Genetic variability in the ADD1 (Gly460Trp) and ADD2 (C1797T) subunits of the cytoskeleton protein adducin plays a role in the pathogenesis of hypertension, possibly via changes in intracellular cation concentrations. ADD2 1797CC homozygous men have decreased erythrocyte count and hematocrit. We investigated possible association between intra-erythrocyte cations and the adducin polymorphisms. In 259 subjects (mean age 47.7 years), we measured intra-erythrocyte Na(+) [iNa], K(+) [iK] and Mg(2+) [iMg], serum cations and adducin genotypes. Genotype frequencies (ADD1: GlyGly 61.5%, Trp 38.5%; ADD2: CC 80.4%, T 19.6%) complied with Hardy-Weinberg proportions. In men, ADD2 CC homozygotes (n=100) compared to T-carriers (n=23) had slightly lower iK (85.8 versus 87.5 mmol/l cells; P=0.107), higher iMg (1.92 versus 1.80 mmol/l cells; P=0.012), but similar iNa (6.86 versus 6.88 mmol/l cells; P=0.93). In men, iK, iMg and iNa did not differ according to ADD1 genotypes. In men, iK (R(2)=0.128) increased with age and serum Na(+), but decreased with serum total calcium and the daily intake of alcohol. iMg (R(2)=0.087) decreased with age, but increased with serum total calcium. After adjustment for these covariates (P<or=0.04 for all), findings in men for iK (CC versus T: 85.8 versus 87.3 mmol/l; P=0.14) and iMg (1.91 versus 1.82 mmol/l; P=0.03) remained consistent. In 136 women, none of the phenotype-genotype relations reached significance. Changes in intra-erythrocyte cations in ADD2 1797CC homozygous men might lead to osmotic fragility of erythrocytes, but to what extent they reflect systemic changes or are possibly involved in blood pressure regulation remains unknown.