Effects of selected histamine H3 receptor antagonists on tele-methylhistamine levels in rat cerebral cortex
| Autor: | Clark E. Tedford, Stephen L. Yates, D.L Boyd, Michael K. Handley, Gary P. Pawlowski, Lindsay B. Hough, Rosilyn Gregory |
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| Rok vydání: | 2000 |
| Předmět: |
Agonist
Male Clobenpropit medicine.medical_specialty medicine.drug_class Methylhistamine Histamine Antagonists Radioimmunoassay Biochemistry Partial agonist Gas Chromatography-Mass Spectrometry Rats Sprague-Dawley chemistry.chemical_compound Internal medicine medicine Animals Receptors Histamine H3 Pharmacology Cerebral Cortex Thioperamide Analysis of Variance Chemistry Methylhistamines Pargyline Rats Endocrinology Histamine H3 receptor Histamine medicine.drug |
| Zdroj: | Biochemical pharmacology. 57(9) |
| ISSN: | 0006-2952 |
| Popis: | Abstract. The H 3 antagonist thioperamide is thought to act on brain H 3 autoreceptors to increase both the release and metabolism of neuronal histamine (HA). Our studies investigated the effects of several new brain-penetrating H 3 antagonists on rat cerebral cortical levels of the HA metabolite tele -methylhistamine ( t -MH). Animals were pretreated with H 3 antagonists (0.3 to 30 mg/kg; 1–4 hr; i.p.) in the presence or absence of the monoamine oxidase inhibitor pargyline to prevent metabolism of t -MH. Cortical t -MH levels were measured by both radioimmunoassay (RIA) and gas chromatography–mass spectrometry (GC–MS). Pargyline (60 mg/kg; 1 hr; i.p.) produced an ∼2-fold increase in t -MH levels as measured by either GC–MS or RIA. Thioperamide (± pargyline) increased t -MH levels as measured by both GC–MS and RIA. In contrast, neither 5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one (GT-2016) (± pargyline), 4-(6-cyclohexylhex- cis -3enyl)imidazole (GT-2227) (± pargyline), nor clobenpropit (minus pargyline) increased t -MH levels as measured by GC–MS. A good agreement was found between t -MH levels as determined by either RIA or GC–MS except after treatment with GT-2016, which increased apparent t -MH brain levels according to the former but not the latter method. Subsequent studies suggest the in vivo formation of a GT-2016 metabolite, which can cross-react in the t -MH RIA. Although all H 3 receptor antagonists studied to date seem capable of enhancing brain HA release, only thioperamide presently was found to enhance cortical t- MH levels. Thus, H 3 receptor antagonists may differentially affect HA release and turnover, and brain t -MH levels may not be reliable predictors of H 3 agonist, partial agonist, or antagonist in vivo activity. |
| Databáze: | OpenAIRE |
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