The differential effects of felodipine and nitrendipine on cerebral dihydropyridine binding ex vivo and the ethanol withdrawal syndrome in mice.
1. The ability of two dihydropyridine calcium channel antagonists, felodipine and nitrendipine both to displace [3H]-isradipine binding in CNS tissue measured ex vivo and to protect against the ethanol withdrawal syndrome has been investigated. 2. Mice were injected with various doses of felodipine or nitrendipine and [3H]-isradipine binding measured in brain homogenates prepared 0.5, 3 or 5 h later. Inhibition versus dose curves were sigmoid and the dose required to produce 50% inhibition increased linearly with time after administration. Felodipine was approximately 10 times more potent than nitrendipine. 3. Nitrendipine (50 mg kg-1, i.p.) and felodipine (10 mg kg-1, i.p.) produced around a 75% inhibition of [3H]-isradipine binding 3 h later. Binding of [3H]-nitrendipine to cerebral tissues measured after in vivo injection of the ligand was decreased by nitrendipine (50 mg kg-1) and felodipine (10 mg kg-1) to a similar extent. 4. Nitrendipine (50 mg kg-1) prevented the behavioural signs of ethanol withdrawal as measured by handling induced convulsions, but felodipine (10 mg kg-1 or 2 mg kg-1) did not provide any protection against this effect of ethanol withdrawal. Felodipine (10 mg kg-1, twice daily) during the course of ethanol treatment also failed to attenuate the withdrawal syndrome. 5. The convulsive response to a mild audiogenic stimulus during ethanol withdrawal was increased following one dose of felodipine (5 mg kg-1, i.p.) but unaffected by nitrendipine. 6. Injection of Bay K 8644 (60 microgram, i.c.v.) produced a significant increase in handling-induced convulsive behaviour. Felodipine (10 mg kg-1, i.p.) reduced this behaviour both 60 and 120 min later, while nitrendipine (50 mg kg-1) showed a modest reduction only at 120 min.7. In contrast, nitrendipine (50mg kg-1) and felodipine (10 mg kg-1) produced similar effects on the hyperexcitability produced by handling following administration of bicuculline. Hexamethonium(8 mg kg-1) had no effect on this response.8. No change was found in [3H]-isradipine or [125I]-w-conotoxin binding to cerebral tissue prepared from ethanol-dependent mice.9. These results demonstrate that while felodipine and nitrendipine have similar actions on some CNS-mediated effects (raising seizure thresholds to several convulsant drugs), felodipine, in contrast to nitrendipine, has no effect on the ethanol withdrawal syndrome. Suggested explanations for the results include the possibility that nitrendipine may protect against the ethanol withdrawal syndrome via sites other than dihydropyridine receptors: that felodipine has partial agonist actions at dihydropyridine receptors in the CNS or that felodipine has actions which mask its protective effect in ethanol withdrawal.
Watson
W P
WP
Department of Pharmacology, Medical School, University Walk, Bristol.
Misra
A
A
Cross
A J
AJ
Green
A R
AR
Little
H J
HJ
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects*; D015736:Felodipine / Q000494:pharmacology*; D017275:Isradipine / Q000378:metabolism*; D008297:Male; D051379:Mice; D009568:Nitrendipine / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*
D000431:Ethanol; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009568:Nitrendipine; D015736:Felodipine; D001640:Bicuculline; D017275:Isradipine