preterm labor. There was no difference in high-affinity binding, an index of efficacy, in any of the groups examined.
Journal of Luminescence, 2010
The beta-2 adrenergic receptor gene has several polymorphisms. Recent studies have demonstrated the clinical importance of the latter. The objective of the present study was to evaluate the influence of the Arg16Gli polymorphism on the incidence of arterial hypotension and ephedrine use in pregnant patients submitted to subarachnoid block for Cesarean section.Healthy parturients (ASA I and II) were submitted to subarachnoid anesthesia for elective Cesarean section (n = 50). Ephedrine was administered in cases of arterial hypotension. The incidence of arterial hypotension and the required dose of ephedrine to correct the arterial pressure were compared between the different genotypes identified.The most prevalent genotype was Arg16Gli (60%, n = 30) followed by Gli16Gli (26%, n = 13) and Arg16Arg (14%, n = 7). No differences were observed regarding the basic characteristics of the genotypes. In comparison to the Arg16Arg genotype, the Gli16Gli presented a 3.95-fold increase in the hazard ratio of arterial hypotension (95%CI 0.86-18.11; p = 0.076), whereas the Arg16Gli presented a 4.83-fold increase (95%CI 1.13-20.50; p = 0.033). The parturients with the Arg16Arg needed, on average, 6.4 ± 8.5 mg of ephedrine to correct the arterial hypotension, whereas those with the Arg16Gli needed 19.5 ± 15.9 mg (p = 0.0445; 95%CI 0.3325-25.78) and the ones with the Gli16Gli genotype, 19.2 ± 14.3 (p = 0.0445, 95%CI 0.3476-25.26).The results show that the genetic variant Arg16Arg presents a lower incidence of arterial hypertension and that lower doses of ephedrine were necessary to reestablish normal arterial pressure in the patients with this genetic profile. We conclude that the Arg16Arg genotype confers better pressure stability to the parturients submitted to subarachnoid anesthesia for Cesarean section.O gene do receptor beta-2 adrenérgico possui diversos polimorfismos. Estudos recentes vêm demonstrando sua importância clínica. O objetivo deste trabalho foi avaliar a influência do polimorfismo Arg16Gli na incidência de hipotensão arterial e uso de efedrina em parturientes submetidas ao bloqueio subaracnoideo para cesariana.Parturientes hígidas (ASA I e II) foram submetidas à anestesia raquidiana para realização de cesariana eletiva (n = 50). Efedrina foi administrada nos casos de hipotensão arterial. A incidência de hipotensão arterial e a dose requerida de efedrina para correção da pressão arterial foram comparadas entre os diferentes genótipos encontrados.O genótipo mais prevalente foi o Arg16Gli (60%, n = 30) seguido pelo Gli16Gli (26%, n = 13) e Arg16Arg (14%, n = 7). Não foram observadas diferenças entre as características básicas dos genótipos. Com relação ao genótipo Arg16Arg, o Gli16Gli apresentou aumento da razão de risco de hipotensão arterial (hazard ratio) de 3,95 vezes (IC 95% 0,86-18,11; p = 0,076), enquanto o Arg16Gli apresentou aumento de 4,83 vezes (IC 95% 1,13-20,50; p = 0,033). As parturientes com Arg16Arg precisaram, em média, de 6,4 ± 8,5 mg de efedrina para correção de hipotensão arterial, enquanto as do Arg16Gli precisaram de 19,5 ± 15,9 mg (p = 0,0445; IC 95% 0,3325-25,78) e as do tipo Gli16Gli, 19,2 ± 14,3 (p = 0,0445, IC 95% 0,3476-25,26).Os resultados mostraram que a variante genética Arg16Arg apresenta menor incidência de hipotensão arterial e que menores doses de efedrina foram necessárias para restabelecimento de normotensão arterial nas pacientes com esse perfil genético. Concluímos que o genótipo Arg16Arg confere maior estabilidade pressórica às parturientes submetidas à anestesia raquidiana para cesariana.El gen del receptor beta-2 adrenérgico posee diversos polimorfismos. Estudios recientes han venido demostrando su importancia clínica. El objetivo de este trabajo, fue evaluar la influencia del polimorfismo Arg16Gli en la incidencia de hipotensión arterial y el uso de efedrina en parturientas sometidas al bloqueo subaracnoideo para cesárea.Parturientas sanas (ASA I y II) fueron sometidas a la anestesia raquídea para la realización de cesárea electiva (n = 50). Efedrina fue administrada en los casos de hipotensión arterial. La incidencia de hipotensión arterial y la dosis requerida de efedrina para la corrección de la presión arterial fueron comparadas entre los diferentes genotipos encontrados.El genotipo que más prevaleció fue el Arg16Gli (60%, n = 30) seguido por el Gli16Gli (26%, n = 13) y Arg16Arg (14%, n = 7). No se observaron diferencias entre las características básicas de los genotipos. Con relación al genotipo Arg16Arg, el genotipo Gli16Gli presentó un aumento de la razón de riesgo de hipotensión arterial (hazard ratio) de 3,95 veces (IC 95% 0,86-18,11; p = 0,076), mientras que el genotipo Arg16Gli presentó un aumento de 4,83 veces (IC 95% 1,13-20,50; p = 0,033). Las parturientas con genotipo Arg16Arg, necesitaron como promedio 6,4 ± 8,5 mg de efedrina para la corrección de la hipotensión arterial, mientras que las del genotipo Arg16Gli necesitaron 19,5 ± 15,9 mg (p = 0,0445; IC 95% 0.3325-25.78) y las del tipo Gli16Gli 19,2 ± 14,3 (p = 0,0445, IC 95% 0.3476-25.26).Los resultados mostraron que la variante genética Arg16Arg presenta una menor incidencia de hipotensión arterial y que menores dosis de efedrina fueron necesarias para el reestablecimiento de la normotensión arterial en las pacientes con ese perfil genético. Concluimos que el genotipo Arg16Arg le da una mayor estabilidad de presión a las parturientas sometidas a la anestesia raquídea para cesárea.