Nieves Martell

Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension.

Objective To evaluate the contribution of angiotensin-(1-7) [Ang-(1-7)] and prostaglandins to the acute and long-term anti hypertensive actions of captopril in mild-to-moderate essential hypertensive patients Design and Methods Blood pressure, cardiac rate and the plasma concentrations of angiotensin I (Ang I), angiotensin II (Ang II), Ang-(1-7), prostaglandin E2 and 6-keto prostaglandin F1α (the breakdown product of prostacyclin) were determined in the peripheral venous blood of 24 essential hypertensive subjects before and 3 h after administration of 50 mg captopril. Eleven of 24 patients completed a 6- month treatment period with captopril monotherapy (50 mg twice a day). The hemodynamic and hormonal response produced by a last 50 mg dose of captopril was determined once again in the 11 subjects who maintained blood pressure control with captopril monotherapy for 6 months. Results The fall in blood pressure produced 3 h after drug intake was comparable for the first and the last 50 mg captopril dose. Although the first response to captopril increased plasma levels of Ang I only, the response to the last dose of the drug (6 months after) caused significantly higher levels of Ang I and Ang-(1-7). Neither acute nor chronic therapy with captopril had a significant effect on plasma concentrations of Ang II. Although plasma levels of prostaglandin E2 and 6-keto prostaglandin F1α were not modified by a first exposure to captopril, the concentrations of 6-keto prostaglandin F1α but not prostaglandin E2 rose significantly in subjects treated with the inhibitor for 6 months. A negative correlation was also demonstrated between diastolic blood pressure and plasma Ang-(1-7) levels in the 11 essential hypertensive subjects in whom blood pressure was controlled with captopril monotherapy. Conclusions Inhibition of angiotensin converting enzyme with captopril had a significant effect on blood pressure that was not directly accounted for by a suppression of plasma Ang II levels. Continuous therapy with captopril unmasked a contribution of Ang-(1-7) and prostacyclin to the antihypertensive actions of this drug.

Characterization of Angiotensin-(1-7) in the Urine of Normal and Essential Hypertensive Subjects

A total of 31 healthy volunteers [39 +/- 7 (SD) years] and 18 untreated essential hypertensive subjects [43 +/- 9 years] collected urine for 24 h after a physical examination and laboratory tests. Radioimmunoassay measurements of angiotensin-(1-7) [Ang-(1-7)] in urine and plasma were done as described previously. Sitting systolic and diastolic blood pressures (+/- SD) averaged 118 +/- 11/74 +/- 7 mm Hg and 146 +/- 16/96 +/- 8 mm Hg in normal and essential hypertensive subjects, respectively (P < .001), whereas 24 h urinary volume was not different in normal and essential hypertensive subjects (P > .05). The concentration of Ang-(1-7) in the urine of normal subjects averaged 62.6 +/- 22.6 pmol/L corresponding to a urinary excretion rate of 98.9 +/- 44.7 pmol/24 h. Concurrent measurements of plasma Ang-(1-7) showed that the content of Ang-(1-7) in urine was 2.5-fold higher than that measured in the plasma. In contrast, untreated essential hypertensive subjects had lower concentrations and 24 h urinary excretion rates of Ang-(1-7) averaging 39.4 +/- 18.0 pmol/L and 60.2 +/- 14.6 pmol/24 h, respectively, (P < .001). Differences in the excretory rate of Ang-(1-7) between normal volunteers and essential hypertensive subjects were not modified by normalization of the data by urinary creatinine excretion rates. Urinary concentrations of Ang-(1-7) correlated inversely with systolic, diastolic and mean arterial pressures (r = -0.48, P < .001). Both urinary Ang-(1-7) [odds ratio of 0.92 (95% CI: 0.88-0.97)] and age were independent predictors of systolic blood pressure. These studies demonstrated the presence of Ang-(1-7) in urine and the existence of reduced levels of the heptapeptide in individuals with untreated essential hypertension. The relatively higher concentrations of Ang-(1-7) in urine compared to plasma agrees with data that showed that Ang-(1-7) may contribute to the regulation of blood pressure. The inverse association between Ang-(1-7) and arterial pressure provides a potential marker for the characterization of forms of essential hypertension associated with reduced production or activity of vasodilator hormones.

High prevalence of secondary hypertension and insulin resistance in patients with refractory hypertension.

Objective: To determine causes of treatment resistance in patients with refractory hypertension, and to estimate the prevalence of true resistant hypertension. Methods: We studied 50 consecutive patients referred with refractory hypertension after exclusion of hypokalemia and stenosis of the renal artery. Ambulatory blood pressure monitoring was performed in all patients to detect white-coat effect. The patients were hospitalized, antihypertensive drugs were withdrawn and a screening for secondary hypertension was performed. In addition, these patients, and a control group of essential hypertensives controlled with three antihypertensive drugs, underwent a OGTT with 75 g of glucose. Results: Primary normokaliemic hyperaldosteronism was diagnosed in seven patients. Two patients had a pheochromocytoma and six had white-coat effect. The 35 remaining patients with true resistant hypertension shown significant differences in serum insulin and HOMA IR when compared with the control group. Conclusions: These findings show that among normokaliemic treatment-resistant hypertension, the presence of hyperaldosteronism and pheochromocitoma is quite high. Moreover, treatment resistance in hypertensive patients appears to be associated with insulin resistance.

