Involvement of the Renin-Angiotensin System in Stress: State of the Art and Research Perspectives.

BACKGROUND: Along with other canonical systems, the renin-angiotensin system (RAS) has shown important roles in stress. This system is a complex regulatory proteolytic cascade composed of various enzymes, peptides, and receptors. Besides the classical (ACE/Ang II/AT1 receptor) and the counter-regulatory (ACE2/Ang-(1-7)/Mas receptor) RAS axes, evidence indicates that nonclassical components, including Ang III, Ang IV, AT2 and AT4, can also be involved in stress. OBJECTIVE AND METHODS: This comprehensive review summarizes the current knowledge on the participation of RAS components in different adverse environmental stimuli stressors, including air jet stress, cage switch stress, restraint stress, chronic unpredictable stress, neonatal isolation stress, and post-traumatic stress disorder. RESULTS AND CONCLUSION: In general, activation of the classical RAS axis potentiates stress-related cardiovascular, endocrine, and behavioral responses, while the stimulation of the counter-regulatory axis attenuates these effects. Pharmacological modulation in both axes is optimistic, offering promising perspectives for stress-related disorders treatment. In this regard, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are potential candidates already available since they block the classical axis, activate the counter-regulatory axis, and are safe and efficient drugs.

Angiotensin converting enzymes in fish venom.

Animal venoms are multifaceted mixtures, including proteins, peptides and enzymes produced by animals in defense, predation and digestion. These molecules have been investigated concerning their molecular mechanisms associated and possible pharmacological applications. Thalassophryne nattereri is a small venomous fish inhabiting the northern and northeastern coast of Brazil, and represents a relatively frequent cause of injuries. Its venom causes severe inflammatory response followed frequently by the necrosis of the affected area. Scorpaena plumieri is the most venomous fish in the Brazilian fauna and is responsible for relatively frequent accidents involving anglers and bathers. In humans, its venom causes edema, erythema, ecchymoses, nausea, vomiting, and syncope. Recently, the presence of a type of angiotensin converting enzyme (ACE) activity in the venom of Thalassophryne nattereri and Scorpaena plumieri, endemic fishes in northeastern coast of Brazil, has been described. The ACE converts angiotensin I (Ang I) into angiotensin II (Ang II) and inactivates bradykinin, there by regulating blood pressure and electrolyte homeostasis, however, their function in these venoms remains an unknown. This article provides an overview of the current knowledge on ACE in the venoms of Thalassophryne nattereri and Scorpaena plumier.

Association of exercise training and angiotensin-converting enzyme 2 activator improves baroreflex sensitivity of spontaneously hypertensive rats.

The present study sought to determine cardiovascular effects of aerobic training associated with diminazene aceturate (DIZE), an activator of the angiotensin converting enzyme 2, in spontaneously hypertensive rats (SHRs). Male SHRs (280-350 g) were either subjected to exercise training or not (sedentary group). The trained group was subjected to 8 weeks of aerobic training on a treadmill (five times a week, lasting 60 min at an intensity of 50-60% of maximum aerobic speed). In the last 15 days of the experimental protocol, these groups were redistributed into four groups: i) sedentary SHRs with daily treatment of 1 mg/kg DIZE (S+D1); ii) trained SHRs with daily treatment of 1 mg/kg DIZE (T+D1); iii) sedentary SHRs with daily treatment of vehicle (S+V); and iv) trained SHRs with daily treatment of vehicle (T+V). After treatment, SHRs were anesthetized and subjected to artery and femoral vein cannulation prior to the implantation of ECG electrode. After 24 h, mean arterial pressure (MAP) and heart rate (HR) were recorded; the baroreflex sensitivity and the effect of double autonomic blockade (DAB) were evaluated in non-anesthetized SHRs. DIZE treatment improved baroreflex sensitivity in the T+D1 group as compared with the T+V and S+D1 groups. The intrinsic heart rate (IHR) and MAP were reduced in T+D1 group as compared with T+V and S+D1 groups. Hence, we conclude that the association of exercise training with DIZE treatment improved baroreflex function and cardiovascular regulation.

