Correlación genotipo-fenotipo cardiovascular de la dopamina B- hidroxilasa (DBH) / Cardiovascular correlation genotype-phenotype of dopamine B-hydroxylase (DBH)

Introducción. Al convertir dopamina en norepinefrina la dopamina β-hidroxilasa (DβH) regula el tono dopaminérgico y adrenérgico. Los alelos rs1989787, rs1611115 y rs1108580 del gen DβH se asocian con actividad deficiente de la enzima y por eso evaluamos sus influencias sobre variables cardiovasculares clínicas, bioquímicas y farmacológicas. Métodos: A 44 voluntarios sanos con los haplotipos triple homocigoto nativo (CC/CC/AA), triple heterocigoto (CT/CT/AG), doble homocigoto mutado (TT/CC/GG) y homocigoto mutado para el rs1611115 (CC/TT/AA) les medimos presión arterial sistólica (PAS), presión arterial diastólica (PAD) y frecuencia cardíaca (FC) en posición decúbito, sentado, de pie, bajo estímulo de frío, con la maniobra de Valsalva y post ingestión de clonidina; adicionalmente medimos actividad enzimática por espectrofotometría y concentraciones séricas de dopamina y norepinefrina por ELISA. Resultados: Edad promedio 21,6±3,5 años, 54,5 porciento mujeres. No hubo diferencias de PAS, PAD y FC obtenidas bajo diferentes condiciones; sólo encontramos cambios significativos en los descensos de la PAS y la PAD postingestión de clonidina. No hubo relación de las variables clínicas, bioquímicas y farmacológicas mencionadas con los alelos rs1989787 y rs1108580, pero los portadores del alelo mutado T del rs1611115 sí tenían frecuencias cardíacas estadísticamente inferiores a los portadores del alelo nativo C. La actividad enzimática y las concentraciones de dopamina y norepinefrina no se correlacionaron con las variables cardiovasculares, pero se encontró correlación directa entre la actividad de la enzima y las concentraciones de norepinefrina. Conclusión: El polimorfismo -970C>T del gen DβH es el único asociado con menores frecuencias cardíacas en portadores del alelo mutado T.

Introduction. To the converting dopamine in norepinephrine the enzymedopamine β-hydroxylase (DβH) regulates dopaminergic and adrenergictone. The alleles rs1989787, rs1611115 and rs1108580 of the gene DβH areassociated with deficient activity of the enzyme and thus the influence ofthese SNPs in clinical, biochemical and pharmacological variables relatedwith the cardiovascular system was evaluated. Methods: 44 healthy volunteerswith homozygous triple native (CC/CC/AA), triple heterozygous (CT/CT/AG), double mutated homozygous (TT/CC/GG) and mutated homozygoushaplotypes for the rs1611115 (CC/TT/AA) were subjected to measurementsof systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate(HR) in the positions prone, sitting, standing, under cold stimulus, with theValsalva maneuver and after clonidine ingestion; additionally the enzymaticactivity of the DβH and the concentrations of dopamine and norepinephrinewere determined by spectrophotometry and ELISA, respectivelly. Results: Theaverage age of the group was 21.6±3.5 years, and 54.5% were women. Therewere no differences in SBP, DBP and HR obtained under different conditions;we only found significant changes in SBP and DBP decrease after clonidineingestion. There were no associations between clinical, biochemical andpharmacological variables with the rs1989787 and rs1108580 alleles, however,carriers of the mutant allele T of the rs1611115 had heart rates statisticallylower than the native C allele carriers. Neither enzymatic activity nor dopamineand norepinephrine levels were correlated with cardiovascular variables, but adirect correlation between enzyme activity and norepinephrine concentrationswas found. Conclusion: The-970C>T polymorphism of DβH gene is the onlyone associated with lower heart rates in carriers of the mutated allele T.

