Proximal sodium reabsorption: An independent determinant of blood pressure response to salt.

The purpose of this study was to evaluate the contribution of renal sodium handling by the proximal tubule as an independent determinant of blood pressure responsiveness to salt in hypertension. We measured blood pressure (BP), renal hemodynamics, and segmental renal sodium handling (with lithium used as a marker of proximal sodium reabsorption) in 38 hypertensive patients and 27 normotensive subjects (15 young and 12 age-matched) on a high and low sodium diet. In control subjects, changing the diet from a low to a high sodium content resulted in no change in BP and increases in glomerular filtration rate (P<0.05), renal plasma flow (P<0.05), and fractional excretion of lithium (FE(Li), P<0.01). In hypertensive patients, comparable variations of sodium intake induced an increase in BP with no change in renal hemodynamics and proximal sodium reabsorption. When analyzed by tertiles of their BP response to salt, salt-insensitive hypertensive patients of the first tertile disclosed a pattern of adaptation of proximal sodium reabsorption comparable to that of control subjects, whereas the most salt-sensitive patients of the third tertile had an inverse pattern with a high FE(Li) on low salt and a lower FE(Li) on high salt, suggesting an inappropriate modulation of proximal sodium reabsorption. The BP response to salt correlated positively with age (r=0.34, P=0.036) and negatively with the changes in FE(Li) (r=-0.37, P=0.029). In a multivariate analysis, the changes in FE(Li) were significantly and independently associated with the salt-induced changes in BP. These results suggest that proximal sodium reabsorption is an independent determinant of the BP response to salt in hypertension.

Calcium entry blockade attenuates the acute blood pressure rise induced by cigarette smoking.

The purpose of this study was to assess whether the administration of a calcium entry blocker can prevent the acute blood pressure rise induced by cigarette smoking. Seven male habitual smokers were included. After 45 min of equilibration, they took in randomized single-blind fashion at a 1 week interval either a placebo or nifedipine, 10 mg p.o. Thirty minutes thereafter, the subjects smoked within 10 min two cigarettes containing 1.4 mg of nicotine each. In addition to heart rate and skin blood flow (laser Doppler method), blood pressure of the median left finger was monitored continuously for 100 min using a noninvasive device (Finapres). Nifedipine induced an increase in skin blood flow that was not influenced by smoking. This skin blood flow response was observed although nifedipine had by itself no effect on systemic blood pressure. The calcium antagonist markedly attenuated the blood pressure rise induced by cigarette smoking. However, it tended to accentuate the heart rate acceleration resulting from inhalation of nicotine-containing smoke.

Cardiac and vascular hypertrophy in Fabry disease: evidence for a new mechanism independent of blood pressure and glycosphingolipid deposition.

OBJECTIVE: Fabry disease is an X-linked disorder resulting from alpha-galactosidase A deficiency. The cardiovascular findings include left ventricular hypertrophy (LVH) and increased intima-media thickness of the common carotid artery (CCA IMT). The current study examined the possible correlation between these parameters. To corroborate these clinical findings in vitro, plasma from Fabry patients was tested for possible proliferative effect on rat vascular smooth muscle cells (vascular smooth muscle cell [VSMC]) and mouse neonatal cardiomyocytes. METHODS AND RESULTS: Thirty male and 38 female patients were enrolled. LVH was found in 60% of men and 39% of women. Increased CCA IMT was equally present in males and females. There was a strong positive correlation between LV mass and CCA IMT (r2=0.27; P<0.0001). VSMC and neonatal cardiomyocyte proliferative response in vitro correlated with CCA IMT (r2=0.39; P<0.0004) and LV mass index (r2=0.19; P=0.028), respectively. CONCLUSIONS: LVH and CCA IMT occur concomitantly in Fabry suggesting common pathogenesis. The underlying cause may be a circulating growth-promoting factor whose presence has been confirmed in vitro.

Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions.

