A pilot study on the effect of telmisartan & ramipril on 24 h blood pressure profile & dipping pattern in type 1 diabetes patients with nephropathy.

Background & objectives: Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have been used to normalize the blood pressure and the dipping pattern in patients with type 1 diabetes mellitus (T1DM) and nephropathy. However, there are no data on the effect of the dual blockade on the dipping pattern in these subjects. We therefore, carried out this study to evaluate the effect of administrating an ACEI followed by ARB in the optimum doses in T1DM patients with nephropathy on 24 h blood pressure (BP) profile and nocturnal dipping pattern. Methods: An open label interventional pilot study was done during a one year period involving 30 consecutive patients who were treated with telmisartan 80 mg (0800-1000 h) for eight weeks followed by addition of ramipril 10 mg (1200-1400 h) for the next eight weeks. Ambulatory BP, dipping pattern and albumin excretion rate were studied after each phase. Twenty patients were hypertensive and 10 patients had macro- and 20 patients had microalbuminuria. Results: Telmisartan produced a fall in the clinic BP by 4/1.3 mm Hg (P<0.05 and P<0.362, respectively), 2/1.9 mm Hg in the mean 24 h BP, 1.4/1.1 mm Hg in the day BP and 3.7/3 mm Hg in the trough BP. Addition of ramipril to telmisartan produced a further reduction of 6.3/5.9 mm Hg in the clinic BP (P<0.001 for both), 4.3/4.2 mm Hg in the mean 24 h BP (P<0.01 and P<0.0001, respectively), 5.8/3.9 mm Hg in the day BP (P<0.01 for both), 4.2/2.5 mm Hg in the trough BP, with a reduction of clinic SBP and DBP of 10.3/7.2 mm Hg from the baseline. Telmisartan restored normal systolic dipping pattern in 33.3 per cent of the nondippers (P<0.01) but addition of ramipril was not complimentary. Hyperkalamia (>5.5 mmol/l) was observed only in 2 patients towards the end of the study. Interpretation & conclusions: The dual blockade with telmisartan and ramipril had complimentary effect on lowering of the BP, however, similar beneficial effect on the nocturnal dipping was not observed. Further studies with large number of subjects with longer duration of follow-up are required to validate these observations.

Anti-albuminuric efficacy of a combination of angiotensin converting enzyme inhibitor & angiotensin receptor blocker in type 1 DM with nephropathy.

Background & objective: The efficacy of the combination of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors in patients of type 1 diabetes mellitus (DM) with nephropathy is debatable. The antialbuminuric efficacy of dual blockade in patients of type 1 DM with micro- or macroabuminuria were evaluated. Methods: In this open label observational study 30 patients (20 male 10 female) with type 1 DM were included who were initially treated with telmisartan 80 mg for eight weeks followed by addition of ramipril 10 mg for a further eight weeks. Albuminuria reduction was studied at the end of each phase. Results: Therapy with telmisartan for 8 wk resulted in a 39 per cent (P<0.01) reduction in albumin excretion rate (AER). Combination therapy with telmisartan and ramipril produced a further reduction in AER of 33.4 per cent (P<0.01), amounting to a total AER reduction of 59 per cent (P<0.001). Dual blockade was more effective in the group of macroalbuminuric as compared to microalbuminuric subjects (P<0.05). Telmisartan produced a significant reduction in SBP (P<0.05). The addition of ramipril produced a further reduction in BP, the total reduction being 10.3 in SBP and 7.2 mmHg in DBP (P<0.001 for both). There was an increase in mean serum potassium of 0.39 mmol/l (P<0.01) from baseline at the end of the study period and two patients had hyperkalemia > 5.5 mmol/l with dual blockade. Interpretation & conclusion: Dual blockade with ramipril enhanced the antialbuminuric efficacy of telmisartan and further reduced blood pressure. The effect of dual blockade was more pronounced in the macroalbuminuric subjects and it was well tolerated. However, careful monitoring of serum potassium is required.

The smoothness of blood pressure control of ramipril in essential hypertensive Thai patients evaluation by 24-hour ambulatory blood pressure monitoring.