Caracterización del gen de la dopamina Beta-hidroxilasa en población mestiza colombiana / Caracterization of dopamine Beta-hydroxylase gene in the Colombian Mestizo Population / Caracterização do gene da dopamina Beta-hidroxilasa em população mestiça

Introducción: la dopamina β-hidroxilasa cataliza la conversión de dopaminaen norepinefrina y es blanco promisorio de intervenciones farmacológicas.Polimorfismos del gen DβH son responsables de las diferencias individuales en el tono dopaminérgico y adrenérgico de los sistemas nervioso central y autónomo. Ya que las mutaciones defectuosas de la enzima y sus frecuencias varían entre las etnias, se justifican los estudios conducentes a la caracterización genotípica yfenotípica de la enzima en mestizos colombianos. Métodos: determinamos las frecuencias de los alelos -2073C>T, -970C>T, 444A>G y 1603C>T del gen DβH en 143 adultos sanos, rasgos mestizos, ambos sexos y no consanguíneos. La genotipificación se hizo por PCR-real time y minisecuenciación (SnaPshot).Resultados: las frecuencias de los genotipos polimórficos fueron: -2073C>T (CC 61,5%, CT 32,9%, TT 5,6%), -970C>T (CC 49,6%, CT 43,4, TT 7%) y 444A>G (AA 42%, AG 41,2%, GG 16,8%). Las tres mutaciones están en desequilibrio de ligamiento (D´=1) pero no se sustituyen mutuamente (r2<0,8). 15 personas (10,5%) tuvieron haplotipo de triple homocigoto nativo (CC/CC/AA). Conclusión: nuestras frecuencias alélicas se asemejan a las reportadas en otros grupos mestizos latinoamericanos.

Introduction: dopamine P- hidroxylase catalyzes the conversion of dopamine to norepinephrine and it is a promising target for pharmacological inventions. DPH gene polymorphisms are responsible for individual differences in dopaminergic and adrenergic tone of the central and autonomic nervous systems. Since defective enzyme mutations and their frequencies vary among ethnic groups, it is justify the studies leading to the genotypic and phenotypic characterization of the enzyme in Colombian mestizos.Methods: we determined the frequencies of the alleles -2073C>T, -970C>T, 444A>G and 1603C>T DfiH gene in 143 healthy adults, mestizo features, both sexes and nonconsanguineous. PCR-real time and minisequencing (SnaPshot) tecnhiques were used for the genotyping.Results: the frequencies of polymorphic genotypes were: -2073C>T (CC 61,5%, CT 32,9%, TT 5,6%), -970C>T (CC 49,6%, CT 43,4, TT 7%) and 444A>G (AA 42%, AG 41,2%, GG 16,8%).The three alleles are in linkage disequilibrium (D'=1) but they do not replace each other (r2<0,8). 15 people (10,5%) had the homozygous triple native haplotype (CC/CC/AA).Conclusion: our allelic frequencies are similar to those reported in other Latin American mestizo groups.

Introdução: a dopamina P-hidroxilasa catalisa a conversão de dopamina em norepinefrina e é alvo promissor de intervenções farmacológicas. Polimorfismos do gene DfiH são responsavéis pelas diferenças individuais no tom dopaminérgico e adrenérgico dos sistemas nervoso central e autonomo. Como as mutações defeituosas da enzima e suas frequências variam entre as etnias, se justificam os estudos conduzentes à caracterização da e fenotípica da enzima en mestiços colombianos.Métodos: determinamos as frequencias alelos -2073C>T, -970C>T, 444A>G e 1603C>T do gene DfiH em 143 adultos sãos, traços mestiços, ambos sexos e não consanguíneos. A genotipificação se fez por PCR-real time e minisequência (SnaPshot).Resultados: as frequências dos genotipos polimórficos foram: -2073C>T (CC 61,5%, CT 32,9%, TT 5,6%), -970C>T (CC 49,6%, CT 43,4, TT 7%) e 444A>G (AA 42%, AG 41,2%, GG 16,8%). As três mutações estão em desiquilibrio de ligamiento (D'=1) mas não se substituem mutuamente (r2<0,8). 15 pessoas (10,5%) tiveram haplotipo de triple homocigoto nativo (CC/CC/AA).Conclusão: nossas frequências alélicas se assemelham às lembradas em outros grupos mestiças latino-americanos.

