The Angiotensin-melatonin axis

Accumulating evidence indicates that various biological and neuroendocrine circadian rhythms may be disrupted in cardiovascular and metabolic disorders. These circadian alterations may contribute to the progression of disease. Our studies direct to an important role of angiotensin II and melatonin in the modulation of circadian rhythms. The brain renin-angiotensin system (RAS) may modulate melatonin synthesis, a hormone with well-established roles in regulating circadian rhythms. Angiotensin production in the central nervous system may not only influence hypertension but also appears to affect the circadian rhythm of blood pressure. Drugs acting on RAS have been proven effective in the treatment of cardiovascular and metabolic disorders including hypertension and diabetes mellitus (DM). On the other hand, since melatonin is capable of ameliorating metabolic abnormalities in DM and insulin resistance, the beneficial effects of RAS blockade could be improved through combined RAS blocker and melatonin therapy. Contemporary research is evidencing the existence of specific clock genes forming central and peripheral clocks governing circadian rhythms. Further research on the interaction between these two neurohormones and the clock genes governing circadian clocks may progress our understanding on the pathophysiology of disease with possible impact on chronotherapeutic strategies

The Syntaxin-1A gene single nucleotide polymorphism rs4717806 associates with the risk of ischemic heart disease

Ischemic heart disease (IHD) has a genetic predisposition and a number of cardiovascular risk factors are known to be affected by genetic factors. Development of metabolic syndrome and insulin resistance, strongly influenced by lifestyle and environmental factors, frequently occur in subjects with a genetic susceptibility. The definition of genetic factors influencing disease susceptibility would allow to identify individuals at higher risk and thus needing to be closely monitored.To this end, we focused on a complex of soluble-N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), playing an important role in metabolic syndrome and insulin resistance, involved in endothelial dysfunction and heart disease. We assessed if genetic variants of the SNARE genes are associated with IHD.SNAP25 rs363050, Stx-1A rs4717806, rs2293489, and VAMP2 26bp ins/del genetic polymorphisms were analyzed in a cohort of 100 participants who underwent heart surgery; 56 of them were affected by IHD, while 44 were not. A statistical association of plasma glycemia and insulin resistance, calculated as Triglyceride glucose (TyG) index, was observed in IHD (P<.001 and P=.03, respectively) after binomial logistic stepwise regression analysis, adjusted by age, gender, diabetes positivity, waist circumference, and cholesterol plasma level. Among genetic polymorphisms, rs4717806(A) and rs2293489(T), as well as the rs4717806 - rs2293489 (A-T) haplotype were associated with higher risk for IHD (Pc=.02; Pc=.02; P=.04, respectively). Finally, a statistical association of rs4717806(AA) genotype with higher TyG index in IHD patients (P=.03) was highlighted by multiple regression analysis considering log-transformed biochemical parameters as dependent variable and presence of coronary artery disease, age, gender, waist circumference, presence of diabetes as predictors. These results point to a role of the Stx-1A rs4717806 SNP in IHD, possibly due to its influence on Stx-1A expression and, as a consequence, on insulin secretion and glucose metabolism

O futuro da profissão de auditoria

Technology is evolving at an unbridled pace, some sectors are not failing to keep up with this evolution. It is estimated that the information processed worldwide in the last 2 years represents 90% of the total information ever created. Software is replacing professionals all over the world, mainly in areas such as accounting, routine data processing tasks are performed without human input and automatically. As the audit profession is highly dependent on data analysis, it is important to understand the impact that this evolution will have on the auditor's life. This dissertation aims to describe the audit profession in this context of global technological evolution. The literature review made it possible to fit into important theoretical concepts and understand how these concepts translate into the audit profession. With the empirical study carried out, the objective is to demonstrate the impacts of these new technologies on the auditor's life. The empirical study was supported by a research with a quantitative analysis, through the use of an inquiry. Through this, it was possible to conclude that the new technologies, despite presenting new risks for the external audit, also present themselves as an opportunity to develop works with more quality and efficiency.A tecnologia está a evoluir a um ritmo desenfreado, alguns setores não estão a conseguir acompanhar esta evolução. Estima-se que a informação processada mundialmente nos últimos 2 anos representa 90% do total de informação alguma vez criada. Softwares estão a substituir profissionais pelo mundo inteiro, principalmente em áreas como a contabilidade, tarefas rotineiras de processamento de dados são desempenhadas sem contributo humano e de forma automática. Sendo a profissão de auditoria altamente dependente de análise de dados é importante perceber o impacto que esta evolução terá na vida do auditor. Esta dissertação tem como finalidade descrever a profissão de auditoria neste contexto de evolução tecnológica global. A revisão de literatura efetuada permitiu enquadrar em importantes conceitos teóricos e perceber como esses conceitos se traduzem para a profissão de auditoria. Com o estudo empírico realizado, procurou-se demonstrar os impactos destas novas tecnologias na vida do auditor. O estudo empírico suportou-se numa pesquisa com uma análise quantitativa, através da utilização de um inquérito. Através deste, foi possível concluir que as novas tecnologias apesar de apresentarem novos riscos para a auditoria externa, também se apresentam como uma oportunidade para desenvolver trabalhos com mais qualidade e eficiência