Pioglitazone Decreases Ambulatory Blood Pressure in Type 2 Diabetics With Difficult-to-Control Hypertension

Blood pressure (BP) control at recently established goals of <130/80 mm Hg is often difficult to achieve in diabetic patients. This work examines the effect of pioglitazone on 24‐hour ambulatory BP monitoring in patients with type 2 diabetes and difficult‐to‐control hypertension. Twenty‐seven participants with difficult‐to‐control hypertension (defined as ambulatory BP monitoring ≥125/75 mm Hg) taking antihypertensive medications (mean, 4.1±0.8 drugs) were enrolled in an open, prospective, blinded end point study of add‐on therapy with pioglitazone 30 to 45 mg for 20 weeks. After 20 weeks of treatment, 24‐hour ambulatory BP monitoring showed significant reductions (from 144±13 to 136±16 mm Hg systolic BP and from 79±9 to 76±10 mm Hg diastolic BP [P=.001]). Treatment was also associated with improvements in insulin sensitivity and glycemic and lipid profile. These findings suggest that pioglitazone could be a therapeutic option in diabetics who still have elevated BP values in spite of receiving treatment with at least 3 antihypertensive drugs.

Influence of target organ lesion detection (assessment of microalbuminuria and echocardiogram) in cardiovascular risk stratification and treatment of untreated hypertensive patients

European guidelines indicate the importance of the evaluation of global cardiovascular risk (CVR) to determine the management of the hypertensive patients (EH). However, in primary care, the diagnostic work-up (PCD) only includes the metabolic risk factors. The aim of this study was to assess the importance of microalbuminuria (MA) and echocardiogram (ECHO) in the process of risk stratification, and the number of patients to be treated with drugs at diagnosis. In total, 155 nontreated EH were included in the study. Blood pressure, a lipid profile and plasma glucose (LG) were determined after an overnight fast. MA was evaluated with dipstick MICRALTEST, and in those patients with two positive results, it was measured again in two 24-h urine samples and was considered positive (MA+) if the average was >30 mg/24 h. Left ventricular mass index was calculated and values >125 g/m2 were considered as LV hypertrophy (LVH+). When the patients were stratified according to PCD, 22 had to be treated with drugs. When MA, ECHO and both tests used together were added to the risk evaluation, the number of patients to be treated were 42, 51 and 64, respectively (P<0.001 vs PCD). It is mainly in patients who have moderate cardiovascular risk that risk changes, whereas risk hardly changes in those having low and very high risk. In conclusion, in EH with moderate risk, measurement of MA, due to its easy availability and low cost, seems to be a cost effective screening test to avoid the underestimation of the CVR.

Induction of microalbuminuria by l -Arginine infusion in healthy individuals: An insight into the mechanisms of proteinuria

Despite evidence from individuals with diabetes mellitus or reduced renal mass, the actual relationship between protein- or amino acid-induced changes in renal function and urinary albumin excretion (UAE) is largely unknown in subjects without renal disease. In humans, infusions of l-arginine have been used recently in vascular and renal pathophysiological studies. The present study was undertaken to analyze the mechanisms involved in a particular effect; namely, the behavior of UAE during amino acid loading. A prospective interventional protocol was performed on 10 healthy adults by means of an intravenous infusion of l-arginine. The main results show that l-arginine induced a significant increase in UAE from 13.1 +/- 3.8 before to 53.3 +/- 11.1 microgram/min after the infusion (P < 0.005). This increment was simultaneous to an increase in glomerular filtration rate (GFR) and renal plasma flow (RPF). Furthermore, l-arginine markedly increased the urinary excretion of beta2-microglobulin. UAE correlated significantly with GFR (r = 0. 738; P = 0.014) and RPF (r = 0.942; P < 0.0001), but not with urinary beta2-microglobulin (r = 0.05; P = not significant). Furthermore, marked differences (P = 0.001) were found between the percentage of increase in UAE (306.8% +/- 163.2%) with respect to either albumin filtered load (FLAlb; 57.9% +/- 16.3%) and beta2-microglobulin excretion (1,088.5% +/- 424.6%). No changes were found in vehicle-infused individuals. In conclusion, the present study shows, in controlled conditions, that l-arginine infusion induces a relevant increase in UAE in healthy individuals that significantly exceeds that expected from the increase in GFR alone. The intense and simultaneous increment in beta2-microglobulin excretion strongly suggests that the effect of l-arginine on UAE is, in a relevant part, mediated through a blockade in the tubular protein reabsorption pathways. However, the profound differences observed in the changes induced by l-arginine on UAE and beta2-microglobulin excretion and the differences in the correlation of UAE and beta2-microglobulin with respect to GFR suggest that substantial diversity exists in the mechanisms by which l-arginine affects the renal management of albumin and beta2-microglobulin. These findings are relevant for understanding the renal response to l-arginine and protein/amino acid loads.

