Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics / Bloqueio do Sistema Renina-Angiotensina Associado a Estatina Melhora a Função Endotelial em Diabéticos

Abstract Background: Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness. Objective: To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness. Methods: Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring), endothelial function (brachial artery flow-mediated dilation), and vascular stiffness (pulse wave velocity) were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively). Results: The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007), and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003) when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820). There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586). Conclusion: Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes.

Resumo Fundamentos: Estudos sugerem que as estatinas possuem efeitos pleotrópicos, como melhora da função endotelial, da rigidez vascular e redução da pressão arterial. Objetivo: Analisar se o uso prévio de estatina influenciou o efeito sobre a pressão arterial, a função endotelial e a rigidez vascular de drogas inibidoras do sistema renina-angiotensina-aldosterona. Métodos: Pacientes hipertensos e diabéticos com pressão arterial de consultório sistólica ≥ 130 mmHg e/ou diastólica ≥ 80 mmHg tiveram suas medicações anti-hipertensivas substituídas por anlodipino durante 6 semanas. Em seguida, foram randomizados para associação de benazepril ou losartana por mais 12 semanas. Pressão arterial (através da monitorização ambulatorial da pressão arterial), função endotelial (dilatação mediada por fluxo da artéria braquial) e rigidez vascular (velocidade da onda de pulso) foram avaliados antes e após o tratamento combinado. Neste trabalho, uma análise post-hoc foi realizada para comparar pacientes que vinham (grupo CE) ou não (grupo SE) em uso de estatina. Resultados: O grupo CE apresentou maior redução na pressão arterial sistólica nas 24 horas (134 para 122 mmHg, p = 0,007) e na dilatação mediada por fluxo da artéria braquial (6,5 para 10,9%, p = 0,003) quando comparado com o grupo SE (137 para 128 mmHg, p = 0,362, e 7,5 para 8,3%, p = 0,820). Não houve diferença estatisticamente significante na velocidade de onda de pulso (grupo CE 9,95 para 9,90 m/s, p = 0,650 e grupo SE 10,65 para 11,05 m/s, p = 0,586). Conclusão: O uso combinado de estatinas, anlodipino e inibidores do sistema renina-angiotensina-aldosterona melhora a resposta anti-hipertensiva e a função endotelial em pacientes hipertensos e diabéticos.

Ivabradine Improves Heart Rate Variability in Patients with Nonischemic Dilated Cardiomyopathy / Ivabradina Melhora a Variabilidade da Frequência Cardíaca em Pacientes com Cardiomiopatia Dilatada Não Isquêmica

Background: Ivabradine is a novel specific heart rate (HR)-lowering agent that improves event-free survival in patients with heart failure (HF). Objectives: We aimed to evaluate the effect of ivabradine on time domain indices of heart rate variability (HRV) in patients with HF. Methods: Forty-eight patients with compensated HF of nonischemic origin were included. Ivabradine treatment was initiated according to the latest HF guidelines. For HRV analysis, 24-h Holter recording was obtained from each patient before and after 8 weeks of treatment with ivabradine. Results: The mean RR interval, standard deviation of all normal to normal RR intervals (SDNN), the standard deviation of 5-min mean RR intervals (SDANN), the mean of the standard deviation of all normal-to-normal RR intervals for all 5-min segments (SDNN index), the percentage of successive normal RR intervals exceeding 50 ms (pNN50), and the square root of the mean of the squares of the differences between successive normal to normal RR intervals (RMSSD) were low at baseline before treatment with ivabradine. After 8 weeks of treatment with ivabradine, the mean HR (83.6 ± 8.0 and 64.6 ± 5.8, p < 0.0001), mean RR interval (713 ± 74 and 943 ± 101 ms, p < 0.0001), SDNN (56.2 ± 15.7 and 87.9 ± 19.4 ms, p < 0.0001), SDANN (49.5 ± 14.7 and 76.4 ± 19.5 ms, p < 0.0001), SDNN index (24.7 ± 8.8 and 38.3 ± 13.1 ms, p < 0.0001), pNN50 (2.4 ± 1.6 and 3.2 ± 2.2 %, p < 0.0001), and RMSSD (13.5 ± 4.6 and 17.8 ± 5.4 ms, p < 0.0001) substantially improved, which sustained during both when awake and while asleep. Conclusion: Our findings suggest that treatment with ivabradine improves HRV in nonischemic patients with HF. .

