No abstract

Our findings show that the ANP/NPRA system significantly contributes to ventricular remodeling in human essential hypertension.

Abstract-Many patients with essential hypertension (EH) exhibit increased left ventricular mass. Similarly, elevated circulating levels of an endogenous ouabainlike factor (OLF) have been described in some but not all patients with EH. Moreover, ouabain has a hypertrophic influence on isolated cardiac myocytes. Accordingly, we investigated relationships among plasma OLF, left ventricular mass, and cardiac function in patients with EH. Plasma OLF was determined in 110 normotensive subjects and 128 patients with EH. Echocardiographic parameters and humoral determinants were measured in EH. Plasma OLF levels were increased (PϽ0.0001) in patients with EH (377Ϯ19 pmol/L) versus normotensive (253Ϯ53 pmol/L) subjects. The distribution of plasma OLF was unimodal in normotensives, whereas it was bimodal in EH. Pϭ0.005). Multiple regression analysis that tested the influence of body mass index, age, gender, 24-hour blood pressure, and OLF on left ventricular mass revealed independent contributions of systolic (13.2%) and diastolic (12.4%) blood pressure and plasma OLF (11.6%) to left ventricular mass. We conclude that Ϸ50% of patients with uncomplicated EH have elevated-high circulating OLF levels, higher diastolic blood pressure, greater left ventricular mass and stroke volume, and reduced heart rate. We propose that the OLF affects cardiovascular function and structure and should be considered as a factor that contributes to the risk of morbid events. Key Words: sodium Ⅲ sodium-potassium pump Ⅲ cardiac glycosides Ⅲ digoxin Ⅲ human Ⅲ hypertension, essential Ⅲ heart A rterial hypertension is a risk factor for sudden cardiac death. Moreover, among hypertensives, this risk is increased further in those with left ventricular hypertrophy. 1,2 The molecular background of cardiac hypertrophy has been associated with changes in myocardial gene expression as well as activation of the tissue renin-angiotensin system and the sympathetic nervous system. The sodium pump is of major importance for active ion transport across the sarcolemma and contributes to the electrical and contractile function of the myocardium. Low concentrations of ouabain, via partial inhibition of the Na pump, cause a small increase in intracellular Na, affect sarcolemmal Na-Ca exchange, and lead to an increase in intracellular Ca and contractility. The rise in cell Ca 2ϩ stimulates the signal transduction pathways that regulate the expression of growth-related genes in heart. 3 It has recently been shown that the incubation of cultured rat neonatal cardiac myocytes with nontoxic concentrations of ouabain induces the transcription of some cardiac earlyresponse proto-oncogenes and late-response fetal genes, 4,5 which have been implicated as markers of myocyte hypertrophic growth. In contrast with these findings, other investigators have demonstrated that the acute inotropic effect of ouabain is associated with the inhibition of protein synthesis in papillary muscle of adult rats. 6 Evaluation of the controversy between these 2 types of findings should take int...

Abstract-The basic requirement for declaring an association study positive is that the "hypertension-favoring" allele is more frequent in hypertensive cases than in normotensive controls. However, both positive and negative associations with hypertension have been found for the same polymorphism when studied in different populations. In the present study, we addressed the question of the possible cause(s) of this discrepancy among populations by using the ␣-adducin polymorphism as a paradigm. Four hundred ninety hypertensives and 176 normotensives enrolled in Sassari, Italy, and 468 hypertensives and 181 normotensives enrolled in Milano, Italy, were genotyped for the ␣-adducin Gly460Trp polymorphism. The blood pressure response to 2 months of hydrochlorothiazide therapy could be evaluated in 143 (85 in Sassari and 58 in Milano) hypertensives with and without the 460Trp ␣-adducin allele. The ␣-adducin 460Trp allele was not significantly more frequent in hypertensives in the Sassari population but was more frequent in hypertensives than in normotensives in Milano (Pϭ0.019). Basal plasma renin activity was lower and blood pressure fall after diuretic therapy more pronounced (PϽ0.01) in hypertensives carrying at least one 460Trp allele than in Gly460Gly homozygotes, irrespective of their membership in the Sassari or Milano cohort. The effect of ␣-adducin genotype in predicting basal plasma renin activity and blood pressure decrease with diuretic treatment is similar in Sassari and Milano, despite the lack of association of the ␣-adducin genotype with hypertension in Sassari. (Hypertension. 1999;34:649-654.)

