title: Effects of angiotensin receptor blockers on endothelial nitric oxide release: the role of eNOS variants.
abstract: BACKGROUND
  • Angiotensin II receptor blockers improve endothelial cell-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide synthase (eNOS) function.
  
  
  CONCLUSIONS
  • The key finding from this study is that angiotensin II receptor blockers (ARBs) differentially enhanced nitric oxide (NO) release in a manner influenced by certain genetic variants of eNOS. This finding provides new insights into the effects of ARBs on endothelial cell-dependent vasodilation and eNOS function that are of high importance in vascular medicine and clinical pharmacology. AIM Angiotensin II receptor blockers (ARBs) improve endothelial cell (EC)-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide (NO) synthase (eNOS) function. To investigate this question, we tested the effects of various ARBs on NO release in ECs from multiple donors, including those with eNOS genetic variants linked to higher cardiovascular risk.
  
  
  METHODS
  The effects of ARBs (losartan, olmesartan, telmisartan, valsartan), at 1 µm, on NO release were measured with nanosensors in human umbilical vein ECs obtained from 18 donors. NO release was stimulated with calcium ionophore (1 µm) and its maximal concentration was correlated with eNOS variants. The eNOS variants were determined by a single nucleotide polymorphism in the promoter region (T-786C) and in the exon 7 (G894T), linked to changes in NO metabolism. RESULTS All of the ARBs caused an increase in NO release as compared with untreated samples (P < 0.01, n= 4-5 in all eNOS variants). However, maximal NO production was differentially influenced by eNOS genotype. Olmesartan increased maximal NO release by 30%, which was significantly greater (P < 0.01, n= 4-5 in all eNOS variants) than increases observed with other ARBs.
  
  
  CONCLUSIONS
  The ARBs differentially enhanced NO release in ECs in a manner influenced by eNOS single nucleotide polymorphisms. These findings provide new insights into the effects of ARBs on EC-dependent vasodilation and eNOS function.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
authors.forename: Robert F
authors.initials: RF
authors.lastname: Jacob
authors.forename: Ruslan
authors.initials: R
authors.lastname: Kubant
authors.forename: Adam
authors.initials: A
authors.lastname: Jacoby
authors.forename: Febee
authors.initials: F
authors.lastname: Louka
authors.forename: J Jose
authors.initials: JJ
authors.lastname: Corbalan
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Malinski
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D007093:Imidazoles; D013777:Tetrazoles; D009569:Nitric Oxide; D000068756:Valsartan; C437965:olmesartan; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D014633:Valine; D019808:Losartan; D000077333:Telmisartan