Methylation of adrenergic 1 receptor is a potential epigenetic mechanism controlling antihypertensive response to metoprolol.

Although metoprolol is used to treat hypertension, clinical responses are variable and unpredictable. Evidence suggests that adrenergic 1 receptor (ADRB1, designated Adrb1 in rodents) gene polymorphisms influence the level of blood pressure response to this drug therapy, but their presence can not predict the response of the individual patient. The question exists whether epigenetic modifications, such as DNA methylation could cause changes in the gene’s expression that are a determining factor in metoprolol’s efficacy. The aim of this study was to verify whether DNA methylation could change the expression of the ADRB1 gene, and epigenetic modification could explain why individuals with identical ADRB1 gene polymorphisms have different antihypertensive responses to metoprolol. H9c2 rat myocardial cells in vitro were randomly divided into 5-aza-2'-deoxycytidine (decitabine)-treated (0.5 to 10.0 μM) and control groups. For the in vivo experiments, 45 spontaneously hypertensive rats (SHRs) were divided into metoprolol-treated and control groups, and after a 4-week intervention myocardia were harvested. Genomic methylation-sensitive PCR was used to assess the methylation status of the Adrb1 promoter after DNA extraction from H9c2 cells and SHR myocardia. Real-time fluorescent quantitative RT-PCR was used to determine levels of Adrb1 mRNA. In H9c2 cells, the least degree of methylation was observed in the 5.0 μM decitabine treated group. Prolonged exposure of cells to 5.0 μM decitabine resulted in downregulating methylation of the Adrb1 promoter. Increased levels of Adrb1 mRNA of the 5.0 μM group demonstrated that this concentration resulted in the highest expression. Accordingly, DNA methylation resulted in the downregulation of Adrb1 transcription. In vivo, the lower level of methylation of the Adrb1 promoter from SHR myocardial samples demonstrated a better antihypertensive effect by metoprolol. The expression of Adrb1 mRNA in the effective group of SHRs was significantly upregulated. In conclusion, as shown in both H9c2 cells and SHRs, downregulated methylation of the Adrb1 promoter is likely to improve the antihypertensive efficacy of metoprolol.

Analgesic Mechanism of Electroacupuncture in an Arthritic Pain Model of Rats: A Neurotransmitter Study

PURPOSE: We investigated what kinds of neurotransmitters are related with electroacupuncture (EA) analgesia in an arthritic pain model of rats. MATERIALS AND METHODS: One hundred rats were assigned to six groups: control, EA, opioid, adrenergic, serotonin and dopamine group. A standardized model of inflammatory arthritis was produced by injecting 2% carrageenan into the knee joint cavity. EA was applied to an acupoint for 30 min in all groups except fo the control group. In the opioid, adrenergic, serotonin and dopamine groups, each receptor antagonist was injected intraperitoneally to their respective group before initiating EA. RESULTS: In the opioid receptor antagonist group, adrenergic receptor antagonist group, serotonin receptor antagonist group, dopamine receptor antagonist group and the control group weight-bearing force decreased significantly from 30 min to 180 min after EA in comparison with the EA group. CONCLUSION: The analgesic effects of EA are related to opioid, adrenergic, serotonin and dopamine receptors in an arthritic pain model of rats.

Molecular components and mechanism of adrenergic signal transduction in mammalian pineal gland: regulation of melatonin synthesis.

Rhythmic neural outputs from the hypothalamic suprachiasmatic nucleus (SCN), which programme the rhythmic release of norepinephrine (NE) from intrapineal nerve fibers, regulate circadian rhythm of melatonin synthesis. Increased secretion of NE with the onset of darkness during the first half of night stimulates melatonin synthesis by several folds. NE binds to both alpha1- and beta-adrenergic receptors present on the pinealocyte membrane and initiates adrenergic signal transduction via cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) generating pathways. The NE-induced adrenergic signal transduction switches 'on' melatonin synthesis during the early hours of night by stimulating expression of the rate-limiting enzyme of melatonin synthesis, N-acetyltransferase (AA-NAT) via cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-cAMP response element (CRE) pathway as well as by increasing AA-NAT activity via cAMP-PKA-14-3-3 protein pathway. Simultaneously, adrenergically-induced expression of inducible cAMP early repressor (ICER) negatively regulates aa-nat gene expression and controls the amplitude of melatonin rhythm. In the second half of night, increased release of acetylcholine from central pinealopetal projections, inhibition of NE secretion by SCN, withdrawal of adrenergic inputs and reversal of events that took place in the first half lead to switching 'off' of melatonin synthesis. Adrenergic signal transduction via cGMP-protein kinase G (PKG)-mitogen activated protein kinase (MAPK)-ribosomal S6 kinase (RSK) pathway also seems to be fully functional, but its role in modulation of melatonin synthesis remains unexplored. This article gives a critical review of information available on various components of the adrenergic signal transduction cascades involved in the regulation of melatonin synthesis.

