RESUMO
OBJECTIVE: To evaluate the role of the chemical burns caused by hydroxide ion in the fatal effects of tetramethylammonium ion (TMA) in dermal exposure to tetramethylammonium hydroxide (TMAH), we conducted a rat study consisting of two-step treatments with dermal exposure to NaOH and tetramethylammonium chloride (TMACl). METHODS: In the first step, NaOH or saline was administered in the gauze on the shaved skin for 5 min, and in the second step, TMAH, TMACl, or saline was administered in the same way. The mean blood pressure (MBP), heart rate (HR), and survival in rats were compared among seven groups. RESULTS: Dermal exposure to saline and then 2.75 M TMACl introduced limited and temporary non-fatal effects. Exposure to 2.75 M NaOH and then saline had almost no effects and caused no deaths. Treatments with more concentrated NaOH or TMACl resulted in suppressions of MBP and HR, and deaths were observed after the dosing of TMACl. CONCLUSION: The toxicity of dermal exposure to TMA alone is limited, but fatal effects can be introduced by pre-treatment with hydroxide ion. Therefore, the chemical burn caused by hydroxide ion plays an essential role in the toxicity, implicating that effective neutralizing may help decreasing the fatality rate.
Assuntos
Fármacos do Sistema Nervoso Autônomo/toxicidade , Queimaduras Químicas/etiologia , Hidróxidos/toxicidade , Compostos de Amônio Quaternário/toxicidade , Hidróxido de Sódio/toxicidade , Administração Cutânea , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Estimativa de Kaplan-Meier , Masculino , Exposição Ocupacional , Ratos , Ratos WistarRESUMO
BACKGROUND: Ozone (O3) is a well-documented respiratory oxidant, but increasing epidemiological evidence points to extrapulmonary effects, including positive associations between ambient O3 concentrations and cardiovascular morbidity and mortality. OBJECTIVE: With preliminary reports linking O3 exposure with changes in heart rate (HR), we investigated the hypothesis that a single inhalation exposure to O3 will cause concentration-dependent autonomic modulation of cardiac function in rats. METHODS: Rats implanted with telemeters to monitor HR and cardiac electrophysiology [electrocardiography (ECG)] were exposed once by whole-body inhalation for 4 hr to 0.2 or 0.8 ppm O3 or filtered air. A separate cohort was tested for vulnerability to aconitine-induced arrhythmia 24 hr after exposure. RESULTS: Exposure to 0.8 ppm O3 caused bradycardia, PR prolongation, ST depression, and substantial increases in atrial premature beats, sinoatrial block, and atrioventricular block, accompanied by concurrent increases in several HR variability parameters that were suggestive of increased parasympathetic tone. Low-O3 exposure failed to elicit any overt changes in autonomic tone, heart rhythm, or ECG. However, both 0.2 and 0.8 ppm O3 increased sensitivity to aconitine-induced arrhythmia formation, suggesting a latent O3-induced alteration in myocardial excitability. CONCLUSIONS: O3 exposure causes several alterations in cardiac electrophysiology that are likely mediated by modulation of autonomic input to the heart. Moreover, exposure to low O3 concentrations may cause subclinical effects that manifest only when triggered by a stressor, suggesting that the adverse health effects of ambient levels of air pollutants may be insidious and potentially underestimated.
Assuntos
Arritmias Cardíacas/fisiopatologia , Frequência Cardíaca , Coração/efeitos dos fármacos , Exposição por Inalação , Oxidantes Fotoquímicos/toxicidade , Ozônio/toxicidade , Aconitina/toxicidade , Animais , Arritmias Cardíacas/induzido quimicamente , Fármacos do Sistema Nervoso Autônomo/toxicidade , Estudos de Coortes , Relação Dose-Resposta a Droga , Eletrocardiografia , Coração/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , TelemetriaRESUMO
The possibilities of using developing chick embryos for evaluating drug activities and toxicities were studied by determining LD50 values for 20 drugs with 14 different pharmacological activities. Fifteen-day old chick embryos received drugs through the air cell and deaths were measured at 48 hr after the treatments. The LD50 values were determined and compared to the i.v., i.p., s.c. and p.o. values from mice listed in the Registry of Toxic Effects of Chemical Substance. The systemic toxicity of 15-day-old chick embryos to drugs were similar to those of mice with the following exceptions. The chick embryos seemed to be more sensitive than mice to antineoplastic or antibiotic agents such as actinomycin D and doxorubicin, whereas, LD50 values of cholinergic and cholinergic blocking drugs by this method were 10 to 20 fold of LD50 (i.v.) of mice. These observations are important for applying the hen's fertile screening test (HEST) to the determination of drug activities other than that of embryo toxicity or teratogenic activity.