OBJECTIVE: Evaluate the efficacy of ramipril 2.5 and 5 mg once daily on the degree and homogeneity of 24-hour blood pressure reduction in essential hypertensive Thai patients. MATERIAL AND METHOD: Nineteen male subjects, aged 30 to 60 years, with newly diagnosed essential hypertension were evaluated using the 24-hour ambulatory blood pressure (24-h ABP) measurement. RESULTS: Twelve subjects responded and/or normalized with ramipril once daily, where the office and 24-h ABP were decreased significantly from baseline (p < 0.01). The percentage and magnitude of 24-h SBP/DBP loads after treatment were significantly decreased from 92 +/- 9.7/91 +/- 15.9 to 67 +/- 23.8/65 +/- 27.6 (p < 0.01) and from 23 +/- 10.6/16 +/- 5.3 mmHg to 17 +/- 10.3/10 +/- 4.8 mmHg ( p < 0.05). Trough to peak ratio for SBP/DBP was 0.59/0.52 (overall estimated) and 0.68 +/- 0.23/0.52 +/- 0.22 (individual estimated), while the smoothness index was 0.89/1.03. CONCLUSION: Ramipril 2.5 and 5 mg once daily exerted the smooth 24-hour blood pressure reduction in essential hypertensive Thai patients.

Los baroquimiorreceptores carotídeos: órganos blanco de la hipertensión arterial / Carotid barochemoreceptors: target organs of arterial hypertension

El cuerpo carotídeo (CC) es el principal quimiorreceptor arterial periférico, capaz de sensar los cambios en la PaO2, la PaCO2 y de pH y transducirlos en señales nerviosas reguladoras de respuestas ventilatorias, circulatorias y endócrinas, que permiten una adaptación a la hipoxemia, la acidosis y la hipercapnia. El seno carotídeo, ubicado próximo al CC, con función barorreceptora, genera respuestas cardiovasculares que descienden la tensión arterial (TA). Ambas estructuras son inervadas por el nervio del seno carotídeo (NSC), que a su vez se proyecta al núcleo del tracto solitario (NTS), y se relacionan íntimamente entre sí y reciben la denominación de baroquimiorreceptores. Últimamente estos órganos se han considerado claves en la regulación de respuestas cardiorrespiratorias homeostáticas que podrían estar íntimamente relacionadas con el desarrollo y el mantenimiento de la hipertensión arterial (HTA). Existe escasa información sobre los cambios estructurales que ocurren en estos órganos durante la HTA y/o como consecuencia de ella. Nuestro planteo es que los baroquimiorreceptores carotídeos representarían un nuevo “órgano blanco” de la HTA. En diversos estudios realizados en seres humanos y en modelos de hipertensión sistólica en animales observamos un daño severo en el CC que se correlacionó significativamente con la elevación de la TA. A su vez, considerando que el sistema renina-angiotensina-aldosterona (SRAA) tendría un papel significativo en la fisiopatología del daño observado, demostramos que el ramipril, versus el atenolol, ejerce un efecto protector sobre el CC más allá de la mera reducción de la TA. Incluso el losartán mostró dicho efecto protector, aun cuando los animales utilizados en los modelos fueron normotensos. Nuestros hallazgos indican que el CC se comporta como un órgano blanco de la HTA y que la activación de un SRAA local sería responsable de los cambios morfológicos y funcionales observados.

The carotid body (CB) is the main peripheral arterial chemoreceptor, able to sense changes in PaO2, PaCO2 and pH, and translate them into nervous signals that regulate ventilating, circulating and endocrine responses which allow adaptation to hypoxemia, acidosis, and hypercapnia. The carotid sinus, located next to the CB, with a baroreceptor function, generates cardiovascular responses that decrease arterial hypertension. Both structures are innervated by the carotid sinus nerve (CSN), which is projected to the solitary tract nucleus (STN), closely inter-related and called barochemoreceptors. Lately, these organs have been considered key in the regulation of homeostatic cardiorespiratory responses that could be intimately related to the development and maintenance of arterial hypertension (AHT). There is scant information on the structural changes that occur in these organs during AHT and/or as its consequence. Our hypothesis is that carotid barochemoreceptors would be a new “target organ” of the AHT. In several studies performed in humans and in models of systolic hypertension in animals we observed a severe damage in the CB which was significantly correlated with elevation of the AT. Hence, considering that the renin-angiotensin-aldosterone system(RAAS) would play a significant role in the pathophysiology of the observed injury, we showed that ramipril versus atenolol has a protective effect on the CB further to the mere decrease of the AT. Even though the animal models used had normal pressure, losartan showed this protective effect. Our findings indicate that the CB behaves as a target organ in AHT and the activation of a local RAAS would be responsible for the morphological and functional changes that were observed.

