Lanosterol Synthase Gene Polymorphisms and Changes in Endogenous Ouabain in the Response to Low Sodium Intake

Abstract

Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, lanosterol synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that lanosterol synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (<100 mEq/d, 2 weeks) among patients with mild essential hypertension. During the low salt diet, the declines in both systolic BP (SBP: -8.7±1.7 versus -3.0±1.5; P=0.013) and diastolic BP (DBP: -5.1±0.98 versus -1.4±0.94 mm Hg; P<0.05), and the slope of the long-term pressure-natriuresis relationship affected significantly the presence of the lanosterol synthase rs2254524 A variant (AA: 0.71±0.22, AC 0.09±0.13, and CC 0.04±0.11 mEq/mm Hg/24 h; P=0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives.

Keywords: Na-K ATPase; diet; digitalis-like factors; genetic polymorphisms; hypertension.

© 2015 American Heart Association, Inc.

Figures

Figure 1

Panel A, changes in systolic (blue bar) and diastolic (red bar) BP among the quartile groups. The 1st quartile group exhibited the greatest fall in BP in response to low salt intake. The 4th quartile group showed a “parodoxical” increase in BP. Panel B. Changes (Δ) in PRA in the 4 groups from baseline. Panel C. Changes (Δ) in plasma EO from baseline.

Figure 2

Decline in systolic and diastolic BP during the low salt diet in the LSS rs2254524 AA + AC carriers (red bar systolic BP, orange diastolic BP) compared to LSS (blue bar systolic BP, light blue diastolic BP) CC among compliant patients.

Figure 3

Circulating EO levels according to the LSS rs2254524 in compliant patients. In LSS AA genotype (red line) no significant changes in circulating EO is present, while increase are observed in AC (light blue) and CC (bluu line) genotypes.

Figure 4

Renal pressure-natriuresis relationship during low salt diet grouped according to the LSS rs2254524 genotypes. Shown is the urinary sodium excretion (UNa) as a function of the systemic mean blood pressure (MBP). The slope of the AA carriers (red diamonds 0.696±0.25 mEq/L/mmHg) was significantly different than the AC heterozygotes (light blue squares, 0.100±0.13 mEq/L/mmHg) and the CC wild type (blue triangle, 0.046±0.18 mEq/L/mmHg).