The relationship between blood pressure and sodium (Na) excretion is less steep in hypertension caused by increased renal tubular reabsorption. We recently demonstrated that one mutation in rat alpha-adducin gene: (1) is responsible for approximately 50% of the hypertension of MHS rats, and (2) stimulates tubular Na-K pump activity when transfected in renal epithelial cell, suggesting that its pressor effect may occur because an increased tubular reabsorption. Linkage and association studies demonstrated that the alpha-adducin locus is relevant for human hypertension. A point mutation (G460W) was found in human alpha-adducin gene, the 460W variant (G/W) is more frequent in hypertensives than in normotensives. The aim of this study was to test whether acute changes in body Na may differently affect blood pressure in humans as a function of alpha-adducin genotype. The pressure-natriuresis relationship was analyzed in 108 hypertensive using two different acute maneuvers: Na removal (furosemide 25 mg p.o.) and, two days later, Na load (310 mmoles i.v. in 2 hr). We found that 80 patients were wild-type homozygous (G/G), 26 were G/W heterozygous, and 2 were W/W homozygous with similar blood pressure, age body mass index, gender, plasma and urinary sodium and potassium. In basal condition G/W-W/W patients showed a lower plasma renin activity and fractional excretion of Na. In either case the pressure-natriuresis relationship was less sleep in G/W-W/W than in G/G patients, obviously negative for Na depletion with furosemide (-0.011 +/- 0.004 vs. -0.002 +/- 0.002 mm Hg/mumol/min, P < 0.03), and positive for Na load (0.086 +/- 0.02 vs. 0.027 +/- 0.007 mm Hg/mumol/min, P < 0.001). The finding of reduced slope after Na depletion or Na load supports the hypothesis that, as MHS rats, humans bearing one W alpha-adducin variant display an increased of renal tubular sodium reabsorption.

Abstract-Renin-angiotensin system reactivity and the constitutive capacity of the renal tubule to reabsorb sodium play a role in the individual response to diuretic therapy; therefore we evaluated the blood pressure (BP) response to hydrochlorothiazide in 87 never-treated individuals with mild essential hypertension, according to ACE gene I/D and ␣-adducin Gly460Trp polymorphism. These genotypes where chosen because previous data showed their interaction in determining the BP response to salt probably was the result of their involvement in the activation of the renin-angiotensin system (ACE) and in the constitutive capacity of the kidney to reabsorb sodium (␣-adducin) (treatment for 2 months). BP was measured after 3 run-in visits and after the first and second months of treatment by means of a standardized procedure. Data were analyzed by ANOVA, t test, and multivariate ANOVA for repeated measures (covarying for gender, age, and body mass index). Although basal mean BP (MBP) was similar in the different ACE and ␣-adducin genotypes, patients carrying at least one I allele of ACE and one 460Trp allele of ␣-adducin had the largest MBP decrease with treatment (12.7Ϯ1.9 mm Hg), the effect of the combination of genotypes being additive but not epistatic. These patients had an odds ratio of 15.75 of being a responder to hydrochlorothiazide compared with patients with Gly460GlyϩDD, with the least MBP decrease (3.4Ϯ1.7 mm Hg). ␣-Adducin and ACE I/D polymorphism may be useful to predict the interindividual degree of response to hydrochlorothiazide; the analysis of the combination of the 2 genotypes increases the accuracy of the prediction of response to the drug.

Our data suggest that -344C/T polymorphism affects LV mass and thickness in essential hypertension, independent of adrenal aldosterone. A role for intracardiac aldosterone synthesis is hypothesized.

Background and methods. Endogenous ouabain (EO) is markedly raised in patients with chronic renal failure. As high EO induces myocardial cell hypertrophy in vitro and it is associated with left ventricular hypertrophy (LVH) in essential hypertensives and in patients with heart failure we investigated the relationship between plasma EO and LV mass and geometry in 156 end-stage renal disease (ESRD) patients. EO was measured by a specific radioimmunoassay and by mass spectrometry.