Xanthoangelol and 4-Hydroxyderricin Are the Major Active Principles of the Inhibitory Activities against Monoamine Oxidases on Angelica keiskei K

Monoamine oxidase inhibitors (MAOI) have been widely used as antidepressants. Recently, there has been renewed interest in MAO inhibitors. The activity-guided fractionation of extracts from Angelica keiskei Koidzumi (A. keiskei K.) led to the isolation of two prenylated chalcones, xanthoangelol and 4-hydroxyderricin and a flavonoid, cynaroside. These three isolated compounds are the major active ingredients of A. keiskei K. to inhibit the MAOs and DBH activities. Xanthoangelol is a nonselective MAO inhibitor, and a potent dopamine beta-hydroxylase (DBH) inhibitor. IC50 values of xanthoangelol to MAO-A and MAO-B were calculated to be 43.4 microM, and 43.9 microM. These values were very similar to iproniazid, which is a nonselective MAO inhibitor used as a drug against depression. The IC50 values of iproniazid were 37 microM, and 42.5 microM in our parallel examination. Moreover, IC50 value of xanthoangelol to DBH was calculated 0.52 microM. 4-Hydroxyderricin is a potent selective MAO-B inhibitor and also mildly inhibits DBH activity. The IC50 value of 4-hydroxyderricin to MAO-B was calculated to be 3.43 microM and this value was higher than that of deprenyl (0.046 microM) used as a positive control for selective MAO-B inhibitor in our test. Cynaroside is a most potent DBH inhibitor. The IC50 value of cynaroside to DBH was calculated at 0.0410 microM. Results of this study suggest that the two prenylated chalcones, xanthoangelol and 4-hydroxyderricin isolated from A. keiskei K., are expected for potent candidates for development of combined antidepressant drug. A. keiskei K. will be an excellent new bio-functional food material that has the combined antidepressant effect.

Electroacupuncture Analgesia Is Improved by Adenoviral Gene Transfer of Dopamine Beta-hydroxylase into the Hypothalamus of Rats

Electroacupuncture (EA) is a modified form of acupuncture that utilizes electrical stimulation. We previously showed that EA stimulated rats were divided into responders that were sensitive to EA and non-responders that were insensitive to EA based on the tail flick latency (TFL) test. The dopamine beta-hydroxylase (DBH) gene was more abundantly expressed in the hypothalamus of responder rats than non-responder rats. To determine whether overexpression of DBH gene expression in the hypothalamus modulate EA analgesia, we constructed a DBH encoding adenovirus and which was then injected into the hypothalamus of SD rats. Microinjection of DBH or control GFP virus into the hypothalamus had no changes on the basal pain threshold measured by a TFL test without EA treatment. However, the analgesic effect of EA was significantly enhanced from seven days after microinjection of the DBH virus, but not after injection of the control GFP virus. DBH expression was significantly higher in the hypothalamus of DBH virus injected rat than control GFP virus or PBS injected rats. Moreover, expression of the DBH gene did not affect the body core temperature, body weight, motor function or learning and memory ability. Although the functional role of DBH in the hypothalamus in the analgesic effect of EA remains unclear, our findings suggest that expression of the DBH gene in the hypothalamus promotes EA analgesia without obvious side-effects.

Anti-stress effects of ginseng via down-regulation of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) gene expression in immobilization-stressed rats and PC12 cells

Catecholamines are among the first molecules that displayed a kind of response to prolonged or repeated stress. It is well established that long-term stress leads to the induction of catecholamine biosynthetic enzymes such as tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) in adrenal medulla. The aim of the present study was to evaluate the effects of ginseng on TH and DBH mRNA expression. Repeated (2 h daily, 14 days) immobilization stress resulted in a significant increase of TH and DBH mRNA levels in rat adrenal medulla. However, ginseng treatment reversed the stress-induced increase of TH and DBH mRNA expression in the immobilization-stressed rats. Nicotine as a ligand of the nicotinic acetylcholine receptor (nAChR) in adrenal medulla stimulates catecholamine secretion and activates TH and DBH gene expression. Nicotine treatment increased mRNA levels of TH and DBH by 3.3- and 3.1-fold in PC12 cells. The ginseng total saponin exhibited a significant reversal in the nicotine-induced increase of TH and DBH mRNA expression, decreasing the mRNA levels of TH and DBH by 57.2% and 48.9%, respectively in PC12 cells. In conclusion, immobilization stress induced catecholamine biosynthetic enzymes gene expression, while ginseng appeared to restore homeostasis via suppression of TH and DBH gene expression. In part, the regulatory activity in the TH and DBH gene expression of ginseng may account for the anti-stress action produced by ginseng.

