Cerebrovascular and cerebral metabolic effects of flurazepam and a benzodiazepine antagonist, 3-hydroxymethyl-beta-carboline.
There is a need in clinical practice for an antagonist which can reverse the sedative action of benzodiazepines. Recently, 3-hydroxymethyl-beta-carboline (3-HMC) has been reported to inhibit the sleep inducing effects of flurazepam. The effects of flurazepam (0.5, 5 and 50 mg/kg) on cerebral blood flow (CBF) and cerebral O2 consumption (CMRO2) were evaluated in rats and the ability of 3-HMC to reverse these changes was determined. Regional CBF was measured with radioactive microspheres and cortical CMRO2 was calculated from sagittal sinus-arterial O2 content differences and cortical CBF. Flurazepam produced dose dependent decreases in CBF and CMRO2 which were significant at 5 and 50 mg/kg. 3-HMC (5 mg/kg) inhibited flurazepam induced changes at the 5 mg/kg dose but had little effect on the CBF and CMRO2 depression produced by 50 mg/kg flurazepam. At a dose of 25 mg/kg, 3-HMC inhibited the effects of both 5 and 50 mg/kg flurazepam. Blood pressure and heart rate were also decreased by flurazepam but these variables were not reversed as effectively by 3-HMC treatment. The results indicate that 3-HMC is an active antagonist of the cerebrovascular and cerebral metabolic depression produced by flurazepam and can stimulate CBF and CMRO2 at high doses when given alone.
D000818:Animals; D001569:Benzodiazepines / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005479:Flurazepam / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D002243:Carbolines; D007211:Indoles; D001569:Benzodiazepines; C031516:3-hydroxymethyl-beta-carboline; D008729:Methoxamine; D005479:Flurazepam