Effect of ramipril therapy on cognitive functions in cases of mild to moderate essential hypertension.

Several studies have questioned the effect of hypertension on cognitive functions. Event related potentials (P300) have been used as a reliable and reproducible indicator of cognitive functions. In this non-randomized, open label study we investigated cognitive functions using event related potentials in newly diagnosed mild to moderate essential hypertensive patients and whether or not there was any effect of antihypertensive treatment with angiotensin converting enzyme inhibitor ramipril on the event related potentials. We selected twenty male patients of newly diagnosed mild to moderate essential hypertension by using ambulatory blood pressure monitoring who were previously untreated and compared their event related potentials with 10 normotensive controls. At the beginning of the study, the hypertensive group showed increased P300 and N2 wave latency as compared to the normotensive control subjects. After three months of Ramipril therapy at a dose of 5mg per day, there was a significant decrease in all the ambulatory blood pressure parameters and the mean P300 latency from the pretreatment values. But no significant change in the N2 latency was observed. Thus, treatment with Ramipril 5 mg daily for a period of three months can reverse some aspects of cognitive dysfunction associated with hypertension.

Proteção miocárdica pelo ramipril na hipertrofia ventricular esquerda: estudo experimental / Protective effect of ramipril on the left ventricle hypertrophy: experimental study

Introdução: A hipertrofia patológica do ventrículo esquerdo é um poderoso e independente fator de risco para complicações cardiovasculares, estando relacionada com aumento de duas a cinco vezes o risco de infarto do miocárdio, seis a dezessete vezes o risco de insuficiência cardíaca e três a dez vezes o risco de acidente vascular cerebral. Objetivo: avaliar em ratos se o ramipril na dose de 1mg/kg/dia apresenta efeito protetor sobre a hipertrofia do ventrículo esquerdo (HVE), induzida pelo isoproterenol (ISO), administrado por via subcutânea (0,3mg/kg/dia). Método: formados quatro grupos de ratos machos e adultos, com 14 exemplares em cada um, sendo o primeiro o grupo controle (CON), segundo o tratado com ramipril (RAM); o grupo seguinte com isoproterenol (ISO) e o último tratado com ambas as drogas (RAM + ISO). Aferidos: o peso úmido do ventrículo esquerdo (PUVE), peso seco do ventrículo esquerdo (PSVE), relação PSVE pelo peso do animal (PSVE/P) e o índice de massa do ventrículo esquerdo (IMVE). Retiradas amostras do ventrículo esquerdo dos animais para estudo morfológico pela microscopia de luz, e em três animais de cada grupo um fragmento foi processado para estudo ultra-estrutural. Resultados: em relação ao PSVE obtiveram-se os seguintes resultados: Grupo CON: 0,14486; Grupo RAM: 0,13771; Grupo ISO: 0,20400; Grupo RAM + ISO: 0,16000; com diferença significante entre o grupo ISO e os demais (p<0, 05). A análise do PSVE/P demonstrou o mesmo comportamento. Na avaliação microscópica de luz e eletrônica de transmissão, observou-se proteção da HVE no Grupo RAM+ISO, em relação ao grupo ISO Conclusões: as análises morfológica e ultra-estrutural demonstraram que isoproterenol induz hipertrofia dos cardiomiócitos e aumento do tecido conjuntivo, com acentuados depósitos de fibras colágenas No grupo RAM + ISO observou-se ação protetora em relação à hipertrofia muscular e a depósitos de colágeno O uso isolado de ramipril não provocou alterações no que diz respeito ao...

Comparative study of angiotensin converting enzyme inhibitor and calcium channel blocker in the treatment of steroid-resistant idiopathic nephrotic syndrome.

