The
calcium antagonistic and
antioxidant properties of a new potential antiatherosclerotic agent,
Org 13061 were compared with those of its (-) and (+) enantiomers (
Org 13471 and
Org 13581) In vitro and with appropriate reference drugs.
Org 13061 antagonized contractions induced by
potassium in rabbit aortic rings with an IC50 value of 0.50 microM and reduced the maximum rate of phase 0 depolarization (Vmax) of the 'slow'
calcium-mediated transmembrane action potentials in cardiac tissue (IC25 = 0.82 microM). Similarly to reference drugs,
Org 13061 was more selective in reducing vascular compared to cardiac contraction. In concentrations overlapping those exerting
vasorelaxant actions,
Org 13061 inhibited
copper ion-induced human
low density lipoprotein (
LDL) peroxidation (0.1-1 microM) and inhibited
lipid accumulation by rat aortic smooth muscle cells in culture (1-3 microM). Higher concentrations (3 microM) modestly inhibited proliferation of these cells. The (-) enantiomer was ten times more potent than the (+) enantiomer as a
vasorelaxant but was equipotent in inhibiting
lipid accumulation and
LDL peroxidation (eg, lag phase of conjugated dienes formation increased by 29 and 61 min and by 22 and 56 min in response to 0.3 and 1 microM (-) and (+) enantiomers, respectively). The
antioxidant probucol was approximately three times more potent than
Org 13061 in inhibiting
lipid accumulation but was 30 times less potent in antagonizing
LDL peroxidation. The classical
calcium channel blocking agents were totally ineffective on
lipid accumulation (1-10 microM), whereas human
LDL peroxidation was slightly reduced by
nifedipine (0.1-3 microM) but unaltered by
diltiazem (0.1-30 microM) and
verapamil (0.1-3 microM). In conclusion, the racemic
Org 13061 selectively blocks voltage-operated
calcium channels (VOCs) in concentrations that also exert marked
antioxidant activity. The (-) enantiomer is largely responsible for
calcium channel block but as
antioxidants, the enantiomers are equipotent. This mixed pharmacological profile of
Org 13061, not shared by known
calcium channel blocking agents, may be potentially useful in the treatment of
atherosclerosis.