Differential interactions between benzodiazepines and the dihydropyridines, nitrendipine and Bay K 8644.
The effects of the dihydropyridine calcium antagonist, nitrendipine and the calcium channel activator, Bay K 8644, have been compared on the anaesthetic, ataxic and anticonvulsant effects of benzodiazepines. Possible interactions between the peripheral benzodiazepine receptor antagonist, PK11195, and the classical benzodiazepines were also examined. Nitrendipine considerably potentiated the anaesthetic effects of benzodiazepines and increased their ataxic effects but had no effect on the anticonvulsant actions. Clonazepam did not produce anaesthesia, at doses up to 1 g kg-1 or when given with nitrendipine. When given alone, nitrendipine did not cause general anaesthesia. Nitrendipine did not appear to alter the metabolism of midazolam. The calcium channel activator, Bay K 8644, reduced the anaesthetic potency of midazolam and, when given alone, produced ataxia. It did not significantly alter central concentrations of midazolam. The "peripheral" benzodiazepine antagonist, PK11195, did not affect the ataxic or anaesthetic actions of benzodiazepines. These results suggest that dihydropyridine-sensitive calcium channels may be more important to the general anaesthetic than to the anticonvulsant actions of benzodiazepines. The "peripheral" benzodiazepine site did not appear to play a role in either of these properties.
Dolin
S J
SJ
Clinical Pharmacology Unit, School of Clinical Medicine, University of Cambridge, England.
Patch
T L
TL
Rabbani
M
M
Taberner
P V
PV
Little
H J
HJ
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002998:Clonazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005479:Flurazepam / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced
D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D001569:Benzodiazepines; D002998:Clonazepam; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009568:Nitrendipine; D005479:Flurazepam; D008874:Midazolam; C037850:PK 11195