Relationships among endogenous ouabain, alpha-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 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.


CONCLUSIONS
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.
Manunta
Paolo
P
Division of Nephrology, Dialysis and Hypertension, Scientific Institute San Raffaele, University Vita-Salute San Raffaele, Milan, Italy. manunta.paolo@hsr.it
Maillard
Marc
M
Tantardini
Cristina
C
Simonini
Marco
M
Lanzani
Chiara
C
Citterio
Lorena
L
Stella
Paola
P
Casamassima
Nunzia
N
Burnier
Michel
M
Hamlyn
John M
JM
Bianchi
Giuseppe
G
D001794:Blood Pressure / Q000235:genetics; D018660:Blood Pressure Monitoring, Ambulatory; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010042:Ouabain / Q000097:blood*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012964:Sodium / Q000378:metabolism*; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D010042:Ouabain; D012964:Sodium; D000099291:Adducins