Fundamento: A ivabradina é um novo agente redutor específico da frequência cardíaca (FC) que melhora a sobrevida livre de eventos de pacientes com insuficiência cardíaca (IC). Objetivo: Avaliar o efeito da ivabradina nos índices temporais da variabilidade da frequência cardíaca (VFC) em pacientes com IC. Métodos: Quarenta e oito pacientes com IC compensada de etiologia não-isquêmica foram incluídos no estudo. O tratamento com ivabradina foi iniciado de acordo com as recomendações mais recentes para a IC. O Holter de 24 horas foi utilizado para analisar os índices da VFC em cada paciente antes e após 8 semanas de tratamento com ivabradina. Resultados: Todos os índices da VFC, o intervalo RR médio, o desvio padrão de todos os intervalos RR normais (DPNN), o desvio padrão de intervalos RR médios de 5 minutos (DPNNM), a média do desvio padrão de todos os intervalos RR normais para todos os segmentos de 5 minutos (índice DPNN), porcentagem de intervalos RR normais sucessivos superiores a 50 milissegundos (pNN50), e a raiz quadrada da média dos quadrados das diferenças entre intervalos RR sucessivos (RMQQD) apresentaram redução no ínicio do estudo, antes do tratamento com ivabradina. Após 8 semanas de tratamento com ivabradina, as médias das FC (83,6 ± 8,0 e 64,6 ± 5,8, p < 0,0001) e todos os índices da VFC, médias dos intervalos RR (713 ± 74 e 943 ± 101 ms, p < 0,0001), DPNN (56,2 ± 15,7 e 87,9 ± 19,4 ms, p < 0,0001), DPNNM (49,5 ± 14,7 e 76,4 ± 19,5 ms, p < 0,0001), índice DPNN (24,7 ± 8,8 e 38,3 ± 13,1 ms, p < 0,0001), pNN50 (2,4 ± 1,6 e 3,2 ± 2,2%, p < 0,0001) e RMQQD (13,5 ± 4,6 e 17,8 ± 5,4 ms , p < 0,0001), foram substancialmente melhorados, e permaneceram nestas ...

Participación del odontólogo en una experiencia clínica utilizando Vareniclina para tratamiento de cesación tabáquica / Dentist´s participation in a clinical experience using Varenicline for the treatment of tobacco cessation

El uso del tabaco es un factor de riesgo para padecer cáncer bucal, lesiones de la mucosa, enfermedad periodontal y problemas de cicatrización después de tratamientos periodontal, cirugía e implantes, además de recesión gingival, caries coronal y radicular. La evidencia disponible sugiere que el riesgo de enfermedad oral se incrementa en pacientes fumadores y su cesación resulta en disminución del riesgo, pudiendo resolverse algunas lesiones de la mucosa oral. La AAP indica incluir cesación tabáquica en la terapia periodontal inicial. Se presenta una experiencia clínica cuyo objetivo era determinar el porcentaje de éxito, reducción o fracaso de los pacientes tratados con Vareniclina(Champix®). Fueron atendidos 75 pacientes fumadores por 10 periodoncistas y 8 cirujanos bucales a los cuales se les presentó una entrevista motivacional explicándoles la fisiopatología de la adicción, los daños y beneficios de dejar de fumar, así mismo, se les realizó historia clínica y Test de Fagerstron para evaluar dependencia a la nicotina y se trataron con terapia cognitiva conductual y farmacológica utilizando tratamiento con Vareniclina por 12 semanas, en dosis de 0,5mgs y 1 mg las primeras 2 semanas y 2 mgs por 10 semanas, se establecieron criterios de inclusión y exclusión, se firmó consentimiento informado, se hicieron consultas de seguimiento por 16 semanas, con un programa de soporte y apoyo conductual creado por Pfizer Venezuela. Los resultados muestran 90 por ciento de éxito, 5 por ciento reducción y 5 por ciento fracaso, siendo los efectos adversos más frecuentes: náuseas y cefaleas. Con bajos síntomas de abstinencia a la nicotina. La intervención del odontólogo en la cesación tabáquica con terapia conductual y vareniclina, resulta exitosa y contribuye con la salud bucal y sistémica de los pacientes.

Different Regulation of Atrial ANP Release through Neuropeptide Y2 and Y4 Receptors

Neuropeptide Y (NPY) receptors are present in cardiac membranes. However, its physiological roles in the heart are not clear. The aim of this study was to define the direct effects of pancreatic polypeptide (PP) on atrial dynamics and atrial natriuretic peptide (ANP) release in perfused beating atria. Pancreatic polypeptides, a NPY Y4 receptor agonist, decreased atrial contractility but was not dose-dependent. The ANP release was stimulated by PP in a dose-dependent manner. GR 23118, a NPY Y4 receptor agonist, also increased the ANP release and the potency was greater than PP. In contrast, peptide YY (3-36) (PYY), an NPY Y2 receptor agonist, suppressed the release of ANP with positive inotropy. NPY, an agonist for Y1, 2, 5 receptor, did not cause any significant changes. The pretreatment of NPY (18-36), an antagonist for NPY Y3 receptor, markedly attenuated the stimulation of ANP release by PP but did not affect the suppression of ANP release by PYY. BIIE0246, an antagonist for NPY Y2 receptor, attenuated the suppression of ANP release by PYY. The responsiveness of atrial contractility to PP or PYY was not affected by either of the antagonists. These results suggest that NPY Y4 and Y2 receptor differently regulate the release of atrial ANP.