Manejo perioperatorio del feocromocitoma / Perioperative management of pheochromocytoma

El feocromocitoma es un tumor secretante de catecolaminas que sólo puede ser tratado quirúrgicamente. Se lo puede encontrar solo o asociado a síndromes endocrinos con claros vínculos genéticos. Su síntoma característico es la hipertensión arterial, pero esta particularidad se observa solo cuando la noradrenalina es el neurotransmisor que predomina en la secreción. En cambio, cuando el neurotransmisor principal es la adrenalina o la dopamina los síntomas son imprecisos: mareos, ataques de pánico, etc. El anestesiólogo debe enfrentar esta cirugía planteándose los riesgos de las etapas pre, intra y postoperatoria. Durante el preoperatorio el enfermo debe ser preparado farmacológicamente para prevenir una crisis hipertensiva durante la cirugía. En la intervención, la etapa posterior a la resección del tumor se caracteriza por una hipotensión severa que requiere de cuidados anestesiológicos, ya que sus consecuencias pueden convertirse en complicaciones graves. Estos cuidados se deben extender durante el postoperatorio y el paciente sólo deberá ser externado cuando sea posible controlar la presión arterial sin necesidad de cuidados críticos. En la actualidad, la resección del feocromocitoma se realiza por vía laparoscópica. Esta técnica no parece brindar mayores beneficios que la cirugía convencional, a excepción de la rápida recuperación postoperatoria.

El papel de la noradrenalina en la depresión / The role of noradrenaline in depression

A partir de las investigaciones realizadas en los años 60 y la respuesta terapéutica al tratamiento con antidepresivos tricíclicos se ha involucrado a la noradrenalina en la etiología del episodio depresivo mayor. La aparición de los inhibidores selectivos de la recaptación de serotonina, con igual eficacia y menor incidencia de efectos secundarios que los antidepresivos tricíclicos, impulsó y desarrolló las etiologías serotoninérgicas en los transtornos afectivos. Las investigaciones recientes y el diseño de moléculas antidepresivas, como la reboxetina, consideradas como inhibidoras selectivas de la recaptación de noradrenalina (NARI), han puesto de relieve nuevamente los aspectos noradrenérgicos en la etiología y terapéutica de los episodios depresivos. En el presente trabajo se revisan los aspectos biomoleculares, los modelos de investigación animal y la farmacodinámica de las nuevas moléculas antidepresivas, de tipo noradrenérgico

Patterns of adrenoceptor change during liver regeneration of the wistar kyoto rat: A bunding study

Background. Adrenoceptors have been involved in the regulation of hepatocyte proliferation after partial hepatectomy, as well as in primary culture. This report characterized Ó1 and ß-adrenoceptor change during the time-course of liver regeneration in adult Wistar Kyoto rats. Methods. Saturation binding assays with [3H]prazosin or [3H]dihydroalprenolol (for Ó1- and ß-adrenoceptors, respectively) were done in liver plasma membranes from 6-monthold rats subjected to 70 percent hepatectomy followed by hepatic regeneration. Results. [3H]Prazosin and [3H]dihydroalprenolol binding gave control Bmax values of 101 ñ 10 and 12 ñ 1 fmol/mg protein and Kd of 0.50 ñ 0.10 and 4.1 ñ 0.4 nM for Ó1- and ß-adrenoceptors, respectively. Ó1-Adrenoceptor number and Kd increades at 24 and 48 h and returned to control values at 72 and 96 h after surgery, whereas ß-adrenoceptors augmented at 48 and 72 h, with a Kd change at 24 and 48 h postherapetectomy. Conclusions.These results suggest that dual control of Ó1- and ß-adrenoceptor membrane expression could be involved in different steps during hepatocyte proliferation, and that Wistar Kyoto rats have a different adrenoceptor pattern expression from other rat strains

Pertubaçöes afetivas: o papel dos receptores / Affective disorders: the role of receptors

O uso crônico de antidepressores tricíclicos aumenta a sensibilidade dos receptores alfa-1 e receptores triptaminérgicos pós-sinápticos, diminuindo a sensibilidade dos receptores ß. O mecanismo destas alteraçöes näo está totalmente elucidado. Além disso, a relaçäo entre os receptores alfa - 2 e dopaminérgicos nas doenças mentais tem sido estudados, sem resultados conclusivos até o momento. Os autores revisam os trabalhos mais recentes acerca do papel destes receptores nas perturbaçöes afetivas

Central histaminoceptor-adrenoceptor interrelations in the release of adrenocorticotrophic hormone.

Intracerebroventricular administration of adrenaline, noradrenaline phenylephrine, clonidine and histamine produced a significant rise in plasma cortisol concentration whereas isoprenaline had no effect. alpha-Adrenoceptor blockers (yohimbine or piperoxon) per se did not alter the plasma cortisol level. Central pretreatment with yohimbine or piperoxin, blocked the rise in plasma cortisol level induced by icv noradrenaline, phenylephrine and clonidine. In another set of experiments, both H1 and H2 receptor antagonists (mepyramine, and metiamide) per se had not significant effect on plasma cortisol concentration. Central histamine induced rise in plasma cortisol concentration was significantly blocked by icv pretreatment with both H1 and H2 receptor blockers. Furthermore, yohimbine also significantly prevented the rise of plasma cortisol level induced by icv histamine.