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

Abstract

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 alpha-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/(muEq 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/(muEq 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.

Figures

Fig. 1

Baseline values of various factors. (a) Baseline values of diastolic blood pressure (DBP), plasma Na, and FELi in patients according to their plasma endogenous ouabain level quartiles. (b) Baseline values DBP, plasma Na, and FELi in patients according to their ADD1 genotype. The number of patients for each subgroup is indicated in bold. The patients with the highest levels of plasma endogenous ouabain had higher DBP, plasma Na, and proximal tubular reabsorption (detected as the decrease in FELi) compared with the low endogenous ouabain subgroups. Patients with the ADD1 Trp allele had higher plasma Na and proximal tubular reabsorption than the ADD1 Gly patients. Statistical significance for trend was achieved for all the parameters, except for the DBP between Trp and Gly ADD1 carriers where the trend was not significant (P = 0.09).

Fig. 2

Interaction between ADD1 genotypes and circulating endogenous ouabain in hypertensive patients after an acute Na load. For this comparison, patients were subdivided into two subgroups according to the level of endogenous ouabain below or above the median level of 236 pmol/l. The changes (Δ) in diastolic blood pressure (DBP) and renal Na handling [as fractional lithium (FELi, %) or sodium (FENa) excretion] are shown. Patients with low endogenous ouabain carrying the wild-type ADD1 Gly genotype (open bar) or at least one ADD1 Trp variant (closed bar) vs. those carrying either high plasma endogenous ouabain with ADD1 Gly (dashed bar) or ADD1 Trp (closed bar) are reported.