Assuntos
Embrião de Galinha/efeitos dos fármacos , Toxicologia/métodos , Animais , Antineoplásicos/toxicidade , Fármacos do Sistema Nervoso Autônomo/toxicidade , Depressores do Sistema Nervoso Central/toxicidade , Dose Letal Mediana , Camundongos , Psicotrópicos/toxicidade , RatosRESUMO
In order to determine the neurotoxicity of prenatal and postnatal exposures to neuroactive drugs in developing rats, we examined placental and blood-brain barrier (BBB) transfers of these radiolabeled drugs when they were administered sc to pregnant rats on Day 19 of gestation, and to pups on Days 2, 7, and 14 after birth. The logarithms of partition coefficients (log Pcorr), used as indices of the lipid solubility of the drugs, decreased in the order propranolol greater than chlorpromazine greater than haloperidol greater than atropine greater than reserpine greater than dopamine greater than epinephrine greater than norepinephrine. The coefficients of correlation between log Pcorr and BBB transfer were statistically significant in all dams, fetuses, and pups. Propranolol, chlorpromazine, and haloperidol, having high lipid solubility, passed rapidly into fetuses. Behavioral teratogenesis occurred to a greater extent with postnatal than with prenatal exposures. All moderately and poorly lipophilic drugs transferred into fetuses, although at lower plasma concentrations than in dams. BBB transfer was low in dams, fetuses, and pups. The behavioral teratogenic potential of these drugs was relatively weaker than that of highly lipophilic drugs. Our results suggest that BBB transfer of drugs, which varies according to lipid solubility, is a major factor in behavioral teratogenesis. Highly lipid-soluble drugs were readily incorporated into developing rat brains, becoming strongly behaviorally teratogenetic by impairing postnatal functional maturation.
Assuntos
Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/fisiologia , Encéfalo/efeitos dos fármacos , Troca Materno-Fetal/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/toxicidade , Fármacos do Sistema Nervoso Autônomo/farmacocinética , Fármacos do Sistema Nervoso Autônomo/toxicidade , Comportamento Animal/fisiologia , Feminino , Gravidez , Ratos , SolubilidadeRESUMO
Atropa belladonna L. (Solanaceae) tincture was compared with atropine for its anticholinergic activity, both in vivo and in vitro. In all tests, the biological activity of A. belladonna resulted greater than that suggested by its alkaloid content. The results suggest the presence in A. belladonna leaves of unknown compounds with a significant biological activity.
Assuntos
Atropa belladonna , Atropina/farmacologia , Fármacos do Sistema Nervoso Autônomo/farmacologia , Comportamento Animal/efeitos dos fármacos , Plantas Medicinais , Plantas Tóxicas , Alcaloides/farmacologia , Animais , Atropina/antagonistas & inibidores , Atropina/toxicidade , Fármacos do Sistema Nervoso Autônomo/antagonistas & inibidores , Fármacos do Sistema Nervoso Autônomo/toxicidade , Avaliação Pré-Clínica de Medicamentos , Feminino , Cobaias , Técnicas In Vitro , Dose Letal Mediana , Masculino , Camundongos , Camundongos Endogâmicos , Oxotremorina/farmacologia , Parassimpatolíticos/antagonistas & inibidores , Parassimpatolíticos/farmacologia , Parassimpatolíticos/toxicidade , Extratos Vegetais/farmacologia , Escopolamina/antagonistas & inibidores , Escopolamina/farmacologia , Escopolamina/toxicidadeRESUMO
The drugs used were methamphetamine, reserpine, norepinephrine, epinephrine, propranolol, chlorpromazine, haloperidol, pilocarpine and atropine. Each drug except for reserpine (days 7-13 and 14-19 of gestation) was administered subcutaneously to dams from day 7 to 19 of gestation. The body weight gain of dams receiving reserpine (days 7-13) and haloperidol was inhibited during the gestation period. Two out of 9 dams receiving methamphetamine died on day 21 of gestation period; However, no effect was observed in dams given other drugs. The body weight gain of pups was inhibited in methamphetamine and haloperidol treated groups. The mortality of pups was comparable in all groups. The behavioral development of the righting reflex, cliff drop avoidance and negative geotaxis of pups given reserpine (days 7-13), norepinephrine, chlorpromazine and haloperidol was significantly retarded in comparison with that of control pups. The spontaneous motor activity of pups measured by Animex was increased in reserpine (days 7-13) and epinephrine treated groups and decreased in the chlorpromazine treated group on day 28 postpartum, but comparable in all groups on day 56 postpartum. The conditioned avoidance responses using the shuttle box revealed deficits of avoidance learning of pups in the reserpine (days 7-13), norepinephrine and atropine treated groups. These findings suggest that the prenatal exposure to drugs acting on the autonomic nervous system may produce adverse effects on the behavioral development of pups; However, the adverse effects were more apparent by postnatal exposure than by prenatal exposure.