Association between polymorphism of dopamine β-hydroxylase and neurological dysfunction hereditary susceptibility of electric welders / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate the relationship between genetic polymorphism of dopamine β-hydroxylase (DBH) and manganese-induced nerve injury.</p><p><b>METHODS</b>In a cross-sectional study, 402 electric welders who had worked over one year in relatively fixed sites were recruited, and the concentration of manganese in which they worked was stable. These samples was divided into high exposure group (CEI > 1) and low exposure group (CEI < 1) by CEI. Between the two groups, the groups were divided into abnormal group and normal group according to the result of neurologic check (there were 81 workers with abnormal neurological dysfunction in high exposure group and 28 workers in low exposure group, P < 0.05). Polymorphism of DBH gene was analyzed with polymerase chain reaction-restriction fragment length polymorphism.</p><p><b>RESULTS</b>The distribution of A2A2 genotype and A2 allele of DBH was significantly different. In high exposure group, the distribution of A2A2 genotype and A2 allele of DBH in abnormal group was significantly wider than in normal group (A2A2 genotype, OR = 1.248, P < 0.05, A2 allele, OR = 1.103, P < 0.05). In low exposure group, the distribution of A2 allele of DBH in abnormal group was significantly wider than in normal group (OR = 1.176, P < 0.05).</p><p><b>CONCLUSION</b>The individuals who carry A2A2 genotype and A2 allele of DBH have increased risk of neurological dysfunction after explosion to manganese for a certain time, which suggests that polymorphism of DBH (intron 5 Taq I) would play a great role in hereditary susceptibility of neurological dysfunction cause by manganese.</p>

Effect of immobilization stress on gene expression of catecholamine biosynthetic enzymes in heart auricles of socially isolated rats

Chronic stress is associated with the development of cardiovascular diseases. The sympathoneural system plays an important role in the regulation of cardiac function both in health and disease. In the present study, the changes in gene expression of the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine-â-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) and protein levels in the right and left heart auricles of naive control and long-term (12 weeks) socially isolated rats were investigated by Taqman RT-PCR and Western blot analysis. The response of these animals to additional immobilization stress (2 h) was also examined. Long-term social isolation produced a decrease in TH mRNA level in left auricles (about 70 percent) compared to the corresponding control. Expression of the DBH gene was markedly decreased both in the right (about 62 percent) and left (about 81 percent) auricles compared to the corresponding control, group-maintained rats, whereas PNMT mRNA levels remained unchanged. Exposure of group-housed rats to acute immobilization for 2 h led to a significant increase of mRNA levels of TH (about 267 percent), DBH (about 37 percent) and PNMT (about 60 percent) only in the right auricles. Additional 2-h immobilization of individually housed rats did not affect gene expression of these enzymes in either the right or left auricle. Protein levels of TH, DBH and PNMT in left and right heart auricles were unchanged either in both individually housed and immobilized rats. The unchanged mRNA levels of the enzymes examined after short-term immobilization suggest that the catecholaminergic system of the heart auricles of animals previously exposed to chronic psychosocial stress was adapted to maintain appropriate cardiovascular homeostasis.

Efecto de agonistas y antagonistas de la dopamina en ambientes de reforzamiento variables / Effects of dopamine agonists and antagonists in variable reinforcing environments

Según la hipótesis de la anhedonia el valor placentero de la comida está determinado por la actividad de dopamina en el cerebro. La evidencia empírica muestra que los agonistas y antagonistas a la dopamina (e.g., metilfenidato y haloperidol, respectivamente) disminuyen la conducta operante mantenida con reforzamiento positivo. Se utilizó la ley generalizada de igualación (Baum, 1974) para evaluar efectos de estas drogas en la motricidad y motivación del organismo por la comida. Treinta y dos ratas buscaron alimento en una situación de elección donde la razón de reforzamiento que proporcionaban dos alternativas cambia diariamente. Los resultados confirmaron que las drogas no impiden la rápida adaptación de las ratas a los cambios dinámicos en las contingencias de reforzamiento. Se evidenció un incremento en la sensibilidad de las razones de respuestas a los cambios en las razones de los reforzadores. La alternativa de mayor demanda motriz para el organismo mostró una reducción en el número de respuestas, sugiriendo efectos de las drogas en la motricidad del organismo.

