Ernesto Bragulat

Endothelial Dysfunction in Salt-Sensitive Essential Hypertension

The aim of this study was to evaluate endothelium-dependent and -independent vasodilation, as well as endothelium biochemical markers, in a group of essential hypertensive patients classified on the basis of salt sensitivity. Changes in forearm blood flow in response to acetylcholine, sodium nitroprusside, and NG-monomethyl-l-arginine (L-NMMA) infusion were determined by means of strain-gauge plethysmography. Moreover, plasma and urinary concentrations of nitrates, cGMP, and endothelin were measured during low (50 mmol/d) and high (250 mmol/d) salt intake. Salt-sensitive hypertension was diagnosed in 26 patients who exhibited a significant increase in 24-hour mean blood pressure assessed by ambulatory blood pressure monitoring after 1 week of high salt intake. Nineteen patients were considered salt resistant. Compared with salt-resistant hypertensives, salt-sensitive patients presented a significant lower (P =0.005) maximal acetylcholine-induced vasodilation (21±6.3 versus 28±7.5 mL · 100 mL−1 · tissue · min−1). On the contrary, maximal sodium nitroprusside–induced vasodilation did not significantly differ between groups (22.4±4.5 versus 23.9±5.3 mL · 100 mL−1 · tissue · min−1). The decrease in maximal acetylcholine-induced vasodilation promoted by the coadministration of L-NMMA was significantly more pronounced in salt-resistant compared with salt-sensitive patients (P =0.003). Finally, high salt intake promoted a significant decrease in 24-hour urinary nitrate excretion in salt-sensitive patients (from 443±54 to 312±54 &mgr;mol/d;P =0.033) compared with salt-resistant hypertensives (from 341±50 to 378±54 &mgr;mol/d). We conclude that salt-sensitive hypertension is associated with endothelial dysfunction characterized by a defective endothelium-dependent vasodilation. Impairment of the l-arginine–nitric oxide pathway may be responsible for this abnormal endothelial response.

Renin-Angiotensin System Genetic Polymorphisms and Salt Sensitivity in Essential Hypertension

We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (P<0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor gene polymorphisms were determined with the use of standard polymerase chain reaction methods. Twenty-four (48%) patients with significantly increased (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6 mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%), high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to 107. 8+/-9 mm Hg), and they were classified as having salt-resistant hypertension. We did not find any significant association between either M235T AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake. However, patients with essential hypertension homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%) and DI patients (62%) compared with DD hypertensives (19%). We conclude that a significant association exists between the I/D polymorphism of the ACE gene and salt-sensitive hypertension. Patients with II and DI genotypes have significantly higher prevalence of salt sensitivity than DD hypertensives.

Salt Intake, Endothelial Dysfunction, and Salt‐Sensitive Hypertension

Numerous epidemiologic and clinical studies have demonstrated a clear relationship between high salt intake and blood pressure. However, the mechanisms of a salt‐induced increase in blood pressure—a phenomenon known as salt sensitivity—and the heterogeneity of this effect are far from being completely understood. Endothelial dysfunction, and especially the nitric oxide system, is implicated in both experimental and clinical hypertension. Animal studies indicate that endogenous nitric oxide plays an important role in renal hemodynamics and sodium homeostasis, inducing renal vasodilation and natriuresis. Studies of essential hypertensive patients have also suggested that both high salt intake and salt sensitivity are associated with impaired endothelial function. Although there are many hypotheses concerning the nature of salt sensitivity, clinical data indicate that salt‐sensitive patients may be unable to up‐regulate the production of nitric oxide in response to salt intake. This endothelial dysfunction, which is more frequent in salt‐sensitive than in salt‐resistant essential hypertensive patients, may partially explain the blood pressure increase in response to salt intake and may underlie the more pronounced target organ damage and cardiovascular risk in salt‐sensitive patients.

Once-daily fixed-combination irbesartan 300 mg/ hydrochlorothiazide 25 mg and circadian blood pressure profile in patients with essential hypertension