Preferential blockade by clozapine of hyperlocomotion induced by non-competitive NMDA antagonist MK-801.

Effect of clozapine on MK-801-induced hyperlocomotion and stereotypy as well as open field behavior was studied. Clozapine (0.1-7.5 mg/kg) dose-dependently blocked MK-801(0.5 mg/kg)-induced stereotypy. Both total and ambulatory responses were blocked by even the lower doses (0.1-0.5 mg/kg) of clozapine. In open field test, clozapine selectively blocked hyperambulation induced by MK-801 (0.1 mg/kg) whereas it potentiated MK-801 (0.1 mg/kg)-induced stereotypy at all the doses used. Haloperidol (0.25 and 0.5 mg/kg) and SCH 23390 (0.5 and 1 mg/kg) showed a dose-dependent effect on MK-801-induced behaviors while sulpiride (25 and 50 mg/kg) failed to modify MK-801-induced open field behavior. This study supports the preferential effect of clozapine on dopamine receptors located in mesolimbic area and further suggests the possibility of using open field behavior induced by MK-801 as a model for studying atypical antipsychotics.

Agents that affect cAMP levels or protein kinase A activity modulate memory consolidation when injected into rat hippocampus but not amygdala

Male Wistar rats were trained in one-trial step-down inhibitory avoidance using a 0.4-mA footshock. At various times after training (0, 1.5, 3,6 and 9 h for the animals implanted into the CA1 region of the hippocampus; 0 and 3 h for those implanted into the amygdala), these animals received microinfusions of SKF38393 (7.5 mug/side), SCH23390 (0.5 mug/side), norepinephrine (0.3 mug/side), timolol (0.3 mug/side), 8-OH-DPAT (2.5 mug/side), NAN-190 (2.5 mug/side), forskolin (0.5 mug/side), KT5720 (0.5 mug/side) or 8-Br-cAMP (1.25 mug/side). Rats were tested for retention 24 h after training. When given into the hippocampus 0 h post-training, norepinephrine enhanced memory whereas KT5720 was amnestic. When given 1.5 h after training, all treatments were ineffective. When given 3 or 6 h post-training, 8-Br-cAMP, forskolin, SKF38393, norepinephrine and NAN-190 caused memory facilitation, while KT5720, SCH23390, timolol and 8-OH-DPAT caused retrograde amnesia. Again, at 9 h after training, all treatments were inffective. When given into the amygdala, norepinephrine caused retrograde facilitation at 0 h after training. The other drugs infused into the amygdala did not cause any significant effect. These data suggest that in the hippocampus, but not in the amygdala, a cAMP/protein kinase A pathway is involved in memory cosolidation at 3 and 6 h after training, which is regulated by D1, Beta, and 5HT1A receptors. This correlates with data on increased post-training cAMP levels and a dual peak of protein kinase A activity and CREB-P levels (at 0 and 3-6 h) in rat hippocampus after training in this task. These results suggest that the hippocampus, but not the amygdala, is involved in long-term storage of step-down inhibitory avoidance in the rat.

Transient expression of an atypical D1-like dopamine receptor system during avian retina differentiation

