Paola Stella

ACE and α-Adducin Polymorphism as Markers of Individual Response to Diuretic Therapy

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 &agr;-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 (&agr;-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 &agr;-adducin genotypes, patients carrying at least one I allele of ACE and one 460Trp allele of &agr;-adducin had the largest MBP decrease with treatment (12.7±1.9 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 Gly460Gly+DD, with the least MBP decrease (3.4±1.7 mm Hg). &agr;-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.

Relationships among endogenous ouabain, α-adducin polymorphisms and renal sodium handling in primary hypertension

Objective The basolateral Na pump drives renotubular reabsorption. In cultured renal cells, mutant adducins, as well as sub-nanomolar ouabain concentrations, stimulate the Na–K pump. Methods To determine whether these factors interact and affect Na handling and blood pressure (BP) in vivo, we studied 155 untreated hypertensive patients subdivided on the basis of their plasma endogenous ouabain or α-adducin genotype (ADD1 Gly460Trp-rs4961). Results Under basal conditions, proximal tubular reabsorption and plasma Na were higher in patients with mutated Trp ADD1 or increased endogenous ouabain (P = 0.002 and 0.05, respectively). BPs were higher in the high plasma endogenous ouabain group (P = 0.001). Following volume loading, the increment in BP (7.73 vs. 4.81 mmHg) and the slopes of the relationship between BP and Na excretion were greater [0.017 ± 0.002 vs. 0.009 ± 0.003 mmHg/(μEq min)] in ADD1 Trp vs. ADD1 Gly carriers (P < 0.05). BP changes were similar, whereas the slopes of the relationship between BP and Na excretion were lower [0.016 ± 0.003 vs. 0.008 ± 0.002 mmHg/(μEq min)] in patients with low vs. high endogenous ouabain (P < 0.05). In patients with high endogenous ouabain, volume loading increased the BP in the ADD1 Trp group but not in the Gly group (P < 0.05). Thus, patients with ADD1 Trp alleles are sensitive to salt and tubular Na reabsorption remains elevated after volume expansion. Conclusion With saline loading, BP changes are similar in high and low endogenous ouabain patients, whereas tubular Na reabsorption increases in the high endogenous ouabain group. Saline loading unmasks differences in renal Na handling in patients with mutant adducin or high endogenous ouabain and exposes an interaction of endogenous ouabain and Trp alleles on BP.

alpha-adducin may control blood pressure both in rats and humans.

1. Previous studies on the pathogenetic mechanisms of hypertension in the Milan hypertensive strain of rat (MHS) showed that a polymorphism within the α‐adducin gene is responsible for up to 50% of the blood pressure difference between MHS and their MNS normotensive control strain. A case‐control study has shown also in humans an association between α‐adducin locus and hypertension using 4 multiallelic markers surrounding the α‐adducin locus.

Erythrocyte calpain activity and left ventricular mass in essential hypertension

Background Calpains are cytoplasmic proteases widely distributed among eucaryotic cells. Low levels of calpain activity were found in hypertrophic hearts from hypertensive rats, but its role in hypertrophic hearts from human hypertensives is unknown. Therefore, calpain activity was investigated in erythrocytes from essential hypertensive patients in relation to their left ventricular mass. Objective To study the role of calpain activity in the development of left ventricular hypertrophy (LVH) in human essential hypertension. Methods A total of 115 hypertensives (72 untreated and 43 with treatment interrupted for at least 4 months) were included in the study. Calpain I activity was measured in human erythrocytes and LVH was measured as left ventricular mass index (LVMI) by M-mode echocardiography. Results Values are given as mean ± SEM. The hypertensives (97 men and 18 women) were 43.5 ± 0.9 years old with mild to moderate levels of hypertension (systolic/diastolic blood pressure of 147.9 ± 1.4/98.7 ± 0.9 mmHg) and relatively recent LVH onset (3.5 ± 0.5 years). An inverse relation between LVMI and erythrocytic calpain activity was present in all (P = 0.0023, R2= 7.9%). This relation was still present considering only untreated hypertensives (P = 0.008; R2 = 9.7%), but was lost in the 43 previously treated hypertensives. Moreover, in the untreated hypertensives, after excluding the possible confounding effects of sex, age, body mass index, blood pressure and duration of hypertension, a stepwise regression showed that only two variables remained significantly related to LVMI: calpain (F = 6.23) and mean arterial pressure (F = 4.689). No relations were found between LVMI and calpastatin activity either in the whole population, or in treated or untreated hypertensives. Conclusions If we assume that the level of erythrocyte calpain activity mirrors the level in cardiomyocytes, these data seem to suggest that increased protein degradation by calpain may prevent the development of LVH in hypertensive patients. This effect is independent of the duration and severity of hypertension.