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- Title
Steroid Biosynthesis and Renal Excretion in Human Essential Hypertension: Association With Blood Pressure and Endogenous Ouabain.
- Authors
Tripodi, Grazia; Citterio, Lorena; Kouznetsova, Tatiana; Lanzani, Chiara; Florio, Monica; Modica, Rossana; Messaggio, Elisabetta; Hamlyn, John M.; Zagato, Laura; Bianchi, Giuseppe; Staessen, Jan A.; Manunta, Paolo
- Abstract
BackgroundEndogenous ouabain (EO) has been linked with long-term changes in sodium balance and cardiovascular structure and function. The biosynthesis of EO involves, cholesterol side-chain cleavage (CYP11A1), 3-β-hydroxysteroid dehydrogenase (HSD3B) with sequential metabolism of pregnenolone and progesterone. Furthermore, the renal excretion of cardiac glycosides is mediated by the organic anion transporter (SLCO4C1) at the basolateral membrane and the P-glycoprotein (PGP) (encoded by MDR1) at the apical membrane of the nephron.MethodsAverage 24-h ambulatory blood pressures were recorded in 729 untreated essential hypertensives. Aldosterone (Aldo), EO, urinary Na+, and K+ excretions were determined. Single-nucleotide polymorphism (SNP) and haplotype-based association study was performed with a total of 26 informative SNPs.ResultsPlasma EO was significantly directly related to both day (r = 0.131, P < 0.01) and nighttime diastolic blood pressure (DBP) (r = 0.143, P < 0.01), and remained significantly related after correction for confounders (sex, body mass index, age). Genotype analysis for EO levels and daytime DBP gave significant results for CYP11A1 rs11638442 and MDR1 rs1045642 (T/C Ile1145) in which the minor allele tracked with higher EO levels (T/T 210.3 (147–272) vs. C/C 270.7 (193–366) pmol/l, P < 0.001). Association was found between HSD3B1 polymorphisms and/or haplotypes with blood pressure (systolic blood pressure (SBP) 140.3 (11.7) vs. 143.8 (11.2) mm Hg, P < 0.01) and plasma Aldo (P < 0.05). Haplotype-based analyses support the data of SNP analysis.ConclusionsAmong patients with essential hypertension, cholesterol side-chain cleavage and MDR1 loci are related to circulating EO and DBP, most likely by influencing EO synthesis and transmembrane transport, respectively. In contrast, variants in HSD3B1 are related with SBP probably via Aldo.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.3American Journal of Hypertension (2009); 22, 4, 357–363. doi:10.1038/ajh.2009.3
- Subjects
HYPERTENSION; BLOOD pressure; SODIUM; CHOLESTEROL; DEHYDROGENASES; PREGNENOLONE; PROGESTERONE; BODY mass index
- Publication
American Journal of Hypertension, 2009, Vol 22, Issue 4, p357
- ISSN
0895-7061
- Publication type
Article
- DOI
10.1038/ajh.2009.3