Local renin angiotensin system and the brain-A continuous quest for knowledge

The ancient renin-angiotensin system (RAS) was discovered more than a hundred years ago by identifying the rate-limiting enzyme of the system and its relevance to blood pressure regulation. Forty years ago, Detlev Ganten et al postulated the existence of a tissue RAS. In these forty years, he kept developing the knowledge of these systems either directly or by training or attracting the interest of many researchers. Through the present review, we try to highlight recent advancements that originated from the postulation of local brain RAS. Although a large amount of knowledge accumulated, this system continues to intrigue and stimulate the interest and imagination of many researchers

Altered circadian rhythm reentrainment to light phase shifts in rats with low brain angiotensinogen

In this study, we aimed to investigate the adaptation of blood pressure (BP), heart rate (HR), and locomotor activity (LA) circadian rhythms to light cycle shift in transgenic rats with a deficit in brain angiotensin [TGR(ASrAOGEN)]. BP, HR, and LA were measured by telemetry. After baseline recordings (bLD), the light cycle was inverted by prolonging the light by 12 h and thereafter the dark period by 12 h, resulting in inverted dark-light (DL) or light-dark (LD) cycles. Toward that end, a 24-h dark was maintained for 14 days (free-running conditions). When light cycle was changed from bLD to DL, the acrophases (peak time of curve fitting) of BP, HR, and LA shifted to the new dark period in both SD and TGR(ASrAOGEN) rats. However, the readjustment of the BP and HR acrophases in TGR(ASrAOGEN) rats occurred significantly slower than SD rats. The LA acrophases changed similarly in both strains. When light cycle was changed from DL to LD by prolonging the dark period by 12 h, the reentrainment of BP and LA occurred faster than the previous shift in both strains. The readjustment of the BP and HR acrophases in TGR(ASrAOGEN) rats occurred significantly slower than SD rats. In free-running conditions, the circadian rhythms of the investigated parameters adapted in TGR(ASrAOGEN) and SD rats in a similar manner. These results demonstrate that the brain RAS plays an important role in mediating the effects of light cycle shifts on the circadian variation of BP and HR. The adaptive behavior of cardiovascular circadian rhythms depends on the initial direction of light-dark changes

Avosentan is protective in hypertensive nephropathy at doses not causing fluid retention

Multiple studies indicate that endothelin antagonism may have a protective effect for chronic kidney disease. Despite that, clinical studies using avosentan have been halted due to adverse effects including fluid overload. Therefore, we aimed at investigating whether avosentan may have protective effects against hypertensive nephropathy at doses below those inducing fluid-retention. We used double transgenic rats (dTGR), overexpressing both the human renin and angiotensinogen gene, which develop malignant hypertension. Effects of avosentan alone or in combination with low-dose of valsartan (angiotensin AT1 receptor antagonist) on end-organ damage were studied. Avosentan induced a decrease of diuresis (18.3%) with a consequent decrease in hematocrit (8.3%) only at the highest dose investigated (100mg/kg). Treatment with the combination of avosentan and valsartan (10 and 0.1mg/kg, once daily by gavage, respectively) decreased albuminuria to a greater extent than each compound given alone (avosentan: 19.6mg/24h; valsartan: 12.9mg/24h; avosentan+valsartan: 1.7mg/24h, data are median values). Histological severity score also showed a drastic reduction of kidney damage. Furthermore, avosentan alone or in combination therapy dramatically decreased mortality compared to the 100% in untreated animals. These data support a therapeutic effect of avosentan at doses below those inducing fluid overload

Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen

We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist (isoproterenol, ISO). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, ISO induced a significantly greater increase LV pressure (dLVP) and maximal contraction ((+dP/dt)max), in the TGR than in the Sprague-Dawley (SD) rats. Left ventricular (LV) hypertrophy induced by ISO treatment was significantly higher in TGR than in SD rats (g LV weight/100 g body weight: 0.28 +/- 0.004 vs 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase 1 (betaARK1) mRNA levels in comparison to SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared to SD (-9.9 +/- 1.7 % vs. -18.1 +/- 1.5 %), while the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that transgenic rats with low brain angiotensinogen are more sensitive to beta-AR agonist induced cardiac inotropic response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart

