X-Message-Number: 12843
Date: Thu, 25 Nov 1999 09:00:18 -0800 (PST)
From: Doug Skrecky <>
Subject: amlodipine lowers membrane thermal transition

Authors
  Mason RP.  Mak IT.  Trumbore MW.  Mason PE.
Institution
  Department of Biochemistry and Medicine, MCP-Hahnemann University School of
  Medicine, Pittsburgh, Pennsylvania, USA.
Title
  Antioxidant properties of
  calcium antagonists related to membrane
  biophysical interactions.
Source
  American Journal of Cardiology.  84(4A):16L-22L, 1999 Aug 19.
Abstract
  The antioxidant activities of representative
  calcium antagonists, including amlodipine,
  verapamil, and diltiazem, were measured in hepatic microsomal membranes by
  the Fe-catalyzed, hydroxyl radical-producing system (dihydroxyfumarate +
  Fe3+) and assessed by malondialdehyde (MDA) formation. Despite the absence of
  L-type calcium channels in this membrane preparation, the
  calcium antagonists showed dose-dependent
  antioxidant activity. The biophysical mechanism for
  calcium-antagonist antioxidant activity was
  evaluated using radioligand binding assays, high-resolution differential
  scanning calorimetry, and small-angle x-ray diffraction approaches. These
  analyses demonstrated that calcium-antagonist
  antioxidant potency correlated directly with the compounds'
  relative affinity for the membrane lipid bilayer and ability to modulate
  membrane thermodynamic properties (amlodipine >> verapamil >
  diltiazem). The charged 1,4-dihydropyridine calcium
  antagonist, amlodipine, had the highest affinity for the membrane lipid
  bilayer (Kp>10(4)) and produced the largest changes in membrane thermodynamic
  properties, including a reduction in thermal phase
  transition temperature (-11%), enthalpy (-14%), and cooperative unit size
  (-59%), relative to control phosphatidylcholine liposomes. Electron density
  profiles generated from x-ray diffraction data demonstrated that amlodipine
  effected a broad and dose-dependent increase in molecular volume associated
  with the membrane hydrocarbon core. These data indicate that lipophilic
  calcium antagonists inhibit lipid
  peroxidation in cellular membranes as a result of modulating physicochemical
  properties of the membrane lipid bilayer, independently of
  calcium channel inhibition. Amlodipine had the most potent
  antioxidant activity as a result of distinct biophysical
  interactions with the membrane lipid bilayer. The nonreceptor-mediated
  antioxidant activity of calcium
  antagonists may contribute to cytoprotective mechanisms of
  action in cardiovascular diseases.

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