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Summary—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 IC50value of 0.50 μM and reduced the maximum rate of phase 0 depolarization (Vmax) of the ‘slow’ calcium‐mediated transmembrane action potentials in cardiac tissue (IC25= 0.82 μM). 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 μM) and inhibited lipid accumulation by rat aortic smooth muscle cells in culture (1–3 μM). Higher concentrations (3 μM) 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 μM (–) 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 μM), whereas human LDL peroxidation was slightly reduced by nifedipine (0.1–3 μM) but unaltered by diltiazem (0.1–30 μM) and verapamil (0.1–3 μM). 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.

Temporary cerebral ischemia (15 min) produced by “four-vessel occlusion” in the rat causes neurological disorders, changes in behavior (locomotor hyperactivity), and neuronal damage in the neocortex, striatum, and especially the CA1 zone of the hippocampus. We have studied the effects of two calcium overload blockers, flunarizine (50 mg/kg p.o. twice a day) and cinnarizine (100 mg/kg p.o. twice a day), on these alterations. Cinnarizine markedly improved the functional abnormalities of ischemia but had little or no effect upon the neuronal damage. In contrast, flunarizine provided far greater neuronal protection but with less obvious effects upon behavioral parameters. However, there was evidence of sedation 2 h after treating animals with this dose of flunarizine that might have masked any positive effect of the drug on behavior. We conclude that under the present experimental conditions, there is no correlation between the early and late behavioral changes observed following a temporary cerebral ischemic episode and the histological damage observed in certain vulnerable neurons, particularly in the hippocampus, 72 h after the insult.