Baroreflex control of heart rate and renal sympathetic nerve activity in rats with low brain angiotensinogen

The main objective of the present study was to evaluate baroreceptor control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in transgenic rats (TG) with low angiotensinogen production in glial cells, TGR(ASrAogen)-680. In addition, the sympathetic and vagal autonomic tonus to the heart was investigated. As previously shown, TG rats presented a lower arterial pressure (AP) and HR. However, TG rats had decreased AP variability during the night (8.9+/-0.4mmHg vs 9.8+/-0.3mmHg, in SD) accompanied by an increase in HR variability (39+/-1beats/min vs 35+/-1beats/min, in SD) and augmented locomotor activity during the night (3.5+/-0.3counts/min vs 2.5+/-0.2counts/min, in SD). In addition, TG rats presented increased baroreflex sensitivity for the RSNA (slope of line that correlates decreases in RSNA and increases in AP=1.36+/-0.18 vs 0.77+/-0.1, in SD) and an increased sensitivity for both the baroreflex bradycardia (0.79+/-0.04ms/mmHg vs 0.52+/-0.04ms/mmHg, in SD) and tachycardia (1.46+/-0.1ms/mmHg vs 0.93+/-0.01ms/mmHg, in SD). Further, TG rats had increased vagal tonus (25+/-3 beats/min vs 11+/-4 beats/min in SD) without significant change in the sympathetic tonus to the heart. These results confirm and extend previous observations showing that glial angiotensinogen, the main source of brain RAS peptides, importantly modulates sympathetic tonus, at least to the renal nerve, and vagal tonus to the heart

Nigral and striatal regulation of angiotensin receptor expression by dopamine and angiotensin in rodents: implications for progression of Parkinson's disease

The basal ganglia have a local renin-angiotensin system and it has been shown that the loss of dopaminergic neurons induced by neurotoxins is amplified by local angiotensin II (AII) via angiotensin type 1 receptors (AT1) and nicotinamide adenine dinucleotide phosphate (NADPH) complex activation. Recent studies have revealed a high degree of counter-regulatory interactions between dopamine and AII receptors in non-neural cells such as renal proximal tubule cells. However, it is not known if this occurs in the basal ganglia. In the striatum and nigra, depletion of dopamine with reserpine induced a significant increase in the expression of AT1, angiotensin type 2 receptors (AT2) and the NADPH subunit p47(phox) , which decreased as dopamine function was restored. Similarly, 6-hydroxydopamine-induced chronic dopaminergic denervation induced a significant increase in expression of AT1, AT2 and p47(phox) , which decreased with L-dopa administration. A significant reduction in expression of AT1 mRNA was also observed after administration of dopamine to cultures of microglial cells. Transgenic rats with very low levels of brain AII showed increased AT1, decreased p47 (phox) and no changes in AT2 expression, whereas mice deficient in AT1 exhibited a decrease in the expression of p47 (phox) and AT2. The administration of relatively high doses of AII (100 nm) decreased the expression of AT1, and the increased expression of AT2 and p47(phox) in primary mesencephalic cultures. The results reveal an important interaction between the dopaminergic and local renin-angiotensin system in the basal ganglia, which may be a major factor in the progression of Parkinson's disease

Transgenic angiotensin-converting enzyme 2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function

Rat models of hypertension, eg, spontaneously hypertensive stroke-prone rats (SHRSP), display reduced angiotensin-converting enzyme 2 (ACE2) mRNA and protein expression compared with control animals. The aim of this study was to investigate the role of ACE2 in the pathogenesis of hypertension in these models. Therefore, we generated transgenic rats on a SHRSP genetic background expressing the human ACE2 in vascular smooth muscle cells by the use of the SM22 promoter, called SHRSP-ACE2. In these transgenic rats vascular smooth muscle expression of human ACE2 was confirmed by RNase protection, real-time RT-PCR, and ACE2 activity assays. Transgene expression leads to significantly increased circulating levels of angiotensin-(1-7), a prominent product of ACE2. Mean arterial blood pressure was reduced in SHRSP-ACE2 compared to SHRSP rats, and the vasoconstrictive response to intraarterial administration of angiotensin II was attenuated. The latter effect was abolished by previous administration of an ACE2 inhibitor. To evaluate the endothelial function in vivo, endothelium-dependent and endothelium-independent agents such as acetylcholine and sodium nitroprusside, respectively, were applied to the descending thoracic aorta and blood pressure was monitored. Endothelial function turned out to be significantly improved in SHRSP-ACE2 rats compared to SHRSP. These data demonstrate that vascular ACE2 overexpression in SHRSP reduces hypertension probably by locally degrading angiotensin II and improving endothelial function. Thus, activation of the ACE2/angiotensin-(1-7) axis may be a novel therapeutic strategy in hypertension