Protection of cardiac membrane phospholipid against oxidative injury by calcium antagonists

Abstract

Calcium antagonists representative of the four major chemical classes were assessed for their abilities to prevent peroxidation of rat heart membrane lipids through xanthine oxidase-dependent, superoxide-driven, iron-promoted oxygen radical chemistry. The dihydropyridines nifedipine and nitrendipine did not affect peroxidation, even at a concentration (500 microM) approaching their solubility limit. The benzothiazepine diltiazem did protect the cardiac lipids against oxidative injury, but at high micromolar concentrations: 50% inhibition of peroxidation (antiperoxidant IC50) required 510 microM diltiazem. The phenylalkylamines verapamil and gallopamil (D-600) were likewise weak antiperoxidants (approximately 35% inhibition of peroxidation at 500 microM). In contrast, two other alkylamines, bepridil and prenylamine, were very effective membrane lipid protectants with respective antiperoxidant IC50 values of 55 and 75 microM. The diphenylpiperazines flunarizine (IC50 = 190 microM) and cinnarizine (IC50 = 180 microM) displayed moderate antiperoxidant activity. No Ca2+ antagonist inhibited xanthine oxidase under conditions whereby 10 microM allopurinol inhibited enzyme activity by 50%. The effects of the Ca2+ antagonist-antiperoxidants on the kinetics of cardiac membrane lipid peroxidation indicate that they inhibit peroxidation by intercepting oxy- and/or lipid free radical intermediates. These data raise the possibility that antiperoxidant action may contribute to the spectrum of pharmacologic and therapeutic activities of certain Ca2+ antagonists.