Association of exercise training and angiotensin-converting enzyme 2 activator improves baroreflex sensitivity of spontaneously hypertensive rats

The present study sought to determine cardiovascular effects of aerobic training associated with diminazene aceturate (DIZE), an activator of the angiotensin converting enzyme 2, in spontaneously hypertensive rats (SHRs). Male SHRs (280–350 g) were either subjected to exercise training or not (sedentary group). The trained group was subjected to 8 weeks of aerobic training on a treadmill (five times a week, lasting 60 min at an intensity of 50–60% of maximum aerobic speed). In the last 15 days of the experimental protocol, these groups were redistributed into four groups: i) sedentary SHRs with daily treatment of 1 mg/kg DIZE (S+D1); ii) trained SHRs with daily treatment of 1 mg/kg DIZE (T+D1); iii) sedentary SHRs with daily treatment of vehicle (S+V); and iv) trained SHRs with daily treatment of vehicle (T+V). After treatment, SHRs were anesthetized and subjected to artery and femoral vein cannulation prior to the implantation of ECG electrode. After 24 h, mean arterial pressure (MAP) and heart rate (HR) were recorded; the baroreflex sensitivity and the effect of double autonomic blockade (DAB) were evaluated in non-anesthetized SHRs. DIZE treatment improved baroreflex sensitivity in the T+D1 group as compared with the T+V and S+D1 groups. The intrinsic heart rate (IHR) and MAP were reduced in T+D1 group as compared with T+V and S+D1 groups. Hence, we conclude that the association of exercise training with DIZE treatment improved baroreflex function and cardiovascular regulation.

Analysis of whey protein hydrolysates: peptide profile and ACE inhibitory activity

The aim of this study was to prepare enzymatic hydrolysates from whey protein concentrate with a nutritionally adequate peptide profile and the ability to inhibit angiotensin-converting enzyme (ACE) activity. The effects of the type of enzyme used (pancreatin or papain), the enzyme:substrate ratio (E:S ratio=0.5:100, 1:100, 2:100 and 3:100) and the use of ultrafiltration (UF) were investigated. The fractionation of peptides was performed by size-exclusion-HPLC, and the quantification of the components of the chromatographic fractions was carried out by a rapid Corrected Fraction Area method. The ACE inhibitory activity (ACE-IA) was determined by Reverse Phase-HPLC. All parameters tested affected both the peptide profile and the ACE-IA. The best peptide profile was achieved for the hydrolysates obtained with papain, whereas pancreatin was more advantageous in terms of ACE-IA. The beneficial effect of using a lower E:S ratio on the peptide profile and ACE-IA was observed for both enzymes depending on the conditions used to prepare the hydrolysates. The beneficial effect of not using UF on the peptide profile was observed in some cases for pancreatin and papain. However, the absence of UF yielded greater ACE-IA only when using papain.

O objetivo deste estudo foi preparar hidrolisados enzimáticos do concentrado proteico do soro de leite com perfil peptídico nutricionalmente adequado e com capacidade para inibir a atividade da enzima conversora da angiotensina (ECA). Os efeitos do tipo de enzima usado (pancreatina ou papaína), da relação enzima:substrato (E:S=0,5:100, 1:100, 2:100 e 3:100) e do uso da ultrafiltração (UF) foram investigados. O fracionamento dos peptídeos foi feito por CLAE de exclusão molecular e a quantificação dos componentes das frações cromatográficas foi realizada pelo método da Área Corrigida da Fração. A atividade inibitória da ECA (AI-ECA) foi determinada por CLAE de fase reversa. Todos os parâmetros testados afetaram tanto o perfil peptídico quanto a AI-ECA. O melhor perfil peptídico foi atingido para os hidrolisados obtidos com papaína, enquanto a pancreatina foi mais vantajosa em termos da AI-ECA. O efeito benéfico do uso de menor relação E:S sobre o perfil peptídico e a AI-ECA foi observado para ambas as enzimas dependendo das condições usadas para o preparo dos hidrolisados. O efeito benéfico da ausência da UF sobre o perfil peptídico foi observado em alguns casos para pancreatina e papaína. No entanto, a ausência da UF produziu maior AI-ECA somente quando a papaína foi usada.