Influence of metabolic syndrome on risk stratification in hypertensive patients: differences between 2003 and 2007 ESH-ESC guidelines:

Objective: To investigate the influence of metabolic syndrome (MS) on risk stratification and ulterior classification in hypertensive patients at entry into a hypertension unit by comparing the criteria of ESH-ESC 2003 and 2007 guidelines. Methods: 720 consecutive patients attending a hospital-located hypertension unit were included in the study. They were classified with or without MS according to the ATP-III 2005 report. Patients underwent repeated office BP measurements and routine blood/urine examinations. In addition ultrasensitive CRP (uCRP), echocardiogram, fasting insulin, urinary albumin excretion were determined and HOMA index was calculated. Results: The prevalence of MS was 58.8 %. Abdominal obesity and fasting glucose were the most prevalent components of MS, and HDL-cholesterol the least prevalent. MS group had higher levels of LDL-cholesterol and higher prevalence of left ventricular hypertrophy and microalbuminuria. Patients with MS also presented a significant elevation in uCRP, fasting insulin and HOMA. BP was controlled in 55.6%. When we applied the 2003 guideline, 48.9% patients showed a high or very high added cardiovascular risk. With the applications of the 2007 guide the prevalence of this two categories reach 73.9%. Conclusions: A significant difference in the risk pattern distribution is found when MS is considered in risk stratification in our hypertensive population. The accompanying increase in the levels of other cardiovascular risk factors and in the prevalence of target organ damage justifies the global intervention on cardiovascular risk recommended by 2007 ESH-ESC guidelines.

Volume Overload, Atrial Natriuretic Peptide, and Left Ventricular Hypertrophy

The development of high blood pressure leads to an increased hemodynamic afterload to the heart, wich is compensated by an increase of cardiac mass in order to maintain the cardiac output. However,despite the casual link between high blood pressure and left ventricular hypertrophy (LVH) clinical studies do not show a close correlation between blood pressure level and the degree of LVH (1).

Clinic Versus Daytime Ambulatory Blood Pressure Difference in Hypertensive Patients: The Impact of Age and Clinic Blood Pressure.

Clinic blood pressure (BP) is usually higher than daytime ambulatory BP in hypertensive patients, but some recent studies have challenged this view, suggesting that this relationship is strongly influenced by age. We used the Spanish ambulatory BP monitoring cohort to examine differences between clinic and daytime BP by age among 104 639 adult hypertensive patients (office systolic/diastolic BP ≥140/90 mm Hg or treated) in usual primary-care practice, across the wide age spectrum. To assess the impact of age, cardiovascular variables, and clinic BP on the clinic–daytime BP differences, we built multivariable regression models of the average BP differences, white-coat hypertension (high clinic BP and normal daytime BP), and masked hypertension (normal clinic BP and high daytime BP). In most patients, mean clinic BP values were higher than daytime BP at all ages. Some 36.7% of patients had white-coat hypertension (amounting to 50% at clinic systolic BP of 140–159 mm Hg) and 3.9% had masked hypertension (amounting to 18% at clinic systolic BP of 130–139 mm Hg). Age explained 0.1% to 1.7% of the variance of quantitative or categorical BP differences (P<0.001). Cardiovascular variables explained an additional 1.6% to 3.4% of the variance (P<0.001). Finally, clinic BP generally explained ≥20% more of the variance (P<0.01). In this large study in usual clinical practice, clinic BP misclassified hypertension status in >40% of patients. This misclassification was not importantly influenced by age but was more evident in patients with borderline/grade 1 hypertension. These findings reinforce the importance of ambulatory BP monitoring for defining BP status in routine clinical practice.

Increased pulse pressure is associated with left atrial enlargement in resistant hypertensive patients

Abstract Resistant hypertension (RH) is frequently associated with a high prevalence of target organ damage, which impairs the prognosis of these patients. Considering cardiac alterations in RH, most attention has been devoted to left ventricular hypertrophy (LVH), but data concerning left atrial enlargement (LAE) is less known. This cross-sectional study assessed the factors associated with LAE, with special focus on blood pressure (BP) estimates obtained by ambulatory blood pressure monitoring (ABPM), in 250 patients with RH, aged 64 ± 11 years. LAE and LVH were observed in 10.0% (95% CI 6.3–13.7) and 57.1% (95% CI 50.8–63.5) of patients, respectively. Compared with patients with normal atrium size, those exhibiting LAE were older, more frequently women, had elevated pulse pressure (PP) measured both at the office and by ABPM, and showed higher prevalence of LVH (83% vs 54%; p = 0.016). In a logistic regression analysis, adjusting for age, gender, body mass index, left ventricular mass index and BP pressure estimates, night-time PP was independently associated with LAE (OR for 5 mmHg = 1.28, 95% CI 1.24–1.32; p = 0.001). In conclusion, besides classical determinants of LAE, such as age and LVH, an elevated night-time PP was independently associated with LAE in patients with RH.