RESUMO
Chlorpromazine (CPZ) binding and the binding to isolated guinea pig superior cervical of a toxic metabolite 7,8-dihydroxychlorpromazine (7,8-diOH-CPZ) were studied under resting and potassium-stimulated conditions. Maximal binding occurred more rapidly in high potassium, with binding of CPZ 10 fold higher than that of 7,8-diOH-CPZ. However, in low potassium media 50% of bound CPZ and 60% of 7,8-diOH-CPZ was retained following a 240-min washout procedure. When the washout of the drugs from the tissue was studied, release was found to be more extensive in high potassium washout media. Under resting conditions, at 10 microM CPZ or 7,8-diOH-CPZ, calcium accumulation by ganglia decreased but increased at higher drug concentrations. Calcium (Ca) uptake increased with both drugs in high potassium medium. Ca efflux from the tissue was accelerated by both phenothiazines in a dose-dependent fashion. CPZ blocked ganglionic transmission at 20 microM while 7,8-diOH-CPZ (up to 100 microM) increased ganglionic potential amplitude. Thus CPZ and 7,8-diOH-CPZ differ in binding to ganglia and in effects on ganglionic transmission.
Assuntos
Cálcio/metabolismo , Clorpromazina/análogos & derivados , Clorpromazina/farmacologia , Gânglios Simpáticos/efeitos dos fármacos , Animais , Clorpromazina/metabolismo , Ditiotreitol/farmacologia , Gânglios Simpáticos/fisiologia , Cobaias , Técnicas In Vitro , Potássio/farmacologia , Transmissão Sináptica/efeitos dos fármacosAssuntos
Encéfalo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fenotiazinas/farmacologia , Trifosfato de Adenosina/biossíntese , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
7,8-Dihydroxychlorpromazine 7,8-diOH-CPZ) is known to undergo auto-oxidation when exposed to air. Hydrogen peroxide is formed during this process, and the amount formed can be calculated from the amount of oxygen produced upon the addition of catalase. In the presence of superoxide dismutase the rate of oxidation of the CPZ metabolite is accelerated, accompanied by an increased production of hydrogen peroxide. When similar incubation are carried out with rat brain mitochondria present, hydrogen peroxide production is no longer detectable. The implications of this finding with regard to in vivo hydrogen peroxide production during the auto-oxidation of 7,8-diOH-CPZ are discussed. A preliminary report has been presented (1).