Recomendación de ramas: actualizaciones en el diagnóstico y tratamiento de la hipertensión arterial en pediatría: Rama de Nefrología, Sociedad Chilena de Pediatría / Up to date in the diagnosis and treatment of high blood pressure in pediatrics: recommendations from the Nephrology Branch of the Chilean Society of Pediatrics

Blood pressure (BP) is a vital sign routinely obtained in adult physical examination. This is not the case in children; therefore, high blood pressure in children is frequently not diagnosed. It should be measured with adequate equipment according to age and height of the child, considering that BP values increase under physiological conditions. Arterial hypertension is defined in percentiles for age, gender and height. Three categories can be established: normal BP, pre-hypertension and hypertension. Clinical studies have determined that the younger the child, the probability of secondary hypertension increases, usually of renal origin. Genetic and metabolic risk factors have been identified intrauterine; this "fetal programming" is related later in life with the onset of high blood pressure. Arterial hypertension evolves without symptoms for long periods of time, making more relevant a complete physical examination that includes BP. The hypertensive patient must be approached by age, clinical history, physical examination and BP values, followed by a laboratory work-up. Complementary studies including BP ambulatory monitoring are being used with increasing frequency in the pediatric population, allowing a big number of BP readings during diary activities of the child. Arterial hypertension treatment in pediatrics begins with the prevention of known risk factors, encouraging a change of lifestyle for the child and his/her family. Drug treatment must be reserved after secondary causes have been corrected and lifestyle modifications did not work out. Pharmacological treatment must be indicated individually, its efficacy monitored and potential adverse effects assessed. Still at an experimental stage, antihypertensive vaccination modifying the renin-angiotensin system is being studied.

La presión arterial (PA), a pesar de ser un signo vital, no se registra habitualmente en pediatría lo que hace que la hipertensión arterial esté sub diagnosticada. El registro de la presión arterial debe hacerse cumpliendo criterios consensuados, con los aparatos adecuados para la edad y talla del niño, ya que los valores de presión arterial aumentan progresivamente en condiciones fisiológicas. La definición de Hipertensión arterial se basa en percentiles para edad, sexo y talla y se distinguen tres etapas: presión normal, pre hipertensión e hipertensión. Mientras menor es el niño es más probable que su hipertensión sea secundaria y tenga origen renal. Se han identificado factores de riesgo genético que aún no podemos prevenir y metabólicos especialmente en la vida intrauterina o "programación fetal" que se relaciona con la presencia de hipertensión arterial posterior. La hipertensión arterial evoluciona asintomática por largos períodos, lo que hace más importante su búsqueda sistemática. El estudio del paciente hipertenso debe orientarse de acuerdo a la edad, los antecedentes anamnésticos, los hallazgos del examen físico y las cifras de presión encontradas para lo que hay estudios de laboratorio sistematizados en fases. El estudio complementario con la monitorización ambulatoria de presión arterial está siendo utilizado frecuentemente en la población pediátrica porque permite tener un gran número de mediciones durante las actividades regulares del niño. El tratamiento de la hipertensión arterial en pediatría comienza con la prevención de los factores de riesgo conocidos propiciando cambios de estilos de vida en él y su familia. El tratamiento farmacológico debe indicarse cuando se han corregido las causas secundarias y/o la modificación de los estilos de vida no han logrado un resultado satisfactorio. El tratamiento farmacológico debe ser individualizado, monitorizando su eficacia y los potenciales efectos secundarios. En etapa experimental está el uso de va...

Interregulación de ECA y ECA-2 (enzima convertidora de angiotensina I homóloga) en el remodelamiento y disfunción ventricular temprano y tardío post infarto del miocardio en la rata / Inter regulation of ACE and ACE-2 (homologous angiotensin I converting enzyme) in left ventricular remodeling early and long term after myocardial infarction in rats

Antecedentes: El sistema renina angiotensina (SRA) es bastante complejo pues a la vía clásica, vasoconstrictora e hipertrofiante, se suma una vía paralela vasodilatadora y antiproliferativa cuyo componente principal es la ECA-2. Objetivo y Métodos: Determinar los cambios en la actividad de ECA y ECA-2 y niveles de angiotensinas (Ang) en el remodelamiento y disfunción ventricular temprano y tardío post infarto al miocardio (IAM) experimental. Se usaron ratas Sprague Dawley 200 +/- 10 g peso, las cuales se sometieron a ligadura de la arteria coronaria izquierda. Como controles se usaron ratas sham (S). La función ventricular se determinó por ecocardiografía transtoráxica bidimiensional después de 1 y 8 semanas de la cirugía, al igual que las actividades enzimáticas de ECA y de ECA-2 (fluorimetría) circulantes y en ventrículo izquierdo (VI), y los niveles circulantes de Ang I, II, (1-7) y (1-9) (HPLC y RIA). Conclusión: La progresión del remodelamiento miocárdico post infarto se asocia a un aumento de la actividad enzimática de ECA, y a una disminución de la actividad enzimática de ECA-2. Estos cambios favorecen la vasocontricción arterial, la fibrosis miocárdica y la hipertrofia ventricular patológica.