Intake of caffeinated beverages might be associated with reduced cardiovascular mortality possibly via the lowering of blood pressure. We estimated the association of ambulatory blood pressure with urinary caffeine and caffeine metabolites in a population-based sample. Families were randomly selected from the general population of Swiss cities. Ambulatory blood pressure monitoring was conducted using validated devices. Urinary caffeine, paraxanthine, theophylline, and theobromine excretions were measured in 24 hours urine using ultrahigh performance liquid chromatography tandem mass spectrometry. We used mixed models to explore the associations of urinary excretions with blood pressure although adjusting for major confounders. The 836 participants (48.9% men) included in this analysis had mean age of 47.8 and mean 24-hour systolic and diastolic blood pressure of 120.1 and 78.0 mm Hg. For each doubling of caffeine excretion, 24-hour and night-time systolic blood pressure decreased by 0.642 and 1.107 mm Hg (both P values <0.040). Similar inverse associations were observed for paraxanthine and theophylline. Adjusted night-time systolic blood pressure in the first (lowest), second, third, and fourth (highest) quartile of paraxanthine urinary excretions were 110.3, 107.3, 107.3, and 105.1 mm Hg, respectively (P trend <0.05). No associations of urinary excretions with diastolic blood pressure were generally found, and theobromine excretion was not associated with blood pressure. Anti-hypertensive therapy, diabetes mellitus, and alcohol consumption modify the association of caffeine urinary excretion with systolic blood pressure. Ambulatory systolic blood pressure was inversely associated with urinary excretions of caffeine and other caffeine metabolites. Our results are compatible with a potential protective effect of caffeine on blood pressure.

Nighttime blood pressure: a target for therapy?

Ambulatory blood pressure (BP) monitoring is increasingly used in the evaluation of hypertensive patients. The ability to monitor BP throughout the day and night allows the detection of abnormal nocturnal BP patterns, the most common being a "nondipping" pattern, which is associated with increased cardiovascular risk; its correction appears to have a positive impact on cardiovascular outcome. Antihypertensive treatment should be individually adjusted to control BP during both daytime and nighttime. However, drug-induced lowering of nocturnal BP, if excessive, could amplify the morning BP surge in patients with daytime BP elevation, increasing the risk of developing a cardiovascular event. Ambulatory BP monitoring therefore represents a unique tool to establish the most appropriate antihypertensive drug regimen for the individual patient.

Genome-wide profiling of blood pressure in adults and children.

Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ≤1.2% (P=9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10(-10)] and 1.4% [P=3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.

The quest for blood pressure reference values in children

Do we need country-specific blood pressure reference values for children? This question will sound weird for clinicians caring for adult hypertensive patients or researchers working in the domain of adult hypertension. Indeed, there are no country-specific reference values for adults. This contrasts with hypertension in children, for whom there is an increasing number of published sets of country-specific reference values [1-5].

Role of reactive hyperreninemia in blood pressure changes induced by sodium depletion in patients with refractory hypertension

Sixteen patients with refractory hypertension were submitted to vigorous sodium depletion while cardiovascular homeostasis was monitored with measurements of hormonal and hemodynamic parameters and repeat saralasin tests. This regimen resulted in a negative sodium balance by an average of 300 mEq. The loss of sodium closely correlated to the decrease of body weight (r = 0.70, p less than 0.005). Blood pressure (BP) decreased from 176/166 +/- 8/3 to 155/109 +/-6/3 mm Hg. There was a significant correlation between percent increments in plasma renin activity (PRA) and the rise in plasma norepinephrine (r = 0.68, p less than 0.05) and a close negative correlation between percent increase in PRA and the ratio of fall in mean blood pressure (MAP) per unit of weight loss (r = -0.73, p less than 0.005). Thus, patients with the least percent increase in PRA demonstrated the greatest fall in BP per unit of weight loss, indicating that relative rather than absolute elevation of renin may be the factor limiting antihypertensive efficacy of sodium depletion. Sodium depletion induced increase in peripheral resistance and decrease in cardiac output, both mostly attributable to relative hyperreninemia. Indeed, the adverse hemodynamic changes were reversed by angiotensin inhibition, during which BP normalized. It is concluded that vigorous sodium depletion complemented by angiotensin blockade or suppression with sympatholytic agents improves management of otherwise refractory hypertension.