The anhedonia hypothesis maintains that pleasure for food-reward is determined by dopamine activity in the brain. The cumulative body of empiricalevidence shows that dopamine agonists and antagonists (e.g., Methylphenidateand Haloperidol, respectively) decrease operant behavior maintained by positive reinforcement. The present study used the generalized matching law (Baum, 1974) to assess effects of these drugs on the motor system and the organism’s motivation for food reinforcers. Thirty-two rats searched for food in a choice situation where the reinforcer ratio provided by two alternativeschanged everyday. The results confirmed that the drugs do not impede the rats’ rapid adaptation to dynamic changes in the contingencies of reinforcement. Preference favored with more responses the alternative associated to the higher probability of reinforcement, showing an increment in sensitivity of behavior ratio to changes in food ratios. The alternative demanding the higher motor requirement showed a decrement in the number of responses, suggesting effects of the drugs in the organism’s motor system.

Neurobiología del TDAH / Neurobiology of attention deficit hyper activity disorder

El trastorno de déficit de atención con hiperactividad es una alteración neurobiológica caracterizada por la presencia de tres síntomas: déficit de atención, hiperactividad e impulsividad, en el cual influyen factores biológicos y ambientales que determinan su manifestación clínica. Afecta al 8-10 por ciento de la población escolar y es más frecuente en varones (3:1). En el trastorno de déficit de atención con hiperactividad existe gran variabilidad fenotípica y comorbilidad. La corteza prefrontal, el núcleo caudado, los circuitos fronto-estriatales y el cerebelo tienen un papel destacado en su fisiopatogenia. El patrón electroencefalográfico con un incremento de la actividad theta sugiere la presencia de baja maduración cerebral en algunos pacientes. El sueño también puede presentar anomalías. Los potenciales evocados cognitivos demuestran una alteración del procesamiento cognitivo y una disfunción de los mecanismos atencionales. La teoría bioquímica se basa en la función de las catecolaminas, las nuevas propuestas destacan el papel fundamental de la dopamina y la norepinefrina. El trastorno de déficit de atención con hiperactividad es poligénico, algunos de los genes candidatos son el gen del transportador de la norepinefrina (NET1), el gen del receptor D1 de la dopamina (DRD1), el gen transportador de la dopamina DAT1 y el gen del receptor D 4 de la dopamina (DRD4).

Analysis of polymorphisms in the dopamine beta hydroxylase gene: association with attention deficit hyperactivity disorder in Indian children.

OBJECTIVE: To study the association of Attention Deficit Hyperactivity Disorder (ADHD) and polymorphism in the dopamine beta hydroxylase (DBH) gene in Indian ADHD cases. SUBJECTS: Forty one ADHD cases were diagnosed as per the DSM-IV-TR criteria and evaluated by Conners Parents and Teachers Rating Scale and Wechslers Intelligence Scale for Children. METHODS: Genomic DNA was amplified for exon 2 *444g/a and intron 5 (Taq I) polymorphism in the DBH gene followed by restriction fragment length polymorphism (RFLP) analysis. Haplotype-based haplotype relative risk (HHRR) was analyzed to ascertain the transmission pattern of these two polymorphisms in ADHD cases. Linkage disequilibrium (LD) between the two polymorphisms was calculated using EH+ and 2LD programs. RESULTS: In the limited number of samples analyzed, a slight increase in transmission of the 444a allele in ADHD subjects was observed for DBH 444g/a. The intron 5 (Taq I) polymorphism showed no significant association with ADHD in these cases. Strong disequilibrium was observed between DBH444g/a and intron 5 (Taq I) polymorphism. CONCLUSION: This is the first molecular genetic study on ADHD in Indian subjects exploring transmission of polymorphisms in the DBH gene. Preliminary investigation shows a trend towards association between the transmission of DBH444a allele and ADHD. No association was noticed between transmission of intron 5 (Taq I) polymorphism and ADHD in the Indian subjects. Presence of strong LD may point towards co-segregation of these two polymorphisms more often than expected.

Association between dopamine beta hydroxylase gene and attention deficit hyperactivity disorder complicated with disruptive behavior disorder / 中华儿科杂志

