RESUMO
Objective: Despite the recognized anti-inflammatory potential of heterocyclic antidepressants, the mechanisms concerning their modulating effects are not completely known. Thus, we evaluated the anti-inflammatory effect of amitriptyline, clomipramine, and maprotiline and the possible modulating properties of these drugs on neutrophil migration and mast cell degranulation. Methods: The hind paw edema and air-pouch models of inflammation were used. Male Wistar rats were treated with saline, amitriptyline, clomipramine or maprotiline (10, 30, or 90 mg/kg, per os [p.o.]) 1 h before the injection of carrageenan (300 μg/0.1 mL/paw) or dextran (500 μg/0.1 mL/paw). Then, edema formation was measured hourly. Neutrophil migration to carrageenan (500 μg/pouch) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) (10-6 M/mL/pouch) was also investigated in 6-day-old air-pouch cavities. Compound 48/80-induced mast cell degranulation was assessed in the mesenteric tissues of antidepressant-treated rats. Results: All tested antidepressants prevented both carrageenan- and dextran-induced edema. The anti-inflammatory effect of these drugs partially depends on the modulation of neutrophil migration, since they significantly counteracted the chemotactic response of both carrageenan and fMLP (p < 0.01). Furthermore, amitriptyline, clomipramine and maprotiline inhibited compound 48/80-induced mast cell degranulation (p < 0.001). Conclusions: These results suggest an important anti-inflammatory role of heterocyclic antidepressants, which is dependent on the modulation of neutrophil migration and mast cell stabilization. .
Assuntos
Animais , Masculino , Ratos , Amitriptilina/farmacologia , Anti-Inflamatórios/farmacologia , Degranulação Celular/efeitos dos fármacos , Clomipramina/farmacologia , Maprotilina/farmacologia , Mastócitos/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Carragenina/efeitos adversos , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Edema/induzido quimicamente , Mastócitos/fisiologia , Ratos WistarRESUMO
OBJECTIVE: Despite the recognized anti-inflammatory potential of heterocyclic antidepressants, the mechanisms concerning their modulating effects are not completely known. Thus, we evaluated the anti-inflammatory effect of amitriptyline, clomipramine, and maprotiline and the possible modulating properties of these drugs on neutrophil migration and mast cell degranulation. METHODS: The hind paw edema and air-pouch models of inflammation were used. Male Wistar rats were treated with saline, amitriptyline, clomipramine or maprotiline (10, 30, or 90 mg/kg, per os [p.o.]) 1 h before the injection of carrageenan (300 µg/0.1 mL/paw) or dextran (500 µg/0.1 mL/paw). Then, edema formation was measured hourly. Neutrophil migration to carrageenan (500 µg/pouch) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) (10-6 M/mL/pouch) was also investigated in 6-day-old air-pouch cavities. Compound 48/80-induced mast cell degranulation was assessed in the mesenteric tissues of antidepressant-treated rats. RESULTS: All tested antidepressants prevented both carrageenan- and dextran-induced edema. The anti-inflammatory effect of these drugs partially depends on the modulation of neutrophil migration, since they significantly counteracted the chemotactic response of both carrageenan and fMLP (p < 0.01). Furthermore, amitriptyline, clomipramine and maprotiline inhibited compound 48/80-induced mast cell degranulation (p < 0.001). CONCLUSIONS: These results suggest an important anti-inflammatory role of heterocyclic antidepressants, which is dependent on the modulation of neutrophil migration and mast cell stabilization.
Assuntos
Amitriptilina/farmacologia , Anti-Inflamatórios/farmacologia , Degranulação Celular/efeitos dos fármacos , Clomipramina/farmacologia , Maprotilina/farmacologia , Mastócitos/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Animais , Carragenina/efeitos adversos , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Edema/induzido quimicamente , Masculino , Mastócitos/fisiologia , Ratos , Ratos WistarRESUMO
Many drugs block delayed rectifier K+ channels and prolong the cardiac action potential duration. Here we investigate the molecular mechanisms of voltage-dependent block of human ether-a-go-go-related gene (HERG) K+ channels expressed in cells HEK-293 and Xenopus oocytes by maprotiline. The IC50 determined at 0 mV on HERG expressed HEK-293 cell and oocytes was 5.2 and 23.7 microM, respectively. Block of HERG expressed in oocytes by maprotiline was enhanced by progressive membrane depolarization and accompanied by a negative shift in the voltage dependence of channel activation. The potency of maprotiline was reduced 7-fold by point mutation of a key aromatic residue (F656T) and 3-fold for Y652A, both located in the S6 domain. The mutation Y652A inverted the voltage dependence of HERG channel block by maprotiline. Together, these results suggest that voltage-dependent block of HERG results from gating dependent changes in the accessibility of Y652, a critical component of the drug binding site.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Maprotilina/farmacologia , Animais , Sítios de Ligação , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Estimulação Elétrica , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/fisiologia , Feminino , Expressão Gênica , Humanos , Potenciais da Membrana/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Oócitos/fisiologia , Mutação Puntual , XenopusRESUMO
The role of para-chlorophenylalanine and alpha-methyl-DL-p-tyrosine in the antinociceptive effects of the intracerebroventricular administration of the antidepressant drugs clomipramine, zimelidine, imipramine and maprotiline was studied using the acetic acid writhing test in mice. The results demonstrated an antinociceptive effect for all these antidepressants. Pretreatment with para-chlorophenylalanine significantly reduced the antinociception induced by the ED50's of imipramine and maprotiline, and did not modify the effects of zimelidine and clomipramine, pretreatment with alpha-methyl-tyrosine did not modify the antinociception induced by these drugs except maprotiline. Pretreatment with para-chlorophenylalanine plus alpha-methyltyrosine significantly reduced the antinociceptive effect of all the antidepressants tested. The main finding of the present study is that the association of para-chlorophenylalanine plus alpha-methyltyrosine reduced the antinociceptive action of all the antidepressants. This means that critical levels of both 5-HT and NA are responsible for mediating the antinociceptive effects of antidepressants on the writhing test in mice.