BACKGROUND: The aim of this study was to evaluate and compare the anti-proteinuric effect of ramipril and verapamil in patients with steroid-resistant idiopathic nephrotic syndrome. Twenty one (21) cases of steroid-resistant idiopathic nephrotic syndrome were randomized to receive ramipril (11) and verapamil (10) and were followed up for 12 months; monthly for the 1st 3 months and then every 3 months for the remaining study period. The degree of reduction of proteinuria, blood pressure, serum creatinine, serum albumin and side effects were noted between the two groups. The comparison within the groups over different time periods was made using paired 't' test and between the groups for specific time period by unpaired 't' test. The level of significance was taken as 5% or below. RESULTS: Seventeen patients (nine in the ramipril group and eight in the verapamil group) completed the study. The mean age of the patients, duration of illness, 24 hours urinary excretion of protein, mean arterial pressure, serum creatinine, cholesterol and albumin were similar in both the groups at time of randomization. The 24 hours urinary protein excretion decreased from 6319.44 +/- 1971.70 mg/day to 1852.44 +/- 1813.74 mg/day in patients receiving ramipril and from 5332.87 +/- 1947.47 mg /day to 2759.37 +/- 1929.6 mg/day in patients treated with verapamil after 12 months. There was no statistically significant difference in the reduction of proteinuria between the two groups. However, reduction in proteinuria was statistically significant from 2nd month onwards in Ramipril group and reduction was sustained throughout the study period. Reduction in mean arterial pressure was better achieved in Ramipril groups. The change in the serum potassium, creatinine, cholesterol and albumin were similar in either group of patients. Cough (2), hypotension (1) and reversible rise in serum creatinine (1) were observed with ramipril and no side effect was noted with verapamil. CONCLUSION: Both ramipril and verapamil can reduce proteinuria in patients suffering from steroid-resistant idiopathic nephrotic syndrome. However, ramipril had a better and sustained reduction in proteinuria with well-controlled mean arterial pressure. Verapamil can be considered as an alternative to ramipril when the use of the latter is not tolerated because of side effects and/or worsening of renal function in patients with chronic renal insufficiency.

Efecto del ramipril sobre el cociente glucosa/insulina y el índice de masa ventricular izquierda en pacientes con hipertensión arterial leve a moderada / Effect of ramipril on the glucose/insulin coefficient and the ventricular mass index in patients with light to moderate arterial hypertension

Este estudio longitudinal, prospectivo se diseñó para evaluar el efecto del ramipril, un inhibidor de la enzima convertidora de angiotensina (IECA) sobre la masa ventricular, la función diastólica del ventrículo izquierdo (VI) y los valores de tensión arterial en pacientes con hipertensión arterial sistémica esencial (HAS) leve a moderada con hiperinsulinemia. La primera alteración del paciente hipertenso es la disfunción diastólica del VI y el dato de mayor peso como factor predictor de morbimortalidad cardiovascular en la HAS es la hipertrofia ventricular. Existen múltiples estudios que demuestran que no existe una correlación directa entre los valores de tensión arterial y el grado de hipertrofia o disfunción diastólica del ventrículo izquierdo, motivo por el cual se asume la participación de otros factores en la génesis de estas alteraciones funcionales. Por otra parte, está descrito que la insulina posee efectos hipertensores por estimulación simpática, por retener sodio y agua a nivel renal y por estimular la expresión de protooncogenes con el subsecuente desarrollo de fibrosis e hipertrofia miocárdica y vascular. A pesar de que existe en el mercado una gran cantidad de fármacos antihipertensivos, algunos de ellos producen efectos metabólicos adversos, mientras que otros como los inhibidores de la enzima convertidora de angiotensina (IECAS), los ARAII y los bloqueadores del calcio además de controlar los niveles de presión arterial tienen un efecto neutro o benéfico sobre dichos parámetros. Considerando el efecto de los IECAS sobre el perfil metabólico, se realizó un estudio con 24 pacientes hipertensos esenciales con hiperinsulinemia, a los cuales se les realizó evaluación clínica cardiológica y general, electrocardiograma y ecocardiograma en condiciones basales y después de 6 meses de tratamiento con ramipril a dosis de 2.5 a 5 mg/día. Los resultados muestran una reducción significativa de la tensión arterial sistólica (12 mmHg) y diastólica (12 mmHg), de los niveles séricos de insulina basal (23.62 pmol/dL vs 10.42 pmol/dL), y del índice de masa ventricular izquierda (143.8 g/m² vs 118.2 g/m²). En las variables que evalúan la función diastólica del VI no hubo diferencias estadísticamente significativas a excepción de la relación onda E/onda A del flujo transmitral en el grupo de mujeres. Ramipril fue bien tolerado y no se reportaron eventos adversos significativos.