<p><b>OBJECTIVE</b>Attention deficit hyperactivity disorder (ADHD), a common behavior disorder of childhood, is a highly heterogeneous disease frequently accompanied by various mental disorders, including disruptive behavior disorder (DBD). Studies show that children suffering from ADHD with DBD are at higher risk of antisocial personality, substance abuse, and social adaptations disorder at their adulthood. The dopamine beta hydroxylase (DbetaH) is the key enzyme to ADHD since it catalyzes the conversion of dopamine to norepinephrine, and dysfunction there of is believed to be one of the causes of the disorder. To explore the association between DBH gene and ADHD complicated with or without DBD, the authors analyzed the transmission of a novel polymorphism DBH -1021C-->T, which is found associated with plasma DbetaH activity, in ADHD nuclear families using transmission disequilibrium test (TDT).</p><p><b>METHODS</b>Consensus diagnoses were based on the DSM-IV. The samples included those from 292 Chinese Han nuclear families with ADHD probands. Genotypes of DBH -1021C-->T polymorphism were determined by PCR amplification, endonuclease digesting and electrophoresis. The transmission of DBH -1021C-->T polymorphism in ADHD nuclear families with or without DBD was analyzed by TDT.</p><p><b>RESULTS</b>The results showed that there was transmission disequilibrium between DBH-1021C-->T polymorphism and ADHD with or without DBD. In ADHD comorbid with DBD, T allele was preferentially transmitted (P < 0.05); and in ADHD without DBD, so was the C allele (P < 0.05). Among the three subtypes of ADHD, only ADHD-C subtype with DBD had an increased transmission of T allele (P < 0.05).</p><p><b>CONCLUSION</b>There is an association between DBH gene and ADHD comorbid with or without DBD, but the preferential transmission alleles are different. The low activity T allele is increased to transmit in ADHD with DBD, while the high activity C allele is preferentially transmitted in ADHD without DBD. The results support the proposition that the genetic mechanism is different between ADHD comorbid with or without DBD. We also found that only ADHD-C subtype with DBD is associated with DBH -1021C-->T polymorphism in three subtypes of ADHD, which may suggest that there is a more intense relationship between DBD and ADHD-C subtype.</p>

Dopamine beta hydroxylase gene polymorphism and Parkinson's disease / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the correlation between the polymorphism of dopamine beta hydroxylase(DBH) gene and the susceptibility of Shanghai Chinese Han population to Parkinson's disease(PD).</p><p><b>METHODS</b>Association study was performed in 144 PD patients and 188 healthy control subjects matched for age, sex and origin. Polymorphism of DBH gene was analyzed with polymerase chain reaction-restriction fragment length polymorphism.</p><p><b>RESULTS</b>The allelic frequency of A2 allele of DBH gene was significantly higher in PD patients than in controls(P<0.01).The risk of suffering from PD increased (OR=1.82) in the individual with A2 allele. And the genotypic frequency of A2/A2 was significantly higher in PD patients(OR=2.11, P<0.01),too. On the other hand, the allelic frequency of A1 allele and the genotypic frequency of A1/A2 genotype of DBH gene in PD patients were significantly lower(A1 alleles: OR=0.54, P<0.01; A1/A2 genotypes: OR=0.45, P<0.01).</p><p><b>CONCLUSION</b>The polymorphism in DBH gene might play an important role in the susceptibility of Shanghai Chinese Han population to PD.</p>

Hypotension Caused by a Disulfiram-Alcohol Reaction

Disulfiram, or antabuse, is used in the treatment of chronic alcoholism since it causes an unpleasant aversive reaction to alcohol. It works by inactivating hepatic aldehyde dehydrogenase, leading to a pronounced rise in the acetaldehyde concentration when ethanol is metabolized. Acetaldehyde causes alcohol sensitivity, which involves vasodilation associated with increased skin temperature, subjective feelings of hotness and facial flushing, increased heart and respiration rates, lowered blood pressure, a drymouth or throat sensation associated with bronchoconstriction and allergy reactions, nausea, and headache. One of its metabolites, diethyldithiocarbamate (DDC) can inhibit the enzyme dopamine beta-hydroxylase (DBH) through copper chelation. This may account for the profound refractory hypotension seen with the disulfiram-ethanol reaction (DAR), resulting from norepinephrine depletion. This report is presents the case of a patient we met, who presented with severe hypotension caused by the disulfiram-alcohol reaction, and along with a brief review of the subject.

