RESUMEN
The present study investigated the protective effect of diethylcarbamazine in inhibiting nuclear factor (NF)-κB activation in isoproterenolinduced acute myocardial infarction (AMI) rats through the poly ADP ribose polymerase (PARP) pathway. Male albino Wistar rats were injected subcutaneously with isoproterenol (100 mg/kg/day) for 2 days to induce an AMI model. Diethylcarbamazine (50 mg/kg) was administered by gavage for 12 days prior to the isoproterenol-induced AMI. It was noted that diethylcarbamazine significantly inhibited AMIinduced casein kinase and lactate dehydrogenase levels, and reduced the AMIinduced wet heart weight to body weight ratio in AMI rats. Diethylcarbamazine treatment significantly weakened reactive oxygen species production and reduced the levels of tumor necrosis factor (TNF)α, interleukin6 and NFκB/p65 in AMI rats. Western blotting demonstrated that diethylcarbamazine significantly suppressed the AMIinduced inducible nitric oxide synthase (iNOS), transforming growth factor (TGF)ß1, cyclooxygenase2 (COX2) and PARP protein expression in AMI rats. The results demonstrated that the protective effect of diethylcarbamazine inhibited isoproterenolinduced AMI through the suppression of inflammation, iNOS, TGFß1, COX2 and the PARP pathway, and revealed the clinical potential of diethylcarbamazine for therapeutic and clinical applications.
Asunto(s)
Dietilcarbamazina/antagonistas & inhibidores , Dietilcarbamazina/uso terapéutico , Isoproterenol/farmacología , Infarto del Miocardio/tratamiento farmacológico , FN-kappa B/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasas/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Animales , Caseína Quinasas/metabolismo , Ciclooxigenasa 2/metabolismo , Dietilcarbamazina/administración & dosificación , Modelos Animales de Enfermedad , Proteínas I-kappa B/metabolismo , Interleucina-6/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Masculino , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In spite of its effectiveness against microfilariae, very little is known about diethylcarbamazine's (DEC) therapeutic mechanism of action or the toxic sequelae which can result from overdose. In preliminary studies, a precipitous decrease in heart rate was noted in rats receiving 1000 mg DEC/kg ip. This effect was less pronounced at 750 mg/kg and was non-existent at 500 mg/kg. In the present study, attempts to attenuate DEC's cardiopulmonary insult by pretreating animals with cyproheptadine failed. Atropine pretreatment failed to block the negative chronotropic effects of DEC, but did restore respiratory function and reduce the lethality associated with the drug. Biochemical studies showed that ATP:ADP ratios in the hearts from rats given high dosages of DEC were elevated over those in controls (11:1 versus 5:1). Inosine levels decreased in cardiac tissues taken from DEC-treated rats. Subsequent enzyme studies revealed that DEC has a potent inhibitory effect on calcium-dependent ATPases from a variety of tissues. Taken together, our data indicate that the mode of acute DEC-lethality involves cardiopulmonary suppression. Furthermore, the cardiac depressant effect of DEC appears related to inhibition of calcium ATPases in cardiac myocytes. To our knowledge, this is the first report of ATPase sensitivity to DEC, a finding that has interesting toxicologic and pharmacologic ramifications.
Asunto(s)
Atropina/farmacología , ATPasas Transportadoras de Calcio/efectos de los fármacos , Ciproheptadina/farmacología , Dietilcarbamazina/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Miocardio/enzimología , Respiración/efectos de los fármacos , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , ATPasas Transportadoras de Calcio/metabolismo , Dietilcarbamazina/antagonistas & inhibidores , Miocardio/química , Ratas , Ratas Sprague-DawleyRESUMEN
Effects of piperazine derivatives, especially of diethylcarbamazine (DEC) on adult Angiostrongylus cantonensis and Dirofilaria immitis were examined. Piperazine (3 X 10(-5)-10(-4) M) paralyzed A. cantonensis and the action was antagonized by picrotoxin. 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (10(-5)-10(-4) M) caused contraction but little effect was produced by strychnine. An inhibitory effect on untreated preparations was caused by lower concentrations (3 X 10(-6)-10(-5) M) of diethylcarbamazine citrate (DEC) and also on the preparations contracted by eserine. A stimulatory effect was also seen when higher concentrations (10(-4)-3 X 10(-4) M) of this drug were applied to both preparations. The inhibitory action of DEC was antagonized by gabergic antagonists such as picrotoxin and bicuculline, but not by alpha-adrenergic antagonists like dibenamine and phentolamine. When the worm preparation was paralyzed by strychnine or hexylresorcinol (inhibitors of the release of acetylcholine in this worm), the stimulatory effect of DEC was blocked, but pyrantel (a nicotinic cholinergic agonist) contracted the paralyzed preparation. However, the effect of DEC on D. immitis (10(-7)-3 X 10(-4) M) was inhibitory, and this action was also antagonized by picrotoxin. These results suggest that the DEC inhibitory and stimulatory action is through the gabergic and cholinergic mechanisms in adult A. cantonensis and D. immitis.