title: Amlodipine increased endothelial nitric oxide and decreased nitroxidative stress disproportionately to blood pressure changes.
abstract: BACKGROUND
  Clinical trials have shown that amlodipine reduces cardiovascular events at a rate that is not predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by the pleiotropic effects of amlodipine on endothelial cell (EC) function. In this study, we elucidated the effect of amlodipine on nitric oxide (NO) bioavailability and cytotoxic peroxynitrite (ONOO(-)) and blood pressure (BP).
  
  
  METHODS
  Spontaneously hypertensive rats (SHRs) were treated with vehicle or amlodipine (5 mg/kg/day) for 8 weeks and compared with untreated, baseline rats. NO and ONOO(-) release from aortic and glomerular ECs were measured ex vivo using amperometric nanosensors following maximal stimulation with calcium ionophore. BP was measured using the tail-cuff method.
  
  
  RESULTS
  As compared with baseline, vehicle treatment had reduced aortic endothelial NO release from 157 ± 11 nM to 55 ± 6 nM and increased ONOO(-) from 69 ± 7 nM to 156 ± 19 nM. The NO/ONOO(-) ratio, a comprehensive measurement of eNOS function, decreased from 2.3 ± 0.3 to 0.3 ± 0.1. Compared with vehicle, amlodipine treatment restored NO to 101 ± 3 nM, decreased ONOO(-) to 50 ± 4 nM, and increased the NO/ONOO(-) ratio to 2.0 ± 0.2, a level similar to baseline. Similar changes were observed for glomerular ECs. Mean arterial blood pressure increased from 149 ± 3 mm Hg (baseline) to 174 ± 1 mm Hg (vehicle). Amlodipine slightly, but significantly, decreased mean arterial blood pressure to 167 ± 3 mm Hg vs. vehicle treatment.
  
  
  CONCLUSIONS
  Amlodipine increased NO bioavailability and decreased nitroxidative stress in SHRs with EC dysfunction disproportionately to BP changes. These direct, vascular effects of amlodipine on EC function may contribute to reduced risk for atherothrombotic events as observed in clinical trials.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
authors.forename: Robert F
authors.initials: RF
authors.lastname: Jacob
authors.forename: J Jose
authors.initials: JJ
authors.lastname: Corbalan
authors.forename: Roman
authors.initials: R
authors.lastname: Kaliszan
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Malinski
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; D030421:Peroxynitrous Acid; D017311:Amlodipine; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: amlodipine; blood pressure; endothelial cells; hypertension; nitric oxide; peroxynitrite; spontaneously hypertensive rats.