RESUMO
1. The block of K+ currents by amitriptyline and the related tricyclic compounds cyproheptadine and dizocilpine was studied in dissociated rat sympathetic neurones by whole-cell voltage-clamp recording. 2. Cyproheptadine (30 microM) inhibited the delayed-rectifier current (Kv) by 92% and the transient current (KA) by 43%. For inhibition of Kv, cyproheptaidine had a KD of 2.2 microM. Dizocilpine (30 microM) inhibited Kv by 26% and KA by 22%. The stereoisomers of dizocilpine were equally potent at blocking Kv and KA. 3. Amitriptyline, a weak base, was significantly more effective in blocking Kv at pH 9.4 (KD = 0.46 microM) where the ratio of charged to uncharged drug was 50:50 compared with pH 7.4 (KD = 11.9 microM) where the ratio was 99:1. 4. N-methylamitriptyline (10 microM), the permanently charged analogue of amitriptyline, inhibited Kv by only 2% whereas in the same cells amitriptyline (10 microM) inhibited Kv by 36%. 5. Neither amitriptyline nor N-methylamitriptyline had a detectable effect on Kv when added to the intracellular solution. 6. It is concluded that the uncharged form of amitriptyline is approximately one hundred times more potent in blocking Kv than the charged form. However, this does not seem to be due to uncharged amitriptyline having better access to an intracellular binding site.
Assuntos
Amitriptilina/farmacologia , Antidepressivos Tricíclicos/farmacologia , Neurônios/metabolismo , Canais de Potássio/metabolismo , Sistema Nervoso Simpático/metabolismo , Amitriptilina/química , Animais , Antidepressivos Tricíclicos/química , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Masculino , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Canais de Potássio/efeitos dos fármacos , Protriptilina/análogos & derivados , Protriptilina/química , Protriptilina/farmacologia , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sistema Nervoso Simpático/citologia , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
The 10, 11-epoxide, 10-hydroxy, and 10, 11-dihydrodiol metabolites of protriptyline were identified in rat urine collected after the administration of 40 mg/kg ip of protriptyline. Mass spectrometric characterization confirmed the structure of these metabolites.
Assuntos
Dibenzocicloeptenos/análogos & derivados , Protriptilina/análogos & derivados , Animais , Cromatografia Gasosa , Cromatografia em Camada Fina , Compostos de Epóxi/urina , Glucuronidase , Hidrólise , Masculino , Espectrometria de Massas , Protriptilina/urina , RatosRESUMO
10,11-Dihydro-10,11-dihydroxyprotriptyline was identified in rat urine following administration of protriptyline 40 mg kg-1 i.p. Gas chromatographic-mass spectrometric characterization confirmed the structure of this stable metabolite, and its identity with a synthetic sample.