Aspectos morfo-funcionales de arterias y venas mamarias usadas en revascularización cardíaca / Morphologic and functional aspects of mammary arteries and veins used for myocardial revascularization surgery

Los vasos sanguíneos están inervados por el sistema nervioso simpático autonómico. La fisiología y neuroquímica de los nervios perivasculares humanos ha sido poco estudiada. Con el propósito de contribuir a las investigaciones sobre la fisiología de la co-transmisión simpática humana, esta investigación se concentró en: i) estudiar el contenido de los neurotransmisores simpáticos, noradrenalina (NA) y neuropéptido y (NPY) en vasos de arteria y vena mamaria interna humana; ii) detectar mediante técnicas inmunohistoquímicas la presencia de los nervios simpáticos perivasculares de estos vasos; iii) caracterizar la reactividad vascular de la arteria mamaria interna, como un modelo usado en implantes de revascularización cardíaca. Se estudió además, la vena mamaria derivada de la misma biopsia. La arteria y vena mamaria contienen 50 veces más NA que NPY, el contenido de NA y NPY en la arteria y en la vena es muy similar. La detección inmunohistoquímica de los nervios simpáticos demuestra que éstos se localizan entre las capas musculares de los vasos. La estimulación de los filetes nerviosos perivasculares produce respuestas vasomotoras sensibles a tetrodotoxina y guanetidina, lo que es consistente con la naturaleza simpática de la respuesta, confirmando que parte de los nervios perivasculares son simpáticos. Los músculos lisos se estimulan por NA y por ATP, que sólo no contrae, facilita las respuestas vasomotoras de la NA. Estos resultados permiten concluir que en la arteria y la vena mamaria interna humana NA, ATP y NPY cooperan en la respuesta vasomotora, evidenciando la co-transmisión simpática en humanos

Dopaminergic Neurons in the Olfactory Bulb: A Differences in the Insectivore and Rodents / 대한해부학회지

These studies document species differences in the distribution of the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) within the main olfactory bulb (MOB) of a number of rodents and insectivore species including the rat, wild mouse, mongolian gerbil, stripped field mouse (apodemus agrarius), hedgehog, mole, laboratory shrew (suncus murinus). TH-containing neuronal perikarya were observed in the MOB of the both species of the rodents and insectivore except the hedgehog and laboratory shrew (suncus murinus). None of these cell groups displayed either dopamine beta hydroxylase (DBH) or phenylethanolamine-N-methyltransferase (PNMT). The number of stained somata and their intensity varied such that label was most prominent in the stripped field mouse followed in decreasing order by the rat, mongolian gerbil, wild mouse and mole. The vast majority of such cells occurred in the glomerular layer as periglomerular cells surrounging the glomeruli of the stripped field mouse, rat, mongolian gerbil, wild mouse and moles. Numerous additional cells were present in the external plexiform layer (EPL) and mitral cell layer (MCL). These often displayed long ascending immunoreactive processes and appeared to correspond to tufted cells. Also a few smaller, multipolar cells were present in the internal granular layer scattered among the granule cells. However, the hedgehog and laboratory shrew displayed no perikaryal staining in the MOB. In conclusion, these data suggest that TH is present in the MOB of stripped field mouse, rat, mongolian gerbil, wild mouse and moles but is not found in the MOB of the hedgehog and laboratory shrew, or that species differences exist in the level of TH.

Immunochemical localization of chromaffin cells during the embryogenic migration

Adrenal medulla together with the sympathetic nervous system constitute an anatomo functional unit. Both tissues derive from precursor cells which originate from the neural crest and later differentiate during migration into sympathetic neurons or chromaffin cells. Biosynthesis enzymes of catecholamines such as DBH (dopamine beta hydroxylase) and PNMT (phenylethanol amine-N-methyl transferase) as well as the neurotransmitter serotonin , can be detected by immunohistochemical techniques from 15 to 20 prenatal days. Cells migrating along the dorsal aorta could be observed at 15 prenatal days. From day 16 on, three distinct cellular groups could be distinguished according to the intensity of the immunoreactivity: chromaffin, paraganglion and sympathetic ganglion cells. From day 18, chromaffin cells immunostained as DBH' PNMT+ or DBH+ PNMT could be detected differentiating into what would be adrenergic or noradrenergic cells, respectively Progenitor cells migrating from the neural crest to the adrenal cortical blastema reach a micro-environment where glucocorticoids could possibly influence gene expression for PNMT in some of these undifferentiated cells, causing adrenaline synthesis. Serotonin(5HT) immunoreactivity is localized from 17 prenatal days in several groups of the paraganglionic cells where they could be a modulator for chromaffin differentiation.