BACKGROUND More than 60% of patients with hypertension included in morbidity and mortality trials needed >or=2 drugs to achieve a substantial, sustained reduction in blood pressure. Tolerable combinations using higher doses of antihypertensive drugs are frequently required to control blood pressure. OBJECTIVE The goal of this study was to assess the effect of a once-daily fixed combination of irbesartan 300 mg/hydrochlorothiazide (HCTZ) 25 mg on the circadian blood pressure profile in patients with essential hypertension that was not controlled with full-dose single therapy or low-dose combined therapy. METHODS Study patients were recruited consecutively from the outpatient hypertension clinics of 3 university hospitals in Spain. After a 1-week washout period, patients with a mean daytime blood pressure >135/85 mm Hg were treated with irbesartan 300 mg/HCTZ 25 mg once daily for 12 weeks. Twenty-four-hour ambulatory blood pressure monitoring was performed at the end of the washout period and during the last week of treatment. RESULTS Fifty-seven patients with essential hypertension (28 men, 29 women) were enrolled; their mean (SD) age was 60.4 (7.2) years (range, 45-78 years). After treatment, a significant reduction in both clinic and ambulatory mean (SD) blood pressure values was observed in the whole group of 57 patients (from 146.0 [11.0] mm Hg to 123.3 [13.3] mm Hg, P < 0.001 for 24-hour systolic blood pressure [SBP]; from 89.9 [8.2] mm Hg to 76.5 [9.4] mm Hg, P < 0.001 for 24-hour diastolic blood pressure [DBP]. The mean lowering of ambulatory SBP and DBP at peak was 25.2 (14.5) mm Hg and 14.7 (9.5) mm Hg, respectively, and at trough, 22.3 (18.3) mm Hg and 12.3 (10.9) mm Hg. The trough-to-peak ratio of the group was 0.92 for SBP (0.97 in responders) and 0.84 for DBP (0.89 in responders). The smoothness index, calculated as the mean of all individual values, was 1.7 (1.0) for SBP (1.8 [0.9] in responders) and 1.3 (0.8) for DBP (1.5 [0.6] in responders). Seven side effects in 6 patients were reported. No metabolic changes were observed, and no patient discontinued the study because of treatment-related adverse effects. CONCLUSIONS The fixed combination of irbesartan 300 mg/HCTZ 25 administered once daily produced a crude meaningful effect in reducing 24-hour blood pressure and was well tolerated. The circadian profile was preserved, as shown by trough-to-peak ratios and smoothness index values for both SBP and DBP.

Lack of correlation between two methods for the assessment of salt sensitivity in essential hypertension.

The existence of a heterogeneous blood pressure (BP) response to salt intake, a phenomenon known as salt sensitivity, has increasingly become a subject of clinical hypertension research, and has important clinical and prognostic implications. However, two different methodologies are currently used to diagnose salt sensitivity. The aim of the present study was to compare the BP response to intravenous sodium load and depletion on the one hand, and to changes in dietary salt intake on the other, in order to assess salt sensitivity in a group of essential hypertensive patients. Twenty-nine essential hypertensives underwent two different procedures separated by 1 month: a dietary test consisting of a 2-week period of low (20 mmol/day) and high (260 mmol/day) salt intakes, and an intravenous test consisting of a 2 litre saline load over a 4-h period, followed by 1 day of low (20 mmol) salt intake and furosemide (40 mg/8 h orally) administration. BP was registered at the end of every period using 24-h ambulatory BP monitoring. In the whole group of hypertensive patients studied, both low salt intake and furosemide administration significantly (P < 0.01) decreased mean BP. Correlation coefficients of BP changes obtained using the two methodologies were between 0.3 and 0.4. Moreover, coefficients of agreement between the oral and the intravenous tests, using several cut points for BP changes, were systematically below 0.5, thus indicating a misclassification of salt sensitivity greater than 50%, depending on the method used. None of the cut points for BP changes during furosemide administration showed a good combination of sensitivity and specificity compared with changes in response to low dietary salt. The present results indicate that the diagnosis of salt-sensitive hypertension should be based on the BP response to changes in dietary salt intake, while BP response to saline and furosemide administration leads to a systematic misclassification of more than 50% of patients, even using different cutpoints for changes in BP.

Effect of long-term irbesartan treatment on endothelium-dependent vasodilation in essential hypertensive patients.

Abstract Endothelial dysfunction plays a pivotal role in the development of essential hypertension and its complications. The purpose of this study is to assess the effect of antihypertensive treatment with the angiotensin receptor blocker irbesartan on endothelial function in a group of essential hypertensive patients. Thirty-two untreated hypertensives are examined at baseline and at the end of a six-month period of irbesartan treatment. Endothelium-dependent and -independent responses are determined by measuring changes in forearm blood flow (FBF) by strain gauge plethysmography in response to intrarterial infusions of acetylcholine (endothelium-dependent vasodilation [EDV]), sodium nitroprusside (endothelium-independent vasodilation [EIV]), with and without the addition of the nitric oxide (NO) synthase inhibitor L-NMMA. Plasma endothelin, plasma and urinary nitrates and nitrites, and cyclic GMP are measured at baseline and at the end of treatment. Irbesartan promoted a significant increase in EDV (from 433±147% to 488±75%; P=0.027) and EIV (from 442±130% to 495±104%; P=0.041). L-NMMA-induced vasoconstriction was significantly enhanced after irbesartan treatment (relative decrease of FBF from 33.4±9.5% to 39.5±5.6%; P=0.001). Plasma concentrations of endothelin fell significantly after irbesartan treatment (from 5.78±1.86 to 4.16±1.52 pg/mL; P=0.001). We concluded that long-term irbesartan treatment enhances both endothelium-dependent and -independent vascular vasodilation capacity. In addition to this non-specific effect, irbesartan restores the vasoconstriction capacity of NO synthase inhibitors, suggesting a direct effect on tonic NO release, and decreases endothelin production. These actions may play an important role in the vascular protecting effects of irbesartan.