Background: The physiology of the renin angiotensin system (RAS) is complex: the vasodilator and anti proliferative effects of ACE-2 are added to the vasoconstrictor and hypertrophy induced effects of traditional ACE. Aim and methods: To determine the changes in ACE and ACE-2 along with angiotensin levels in relation to left ventricular remodeling and dysfunction, early an late after experimental myocardial infarction (MI). Sprague-Daley rats with weight 200 +/- 10 g were submitted to left coronary artery legation. Left ventricular function was estimated by transthoracic bidimensional echocardiography, one and 8 weeks after surgery. Activities of ACE and ACE-2 were determined y photometry both in plasma and in the left ventricle: angiotensin I and II (1-7 and 1-9) were measure by HPLC and RIA. Conclusion: Evolving myocardial remodeling after myocardial infarction is associated to increased levels of ACE and decreased levels of ACE-2. These changes would lead to arterial vasoconstriction, myocardial fibrosis and pathologic left ventricular hypertrophy.

T-kinin is resistant to hydrolysis by angiotensin I-converting enzyme.

Several enzymes of are capable of cleaving kinins at either the N- or C-terminal end. In this work, we investigated the hydrolysis of T-kinin (TK) and bradykinin (BK) by carboxypeptidase B (CpB) and angiotensin I-converting enzyme (ACE). The kinins were incubated with the enzymes in Tyrode solution kept at 37 degrees C for 25 min. The kinin residual activity in the incubation medium was bioassayed on the isolated guinea pig ileum. BK (5 micrograms/ml) and TK (5 micrograms/ml) were rapidly and similarly degraded by CpB (0.088 mU/ml) since half of both kinins was inactivated within 5 min of incubation. At 25 min of incubation with CpB the TK and BK-like activities were 20.8 +/- 3.9 (1.04 +/- 0.20 micrograms/ml) and 31.8 +/- 5.0% (1.59 +/- 0.25 micrograms/ml) of the initial kinin concentrations, respectively. BK was also rapidly inactivated by ACE (5 mU/ml) while TK activity was unaffected. At 25 min the BK and TK residual activities corresponded to 39.4 +/- 2.5 (1.97 +/- 0.13 micrograms/ml) and 93.8 +/- 9.2% (4.69 +/- 0.46 micrograms/ml) of the initial kinin concentrations, respectively. It was concluded that TK, a kinin elongated at the N-terminal position, is resistant to ACE degradation.

Inhibition of the effects of different agonists on the rat uterus and guinea-pig ileum by Mandevilla velutina extract

O extrato de Mandevilla velutina inibe as contraçöes induzidas pela bradicinina e cininogenases (calicreína, tripsina e tonina) no útero de rata. As contraçöes por angiotensina II e mesmo por cloreto de bário também foram inibidas, quando o íleo de cobaia foi usado, a contraçäo evocada pela histamina foi inibida. Esses experimentos sugerem que a inibiçäo causada pelo extrato de Mandevilla velutina näo é seletiva para bradicinina

Tonin and kallikrein-kinin system.

The kininogenase activity of tonin has been demonstrated by Ikeda and Arakawa, 1984. Tonin of the rat submandibular gland contracts the rat uterus independent of addition of the substrate. On repetition, the same dose of enzyme elicited desensitization. When a double dose was used the contraction again occurred. After desensitization to tonin the contraction to kallikrein was reduced about 80% of the control. The desensitization to kallikrein lightly reduced the contraction to tonin. When the muscle was desensitized to trypsin tonin did not evoke contraction. These experiments suggest the presence of two different substrates in the uterus, one more specific to kallikrein and the other for tonin. The experiments with the parallel uterus preparation strongly suggest release of kinin in the process of contraction of the uterus by tonin.

Fármacos de uso actual en hipertensión arterial / Drugs presently used in arterial hypertension

La hipertensión arterial afecta alrededor del 15% de los adultos, siendo, en nuestro medio, la más frecuente de las enfermedades crónicas no transmisibles después del alcholismo. El arsenal terapéutico disponible es muy amplio y está demostrado que el tratamiento médico continuado y bien controlado modifica la historia natural de la enfermedad hipertensiva. Las consideraciones anteriores han impulsado a los autores a revisar y exponer en forma esquemática y práctica las características de los diversos fármacos hipotensores actualmente disponibles; sus mecanismos de acción, efectos adversos; posología e indicaciones clínicas