Intact cultured retina cells from chick embryos at stage E9C5 (cultures initiated with retinae from 9-day old embryos followed by 5 days in culture), preincubated with 2 nM unlabelled SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) for 20 to 60 min at 37 degrees Celsius and then washed 5 to 25 times (approximately 1.5 min/wash) with 2 ml SCH 23390 free medium, responded to dopamine with cAMP accumulation that corresponded to 30-50 per cent of the dopamine-promoted cAMP accumulation observed in untreated cells or in cells exposed to the inactive isomer of SCH 23390. Therefore, 50 to 70 per cent of the dopamine response of SCH 23390-pretreated cells was inhibited after extensive washings of the cultures. At E9C12 the fraction of the dopamine response that remained inhibited by SCH 23390 after the washings declined to 30 per cent of the control cultures or the cultures exposed to the SCH 23390 enantiomer. Cultures at stage E9C5 treated with SCH 23390 followed by extensive washings as above and then used for measuring the number of [3H]-SCH 23390 specific binding sites revealed that 60 per cent of the sites did not interact with the tritiated compound when compared to untreated cultures or to cultures preincubated with the inactive isomer of SCH 23390. When E9C12 cultures were subjected to the same experimental protocol less than 10 per cent of D1-like sites did not interact with [3H]-SCH 23390 after the cells had been exposed to the unlabelled compound. Dissociated cells prepared from intact retinae obtained from 12-13-day old embryos also displayed a subpopulation of D1-like sites that interacted irreversibly with SCH 23390 in a stereospecific way. These sites corresponded to 25 per cent of the total number of D1-like sites present in the retina at this developmental stage. In retina cells obtained from one-day old posthatched chicks these sites were no longer detected. These data show that cultured retina cells as well as cells obtained from retina developing in ovo display two populations of D1-like receptors. One interacts irreversibly with SCH 23390 and is present only in the undifferentiated tissue or in cells at the early stages of culture and the other has a lower affinity for SCH 23390 with which its interaction follows reversible kinetics. These sites are present throughout the differentiation stages studied.

On the characterization of dopamine-induced contractile response of rat anococcygeus muscle preparation.

Presence of specific dopamine (DA) receptors and their characterization was attempted in rat anococcygeus muscle preparation. Dopamine (10(-6) M) and B-HT 920 (10(-6) M) produced concentration dependent contractions of the rat anococcygeus muscle preparation. The response of DA was shifted towards right in presence of haloperidol (10(-6) M; pA2 = 6.8) and sulpiride (10(-4) M) in a competitive manner. Alpha 2 antagonists yohimbine (10(-5) M) and idazoxan (10(-5) M) blocked the response to DA in a competitive manner, while alpha 1 antagonist prazosin (10(-5) M) completely blocked the response to DA. SCH 23390 (10(-5) M), a D1 DA antagonist potentiated the response to DA. Reserpinization (5 mg/kg, 24 hr prior) brought about a shift towards the right, and this response was similarly blocked by haloperidol, sulpiride and yohimbine without affecting the maximum response. Desipramine (10(-5) M) blocked the response of DA in a non-competitive manner. Pretreatment of animals with desipramine (10 mg/kg) followed by reserpine, brought about a reversal of action of reserpine. The response to B-HT 920 (10(-6) M), was blocked similarly by haloperidol and yohimbine. However, the effect of desipramine was more pronounced when compared to DA per se. SKF 38393, a D1 DA agonist, potentiated the response to B-HT 920. The findings suggest the presence of both D1 and D2 DA receptors in rat anococcygeus muscle and that DA also acts on adrenergic receptors to produce a contractile response of this muscle preparation.

Effects of central epinephrine synthesis inhibition on stress-induced prolactin secretion in male rats

1. The present study was designed to examine the role of central epinephrine pathways in the control of stress-induced prolactin secretion in male adulto Wistar rats. 2. Intracerebroventricular adminsitration of two epinephrine synthesis inhibitors, SKF64139 (5 and 10 µg/rat) and LY 134046 (10 and 20 µg/rat), 6 h before the onset of immobilization stress blocked prolactin secretion in a dose-dependent manner. Prolactin values before stress were about 4.0 ng/ml and increased to almost 50 ng/ml in the control group. SKF 64139 injection in the higher dose (10 µg/rat) induced a complete blockade of the stress-induced prolactin release, whereas partial blockade was observed after the higher dose (20 µg/rat) of LY 134046. 3.Salbutamol pretreatment (10 µg/rat) completely restored stress-induced prolactin secretion in animals receiving a central injection of both epinephrine synthesis inhibitors under the same conditions as described above. 4. It is suggested that epinephrine pathways in the brain play an important role in the control of prolactin release occuring during immobilization stress

Gastric cytoprotection induced by prostaglandin-dopaminergic mechanism

Se estudió el efecto citoprotector sobre la mucosa gástrica de la Bromcriptina ante la injuria del etanol absoluto, donde dio citoprotección gástrica similar al Misoprostol. Pretratamiento con SCH 23390 (un antagonista de los receptores dopaminérgicos vasculares periféricos) y Domperidona ( un antagonista de los receptores dopaminérgicos neurales periféricos), mostró que Misoprostol fue dependiente de los receptores dopaminérgicos periféricos en su mecanismo citoprotector; así como Bromocriptina fue un agonista dopaminérgico neuronal periférico en su mecanismo citoprotector. Pretratamiento con Indometacina, mostró que los receptores dopaminérgicos periféricos fueron dependientes de las prostaglandinas endógenas en su mecanismo citoprotector. En conclusión, fue postulado un mecanismo prostaglandino-dopaminérgico periférico en la citoprotección de la mucosa gástrica