In vitro calcium antagonistic and antioxidant effects of Org 13061 and its enantiomers, new potential antiatherosclerotic compounds.

Abstract

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.