This longitudinal prospective study was designed to assess the effects of the angiotensin converting enzyme inhibitor (ACEI) ramipril on ventricular mass, left ventricle (LV) diastolic function and blood pressure in patients with mild to moderate essential hypertension and hyperinsulinemia. LV diastolic dysfunction is the first target organ alteration occurring in hypertensive patients, while ventricular hypertrophy is the most relevant predictive factor for cardiovascular morbility and mortality in systemic hypertension. Because several studies have demonstrated that there is no direct correlation between blood pressure values and the severity of LV hypertrophy or diastolic dysfunction, it is assumed that other factors are involved in the genesis of these functional alterations. Moreover, the hypertensive effect of insulin is caused by sympathetic stimulation, sodium and water renal retention and protooncogene stimulation leading to myocardial and vascular fibrosis and hypertrophy. We studied 24 hypertensive patients with hyperinsulinemia. All patients underwent an overall and cardiologic clinical evaluation, and electrocardiographic and ecocardiographic studies were performed at baseline and 6 months after being treated with 2.5 to 5 mg/day ramipril. Ramipril treatment significantly reduced systolic (12 mmHg) and diastolic (12 mmHg) pressure levels, basal insulin serum levels (23.62 pmol/dL vs 10.42 pmol/dL), and left ventricle mass index values (143.8 g/m² vs 118.2 g/m²). Among the variables assessing LV diastolic function, only the transmitral flow E/ A wave ratio showed significant differences in women. Ramipril was well tolerated and no significant adverse events were reported. (Arch Cardiol Mex 2003; 73:24-30).

Prevençäo da hipertrofia ventricular esquerda em ratos induzida pelo isoproterenol: comparaçäo entre Ramipril e Losartan / Prevention of left ventricular hypertrophy in rats induced by isoproterenol: the relationship between Ramipril and Losartan

Obetivo: Avaliar comparativamente a capacidade do losartan (bloqueador do receptor AT1 da angiotensina II) e o ramipril (inibidor da enzima de conversäo da angiotensina) em prevenir a hipertrofia ventricular esquerda induzida por isoproterenol em ratos. Métodos: Foram estudados 64 ratos divididos em 4 grupos por um período de 15 dias, após foram sacrificados e comparados através dos pesos dos ventrículos e estudo anatomo-patologico. Resultados: Os animais tratados com losartan apresentaram pesos dos ventrículos esquerdos menores com significância estatística, assim como menor tamanho das fibras miocárdicas e menos colágeno quando comparados aos tratados com ramipril. Conclusäo: O losartan foi superior ao ramipril na prevençäo da hipertrofia ventricular esquerda induzida por isoproterenol em ratos.

Estudio multicéntrico colaborativo abierto de ramipril en hipertensión arterial leve y moderada

Objetivo: Estudiar la efectividad y seguridad del tratamiento de la hipertensión arterial (HTA) leve y moderada (Estadios I, II y III) con un inhibidor de enzima convertidora, ramipril administrado en dosis de 2.5 mg día o ramipril 5 mg día, como medicamento único o con la adición de hidroclorotiazida. Diseño: Experimento abierto no controlado, multicéntrico, en tres países (Colombia, Ecuador y Venezuela). La duración total fue de 10 semanas: Dos semanas de lavado y períodos de seguimiento de dos semanas cada uno, con cambios en el esquema terapéuticos, si era necesario, en las semanas seis y ocho; evaluación final en la semana diez. Pacientes: 216 sujetos de ambos sexos con HTA leve o moderada en los tres países participantes (rango de edad 25-79). Hubo 200 pacientes disponibles para el análisis final de efectividad, 200 pacientes para el análisis de seguridad hecho por el investigador y 189 pacientes para el análisis hecho por el paciente. Intervenciones: 1)ramipril 2.5 mg una vezal día; 2)En quienes no se controlaba la presión arterial 5 mg una vez al día; 3)En aquellos aun no controlados se adicionaba hidroclorotiazida 25 mg una vez al día. Mediciones: Determinación de la presión arterial cada dos minutos por tres veces en posición supina y lo mismo con el sujeto sentado y registro estandarizado de efectos adversos. En cada visita además peso, frecuencia cardíaca y fundoscopia; radiografía del tórax en la semana cero y electrocardiograma en las semanas dos y diez. Pruebas de laboratorio en las semanas dos, seis y diez. Resultados: La efectividad, medida en términos de disminución de la presión arterial un mínimo de 10 mmHg o hasta normalización (valor igual o menor de 90 mmHg) fue alcanzada en 152 sujetos...