Ambulatory blood pressure monitoring in the elderly hypertensive patient.

In this retrospective analysis, we assessed the usefulness of ambulatory blood pressure monitoring in the evaluation of elderly hypertensive patients. Thirty-eight untreated and 31 treated hypertensives aged 70 years or more had a systolic blood pressure greater than or equal to 160 mmHg and/or a diastolic blood pressure greater than or equal to 95 mmHg in the clinic. All 69 patients underwent blood pressure monitoring during their customary daily activities using a portable semi-automatic blood pressure recorder (Remier M2000). The mean of all blood pressures obtained with this device was taken as the ambulatory recorded blood pressure. Recorded blood pressures were greater than or equal to 160 mmHg systolic and greater than or equal to 90 mmHg diastolic in 17 untreated and 17 treated patients. In these patients, the introduction of antihypertensive therapy, or its modification, markedly reduced blood pressure during a 4-8 month follow-up. A further 21 untreated and 14 treated patients had recorded blood pressures of less than 160/90 mmHg. The treatment status of these patients was left unchanged for 4-8 months of follow-up. Nevertheless, office blood pressure in these groups, with no change in treatment, decreased significantly during the observation period. At the last visit to the outpatient clinic, there was no significant difference in blood pressure between the four subgroups of patients. Thus, ambulatory blood pressure monitoring appears to be useful in the elderly hypertensive patient in detecting those patients whose blood pressure is elevated only in the clinic. Blood pressure profiles obtained outside the clinic may therefore be useful in making therapeutic decisions in the aged hypertensive.

Assessment of drug compliance in patients with high blood pressure resistant to antihypertensive therapy.

The persistence of high blood pressure under antihypertensive treatment (resistant hypertension) entails an increased cardiovascular risk. It occurs in three of ten treated hypertensive patients, and has several possible contributing factors, notably insufficient therapeutic adherence. There are a number of ways to evaluate whether patients take their medication as prescribed. These include interviewing the patient, pill counting, prescription follow-up, assay of drugs in blood or urine, and use of electronic pill dispensers. None is perfect. However, the essential is to discuss with the patient the importance of complying with the treatment as soon as it is prescribed for the first time, and not waiting for the appearance of resistant hypertension. The measurement of blood pressure outside the medical office and the monitoring of adherence may help to identify patients in whom hypertension is truly resistant and so to tailor the measures required to improve the control of blood pressure in the most appropriate manner.

Aliskiren monotherapy does not cause paradoxical blood pressure rises: meta-analysis of data from 8 clinical trials.

Angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics all cause reactive rises in plasma renin concentration, but particularly high levels have been reported with aliskiren. This prompted speculation that blockade of plasma renin activity with aliskiren could be overwhelmed, leading to paradoxical increases in blood pressure. This meta-analysis of data from 4877 patients from 8 randomized, double-blind, placebo- and/or active-controlled trials examined this hypothesis. The analysis focused on the incidence of paradoxical blood pressure increases above predefined thresholds, after > or =4 weeks of treatment with 300 mg of aliskiren, angiotensin receptor blockers (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), 10 mg of ramipril, 25 mg of hydrochlorothiazide, or placebo. There were no significant differences in the frequency of increases in systolic (>10 mm Hg; P=0.30) or diastolic (>5 mm Hg; P=0.65) pressure among those treated with aliskiren (3.9% and 3.1%, respectively), angiotensin receptor blockers (4.0% and 3.7%), ramipril (5.7% and 2.6%), or hydrochlorothiazide (4.4% and 2.7%). Increases in blood pressure were considerably more frequent in the placebo group (12.6% and 11.4%; P<0.001). None of the 536 patients with plasma renin activity data who received 300 mg of aliskiren exhibited an increase in systolic pressure >10 mm Hg that was associated with an increase in plasma renin activity >0.1 ng/mL per hour. In conclusion, the incidence of blood pressure increases with aliskiren was similar to that during treatment with other antihypertensive drugs. Blood pressure rises on aliskiren treatment were not associated with increases in plasma renin activity. This meta-analysis found no evidence that aliskiren uniquely causes paradoxical rises in blood pressure.