title: Steroid biosynthesis and renal excretion in human essential hypertension: association with blood pressure and endogenous ouabain.
abstract: BACKGROUND
  Endogenous 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-beta-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.
  
  
  METHODS
  Average 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.
  
  
  RESULTS
  Plasma 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.
  
  
  CONCLUSIONS
  Among 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.
authors.affiliation: Prassis Sigma-Tau, Research Institute, Milan, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Tripodi
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kouznetsova
authors.forename: Chiara
authors.initials: C
authors.lastname: Lanzani
authors.forename: Monica
authors.initials: M
authors.lastname: Florio
authors.forename: Rossana
authors.initials: R
authors.lastname: Modica
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Messaggio
authors.forename: John M
authors.initials: JM
authors.lastname: Hamlyn
authors.forename: Laura
authors.initials: L
authors.lastname: Zagato
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010042:Ouabain / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000652:urine; D012964:Sodium / Q000652:urine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010042:Ouabain; D012964:Sodium; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme; D011188:Potassium