Effects of “Nitrendipine” on Nitrous Oxide Anesthesia, Tolerance, and Physical Dependence

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Abstract
Studies with ethanol have indicated that dihydropyridine-sensitive calcium (Ca++) channels may be involved in the adaptation to prolonged exposure to ethanol. This study investigated the effects, in mice, of the dihydropyridine Ca++ antagonist, nitrendipine, on acute tolerance to nitrous oxide after 60 min exposure to anesthetizing concentartions, and also the withdrawal syndrome which occurred following removal from nitrous oxide. Control mice were anesthetized by nitrous oxide concentrations in the range 1.28-1.51 atmospheres. Nitrendipine 10, 50, and 100 mg .cntdot. kg-1, i.p., produced a dose-dependent potentiation of nitrous oxide anesthesia (P < 0.05 for nitrendipine 50 and 100 mg .cntdot. kg-1). Tolerance to nitrous oxide anesthesia developed over 60 min (13% increase in ED50, P < 0.05). Concurrent administration of nitrendipine at all doses prevented the development of nitrous oxide tolerance. After 60 min exposure to nitrous oxide 1-1.5 atmospheres, all control mice showed handling seizures. Nitrendipine diminished or prevented nitrous oxide withdrawal seizures, in a dose-dependent manner (P < 0.05 for nitrendipine 50 and 100 mg .cntdot. kg-1). These results support the importance of the role of dihydropyridine-sensitive Ca++ channels in the mechanism of tolerance and dependence to central depressant drugs. They also suggest that acute and chronic tolerance to sedative drug action may share some common pathways, and that tolerance and physical dependence may share a common mechanism through voltage-operated Ca++ channels.