Assuntos
Analgesia , Antidepressivos/farmacologia , Fenclonina/farmacologia , Metiltirosinas/farmacologia , Serotoninérgicos/farmacologia , Acetatos/administração & dosagem , Acetatos/intoxicação , Ácido Acético , Animais , Clomipramina/farmacologia , Interações Medicamentosas , Fenclonina/administração & dosagem , Imipramina/farmacologia , Injeções Intraventriculares , Maprotilina/administração & dosagem , Maprotilina/farmacologia , Metiltirosinas/administração & dosagem , Camundongos , Norepinefrina/metabolismo , Distribuição Aleatória , Serotonina/metabolismo , Serotoninérgicos/administração & dosagem , Zimeldina/farmacologia , alfa-MetiltirosinaAssuntos
Antracenos/farmacologia , Violeta Genciana/farmacologia , Maprotilina/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/prevenção & controle , Doença de Chagas/transmissão , Fenômenos Químicos , Química , Camundongos , Reação Transfusional , Trypanosoma cruzi/patogenicidadeRESUMO
Se evaluó por inoculación en ratón la actividad tripanocida del Clorhidrati de Maprotilina comparativamente con la presentada por el Violeta de Genciana cuando estos compuestos se adicionaron a muestras de sangre conteniendo bajas concentraciones de parásitos. Ambas drogas presentaon actividad tripanocida cuando se las utilizó en concentraciónes del orden 10**-3M. Sin embargo, aun empleando esta concentración pudo detectarse esporádicamente infección en alguno de los animales inyectados con muestras de sangre conteniendo 10 o 100 tripomastigotes, despues de haber sido incubadas 24 h a 4-C con uno de ambos compuestos. Debido a la baja solubilidad del Clorhidrato de Maprotilina el presente estudio se realizó con muestras de sangre diluidas al medio siendo imposible evitar esta condición para la concentración 10**-3M de este compuesto. Estos resultados descartan el uso de clorhidrato de Maprotilina en bancos de sangre y previenen sobre la posibilidad eventual de transmitir infección por Trypanosoma cruzi aun con sangre tratada con Violeta de Genciana. De los 3 métodos utilizados para evaluar viabilidad parasitaria remanente en las muestras de sangre químicamente tratadas, el microhematocrito fue el más sensible
Assuntos
Camundongos , Animais , Violeta Genciana/farmacologia , Maprotilina/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Transfusão de Sangue/efeitos adversos , Doença de Chagas/prevenção & controle , Trypanosoma cruzi/patogenicidadeRESUMO
Se evaluó por inoculación en ratón la actividad tripanocida del Clorhidrati de Maprotilina comparativamente con la presentada por el Violeta de Genciana cuando estos compuestos se adicionaron a muestras de sangre conteniendo bajas concentraciones de parásitos. Ambas drogas presentaon actividad tripanocida cuando se las utilizó en concentraciónes del orden 10**-3M. Sin embargo, aun empleando esta concentración pudo detectarse esporádicamente infección en alguno de los animales inyectados con muestras de sangre conteniendo 10 o 100 tripomastigotes, despues de haber sido incubadas 24 h a 4-C con uno de ambos compuestos. Debido a la baja solubilidad del Clorhidrato de Maprotilina el presente estudio se realizó con muestras de sangre diluidas al medio siendo imposible evitar esta condición para la concentración 10**-3M de este compuesto. Estos resultados descartan el uso de clorhidrato de Maprotilina en bancos de sangre y previenen sobre la posibilidad eventual de transmitir infección por Trypanosoma cruzi aun con sangre tratada con Violeta de Genciana. De los 3 métodos utilizados para evaluar viabilidad parasitaria remanente en las muestras de sangre químicamente tratadas, el microhematocrito fue el más sensible (AU)
Assuntos
Camundongos , Animais , Estudo Comparativo , Trypanosoma cruzi/efeitos dos fármacos , Maprotilina/farmacologia , Violeta Genciana/farmacologia , Transfusão de Sangue/efeitos adversos , Doença de Chagas/prevenção & controle , Trypanosoma cruzi/patogenicidadeRESUMO
The purpose of the present study was to compare the extent of salivary flow and finger sweating after single acute oral doses of mianserin (30 mg), amitryptiline (75 mg), imipramine (75 mg) and maprotiline (75 mg) and placebo in healthy volunteers in a double-blind assay. Maprotiline and mianserin were less active in reducing salivary flow but were more active than amitryptiline and imipramine in reducing finger sweating. The lack of association between these methods for the measurement of the anticholinergic effect of antidepressant drugs is analyzed in terms of possible mechanisms for the control of palmar sweating.