Nifedipine and nimodipine competitively inhibit uridine kinase and orotidine-phosphate decarboxylase: theoretical relevance to poor outcome in stroke.
Nifedipine and nimodipine, dihydropyridine calcium channel blockers, are commonly used as antihypertensive and antianginal agents in patients at risk for stroke. At least one stroke trial suggests that patients receiving calcium channel blockers at the time of an acute stroke have worse outcomes than those receiving other or no antihypertensive medications. We hypothesize that the poor outcome may not be related to blood pressure changes but instead may be mediated by competitive inhibition of important enzymes of pyrimidine synthesis whose products are needed to repair nerve cell membranes after an acute stroke. Both drugs acted as competitive inhibitors of the only enzymes that are known to synthesize the nucleotide uridine-5'-phosphate: uridine kinase and orotidine-5'-phosphate decarboxylase. Nifedipine produced Ki values of 28 microM for uridine kinase and 105 microM for orotidine-5'-phosphate decarboxylase. Nimodipine produced Ki values of 20 microM for uridine kinase and 18 microM for orotidine-5'-phosphate decarboxylase. For uridine kinase, these inhibitors bound more tightly than the physiologic substrates uridine or cytidine. For the decarboxylase, the inhibitors bound less tightly than the normal physiologic substrate orotidine-5'-phosphate. Additional experiments are needed to determine whether the concentrations of nifedipine or nimodipine, and of cytidine, uridine, and orotidine-5'-phosphate in human brain, are such that this inhibition would affect stroke outcome.
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Medical Online, Inc., Lexington, Massachusetts 02421-7966, USA. tnajarian@mediol.com
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D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000009:adverse effects / Q000378:metabolism; D009553:Nimodipine / Q000009:adverse effects / Q000378:metabolism; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000187:drug effects* / Q000502:physiology; D010599:Pharmacokinetics; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control*; D016896:Treatment Outcome; D014541:Uridine Kinase / Q000187:drug effects* / Q000378:metabolism
D002121:Calcium Channel Blockers; D009553:Nimodipine; D014541:Uridine Kinase; D009964:Orotidine-5'-Phosphate Decarboxylase; D009543:Nifedipine