Mechanism of calcium channel inhibition by phenytoin: comparison with classical calcium channel antagonists.
The mechanism of calcium channel antagonism by phenytoin was studied by comparing the effects of phenytoin and classical calcium channel antagonists on K+-stimulated 45Ca uptake and [3H]nitrendipine binding in the PC12 pheochromocytoma cell line. Inhibition of K+-stimulated 45Ca uptake occurred at clinically relevant concentrations of phenytoin (IC50 = 9.6 +/- 2.1 microM) and was not significantly modified by Na channel blockade with tetrodotoxin, K channel blockade with tetraethylammonium or depolarization with carbachol rather than K+. Phenytoin, verapamil and diltiazem inhibited 45Ca uptake with Hill coefficients of less than 0.7, whereas values for nimodipine and flunarizine were close to 1.0. Phenytoin inhibited binding of the dihydropyridine Ca channel antagonist [3H]nitrendipine to PC12 membranes (Ki = 31 +/- 3 microM) by decreasing binding affinity, with no change in the maximal number of binding sites. Phenytoin and nimodipine reduced [3H]nitrendipine binding without altering the first-order rate constant for dissociation; this rate was increased by verapamil and flunarizine and decreased by diltiazem. Diltiazem enhanced inhibition of [3H]nitrendipine binding by phenytoin, reversed inhibition by verapamil and flunarizine and had no effect on inhibition by nimodipine. These findings suggest that phenytoin and classical Ca channel antagonists inhibit voltage-gated Ca++ flux by distinct but functionally linked mechanisms.
R O
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Messing
C L
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Carpenter
D A
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Greenberg
D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002936:Cinnarizine / Q000031:analogs & derivatives / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D005444:Flunarizine; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D009539:Nicotinic Acids / Q000378:metabolism; D009543:Nifedipine / Q000031:analogs & derivatives / Q000378:metabolism; D009553:Nimodipine; D009568:Nitrendipine; D010672:Phenytoin / Q000494:pharmacology*; D010673:Pheochromocytoma / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007473:Ion Channels; D009539:Nicotinic Acids; D002936:Cinnarizine; D009553:Nimodipine; D010672:Phenytoin; D002217:Carbachol; D009568:Nitrendipine; D012964:Sodium; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine; D005444:Flunarizine; D011188:Potassium; D002118:Calcium