Impacto de los componentes y sistemas de medición de la presión arterial sobre la lesión de órgano diana y las complicaciones cardiovasculares en la hipertensión arterial

Fundamento Evaluar el impacto de los diferentes componentes de la presion arterial (PA), determinados tanto en la consulta como por monitorizacion ambulatoria de la PA (MAPA), sobre el desarrollo de la lesion de organo diana y los episodios cardiovasculares (ECV) de la hipertension arterial (HTA) Pacientes y Metodo Estudio retrospectivo llevado a cabo en 390 pacientes (55% varones; edad media de 56 anos) atendidos en una unidad de HTA entre 1989 y 1998. En todos los pacientes se disponia de las determinaciones iniciales de la PA clinica mediante esfigmomanometro de mercurio y de MAPA de 24 h, con el paciente libre de tratamiento antihipertensivo. Se obtuvieron los indices de Cornell y Sokolow del ECG como reflejo de la afeccion cardiaca hipertensiva y la creatinina serica, aclaramiento de creatinina y excrecion urinaria de proteinas en 24 h, como medida del dano renal. La metodologia estadistica empleada fue la regresion lineal multiple y la regresion logistica Resultados Cuarenta y nueve pacientes desarrollaron ECV (26 accidentes cerebrovasculares, 18 infartos de miocardio y 5 pacientes con ambos episodios). De todas las mediciones de PA, fue el aumento de la presion de pulso (PP) en la clinica el factor independiente mejor relacionado con la aparicion de ECV (odds ratio multivariado=1,03; intervalo de confianza [IC] del 95%, 1,00–1,05; p=0,0095). Respecto a la correlacion con los diferentes indicadores de lesion del organo diana, los analisis de regresion lineal multiple pusieron de manifiesto una asociacion del indice de Cornell del ECG con la PAS nocturna obtenida en MAPA (coeficiente estandarizado s=0,260; p Conclusiones El desarrollo de ECV en la HTA se correlaciona con las cifras de PA clinica (especialmente con la PP), mientras que los indicadores de la lesion del organo diana (hipertrofia cardiaca, lesion renal) se correlacionan mejor con la PA obtenida mediante MAPA (especialmente con la PAS y PP)

Endothelial dysfucntion and vascular inflammation in essential hypertension

Abstract P-99 Key Words: Endothelium-Dependent Vasodilation, Selectines and Adhesion Molecules, Matrix Metalloproteinases

Validación del aparato oscilométrico Angelini Línea F1 para la medida clínica y la automedida de presión arterial

Fundamento La utilizacion creciente de aparatos automaticos y semiautomaticos para la medida de la presion arterial (PA) hace necesario que sean sometidos a procesos de validacion a partir de unos criterios estandarizados. El objetivo del presente estudio ha sido el de evaluar la fiabilidad del aparato oscilometrico de medida de presion arterial en el brazo Angelini Linea F tomando como base los criterios propuestos por el Grupo de Trabajo sobre Monitorizacion de la Presion Arterial de la Sociedad Europea de Hipertension. Metodos Se han estudiado 33 individuos con rangos de PA inferiores a 130/60 mmHg (11 sujetos) entre 130-160/80-100 mmHg (11 sujetos) y superiores a 160/100 mmHg (11 sujetos). En cada individuo se han realizado tres pares de medidas de presion con esfigmomanometro de mercurio y con el aparato oscilometrico a validar, obteniendose un total de 99 comparaciones. Resultados De las 99 comparaciones, 47 para la PA sistolica (PAS) y 70 para la PA diastolica (PAD) presentaron diferencias ??5 mmHg, 83 para la PAS y 89 para la PAD diferencias ??10 mmHg y 91 para PAS y PAD diferencias ?15 mmHg, cumpliendo los requisitos establecidos por la Sociedad Europea de Hipertension. Las diferencias medias entre ambos procedimientos fueron de 2,8 ± 8,45 mmHg para la PAS y de 1,2 ± 6,55 mmHg para la PAD. Los coeficientes de correlacion intraclase fueron de 0,969 para la PAS y de 0,925 para la PAD. Conclusiones El aparato oscilometrico de medida de PA en el brazo Angelini Linea F cumple los requisitos de la Sociedad Europea de Hipertension y puede considerarse valido para la medida clinica y la automedida de la PA.