Dopamine beta-hydroxylase activity in familial mediterranean fever

The diagnosis of the familial Mediterranean fever [FMF] is based primarily upon clinical presentation, familial history, therapeutic trial with colchicine and remains a diagnosis of exclusion as there is no specific laboratory test. On the hypothesis that the pathogenesis of FMF is related to abnormality in catecholamine metabolism, the activity of plasma dopamine beta-hydroxylase [DBH], an enzyme released simultaneously with catecholamines, was assayed spectrophotometrically in 23 patients with FMF and 30 controls. The activity was significantly higher in untreated, symptom-free patients and in patients with acute attacks than in controls or patients with FMF receiving colchicine. It can be concluded that the measurement of plasma DBH activity may be useful for the diagnosis of FMF

Noradrenergic Changes in an Experimental Model of Parkinsonism Using 6-hydroxydopamine

BACKGROUND & OBJECTIVE: Stereotaxic injection of 6-hydroxydopamine(6OHDA) into the ventral midbrain is the most commonly used Parkinsonian animal model. In the presence of norepinephrine(NE) uptake blockers, 6OHDA is believed to be selectively toxic to the dopamine(DA) system. However, it was observed in this model that there is a massive fiber degeneration in the fornix, where there are no known DA fibers. There are NE fibers in the fornix arising from the locus ceruleus (LC) terminating in the cerebral cortex including hippocampus. The study was done to examine whether there is a change in the NE system and characterize the neurochemical nature of the previously demonstrated degenerating fornix fibers. METHODS: 6OHDA was injected stereotaxically into the unilateral ventral midbrain in desipramine pretreated rats. DA and NE were measured in the striatum, cortex, hippocampus, and LC. Silver staining was done to demonstrate degenerating neurons and nerve terminals. Immunohistochemistry using tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) was done to demonstrate catecholamine neurons and nerve fibers. RESULTS: DA was markedly depleted in the ipsilateral striatum. NE was decreased in the striatum, cortex, and hippocampus, but not in the LC. Silver staining showed massive fiber degeneration in the fornix, but did not show degenerating neurons in the LC. TH and DBH Immunohistochemistry failed to show catecholaminergic fibers in the fornix. There was no side difference on immunostaining in the LC neurons. CONCLUSION: 6OHDA Parkinson model does not make selective lesion to the DA system, and damages ascending NE fibers. Neuronal cell bodies in the LC remain intact in this model. The neurochemical nature of the degenerating fornix fibers is not clearly characterized.

In vitro effect of dithiocarbamate pesticides and of CaNa2EDTA on human serum dopamine-beta-hydroxylase / 生物医学与环境科学（英文）

Serum dopamine-beta-hydroxylase (DBH) inhibition has been reported in lead workers treated with CaNa2EDTA and in alcoholic patients repeatedly treated with the alcohol aversive drug Disulfiram. The mechanism of inhibition involves Cu++ chelation at the active site of DBH. The effect of CaNa2EDTA and Disulfiram on serum DBH has been compared to the effect of dithiocarbamate pesticides in vitro for the possible use of serum DBH determination for the biological monitoring of workers exposed to these pesticides. Most dithiocarbamates inhibit human serum DBH at micromolar concentrations (range of I50, 0.027-1.6 mumol/L). The inhibitory potency increased from methyl- and dimethyl dithiocarbamates to diethyl dithiocarbamates up to the most potent ethylene bisdithiocarbamates. The I50 of CaNa2EDTA was 3.8 mumol/L, higher than those of dithiocarbamates. Copper addition to the test system reactivated at stoichiometric concentrations dithiocarbamate-inhibited DBH indicating that both base line values and percent of inhibition can be calculated in a single blood sample. Results suggest that serum DBH determination could be useful in case of acute poisoning involving high doses of dithiocarbamate pesticides.

Familial dysautonomia: (Riley-Day syndrome)

A disautonomia familial, também conhecida por síndrome de Riley-Day, é desordem do sistema nervoso autônomo como herança autossômica recissiva. Reduçäo e/ou perda de fibras pouco mielinizadas e näo mielinizadas é encontrada, bem como reduçäo da dopamina beta-hidroxilase no sangue. O diagnóstico é clínico: diminuiçäo do lacrimejamento, insensibilidade à dor, distúrbio do controle têrmico, reflexos profundos abolidos ou hipoativos, hipotensäo postural, vômitos, pobre coordenaçäo motora e retardo mental. O tratamento é sintomático e amaioria das crianças morre nos primeiros anos de vida, geralmente por pneumonias aspirativas de repetiçäo. Relatamos o caso de uma criança de 1 ano de idade com disautonomia familial