title: Synergistic effect of amlodipine and atorvastatin in reversing LDL-induced endothelial dysfunction.
abstract: OBJECTIVE
  Statins and certain calcium channel blockers may improve nitric oxide (NO) release and endothelial function through various mechanisms, but their combined effects are not well understood.
  
  
  METHODS
  The separate versus combined effects of amlodipine (AML) and atorvastatin (AT) on NO and peroxynitrite (ONOO-) were measured in human umbilical vein endothelial cells (HUVEC) in the presence and absence of low-density lipoprotein (LDL) using electrochemical nanosensors.
  
  
  RESULTS
  The combination of AML (5 micromol/l) and AT (3-6 micromol/l) directly stimulated NO release that was about twofold greater than the sum of their separate effects (p < 0.05). This synergistic activity is attributed to enhanced endothelial NO synthase (eNOS) function and decreased cytotoxic ONOO-. LDL (100 mg/dl) caused a dysfunction of HUVEC manifested by a 60% reduction in NO and an almost twofold increase in ONOO-. Treatment with AML/AT partially reversed the effects of LDL on endothelial function, including a 90% increase in NO and 50% reduction in ONOO-. Small-angle X-ray diffraction analysis indicates that AML and AT are lipophilic and share an overlapping molecular location in the cell membrane that could facilitate electron transfer for antioxidant mechanisms.
  
  
  CONCLUSIONS
  These findings indicate a synergistic effect of AML and AT on an increase in NO concentration, reduction of nitroxidative stress. Also, AML/AT partially restored the NO level of LDL-induced dysfunctional endothelium. Their combined effects may be enhanced by antioxidant properties related to their intermolecular actions in the cell membrane and an increase in the expression and coupling of endothelial nitric oxide synthase.
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: R Preston
authors: RP
authors: Mason
authors: Ruslan
authors: R
authors: Kubant
authors: Gehan
authors: G
authors: Heeba
authors: Robert F
authors: RF
authors: Jacob
authors: Charles A
authors: CA
authors: Day
authors: Yehudi S
authors: YS
authors: Medlin
authors: Philipp
authors: P
authors: Funovics
authors: Tadeusz
authors: T
authors: Malinski
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000069059:Atorvastatin; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008051:Lipid Bilayers; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008563:Membrane Lipids / Q000737:chemistry; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D030421:Peroxynitrous Acid / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D014652:Vascular Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D014961:X-Ray Diffraction
chemical_list: D002121:Calcium Channel Blockers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008051:Lipid Bilayers; D008077:Lipoproteins, LDL; D008563:Membrane Lipids; D011758:Pyrroles; D030421:Peroxynitrous Acid; D017311:Amlodipine; D009569:Nitric Oxide; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III