Lack of acute pathogenicity and toxicity in mice of an isolate of Metarhizium anisopliae var. anisopliae from spittlebugs.

A monospore strain of Metarhizium anisopliae var. anisopliae (EH-479/2), isolated in Mexico from Aeneolamia sp., was tested for oral acute intragastric pathogenicity and toxicity in CD-1 mice, including a thorough histological study. Animals were inoculated by gavage with one dose (10(8) conidia/animal) of viable (72 mice) and nonviable (24 mice) conidia and compared to 18 control mice. Clinical observations were done daily; mycological and histological tests were performed during necropsies at days 3, 10, 17, and 21 after the inoculation. At the end of the study, no mice showed clinical symptoms of illness, and the animals' mean weight corresponded to that of healthy adults. No inflammatory reactions were identified in analyzed organs, suggesting the nonimmunogenic status of this fungal strain. Evidence of fungal germination was noted in two lymph nodes and in liver and lung of one dead mouse, out of 72 viable-conidia treated mice. There was no evidence of toxicity symptoms in mice inoculated with nonviable conidia. The results obtained support the nonpathogenic and nontoxic status of this fungal strain when administered in a sole intragastric dose in mice.

Enhancement of hydralazine hypotension by low doses of isoniazid. Possible role of semicarbazide-sensitive amine oxidase inhibition.

The influence of pretreatment with 1 through 300 mg/kg ip of isoniazid (ISO) on blood pressure and heart rate responses to 0.1 mg/kg iv of hydralazine (HYD) was assessed in rats anesthetized with chloralose--urethane. HYD hypotension was significantly enhanced by ISO at doses between 3 and 300 mg/kg ip. Heart rate was not influenced by HYD in control or pretreated animals. Depressor responses to 0.2 mg/kg iv of pinacidil (PIN) were also potentiated by ISO at 100 and 300, but not at 30 mg/kg. Similarly, ISO decreased cerebral gamma-aminobutyric acid (GABA) at the two highest doses; 30 mg/kg was without effect. Pretreatment of rats with ISO at 1 through 300 mg/kg failed to influence HYD-induced relaxation of aortic rings. These results were interpreted as indicating that potentiation of HYD hypotension by high doses of ISO is not specific for that vasodilator and is related to decreased cerebral GABA, as postulated previously. Lower doses could specifically potentiate the HYD-induced hypotensive effect by inhibition of semicarbazide-sensitive amine oxidase (SSAO), since both ISO and HYD are potent inhibitors of this enzyme. In support of this hypothesis, the SSAO inhibitors, benserazide (100 mg/kg ip) and mexiletine (50 mg/kg ip), were also found to enhance HYD hypotension.

Effect of the menstrual cycle in ethanol pharmacokinetics.

Differences in ethanol pharmacokinetics within the menstrual cycle have previously been reported and attributed to variations in body composition, hormonal influences and gastric emptying. To establish the role of the menstrual cycle in ethanol pharmacokinetics associated with changes in body composition, ethanol blood concentrations were measured in nine healthy women during the midfollicular (P1, days 8-10) and midluteal (P2, days 22-24) phases of the menstrual cycle after a postprandial oral ethanol dose (0.3 g kg(-1)). Total body water was assessed by dual-energy x-ray densitometry (DEXA) on both occasions. Median total body water did not vary during either phase of the menstrual cycle (P1 = 54.54%, P2 = 54.66%; P = 0.9296). Median area under the ethanol concentration-time curve (AUC) was lower during P1 (215.33 mg.h dl(-1)) than during P2 (231.33 mg.h dl(-1))(P = 0.8253). No significant differences were found on ethanol pharmacokinetics in either phase of the menstrual cycle.

Vasoconstrictor effect of Cissus sicyoides on guinea-pig aortic rings.

1. The effect of the aqueous extract of Cissus sicyoides (CS) on isolated guinea pig aortic rings was studied. CS contracts the smooth muscle of the aorta in a dose-response relation. 2. The extract of CS increases the norepinephrine contraction in normal calcium and in solutions without calcium. 3. Lanthanum inhibits the contraction induced by CS. 4. The vasoconstrictor effect of CS was increased in solutions without calcium or with low calcium, which is an inverse calcium-dependent contraction. 5. Prolonged exposure to calcium-free solution did not abolish CS contraction. These contractions can be elicited repeatedly even after 6 hr of continuous exposure to calcium-free solutions. 6. Caffeine reduces contractile response induced by CS in normal calcium, as well as in solutions without calcium. 7. Our results support the idea that the aqueous extract of CS acts at the membrane level, increasing the calcium entry through the membrane as well as acting on the internal calcium deposits, possibly on the sarcoplasmic reticulum.

Behavioral effects of chronic toluene exposure in the developing rat.

The effects of acute and chronic toluene exposure on the hypnotic effect, the righting reflex latencies and the blood and tissue toluene contents were studied in rats during development. The data showed a progressive significant prolongation of the hypnotic effect latencies until the third and fourth postnatal weeks, followed by a significant continuous declining trend until the eighth week postpartum. The measure of the righting reflex latencies followed an opposite temporal course compared to that of hypnotic effect measurements. The acute and chronic toluene exposure did not reveal significant differences in toluene concentrations of blood, brain and liver tissues. The data suggest that chronic toluene treatment may probably be inducing behavioral manifestations of a tolerance phenomenon combined with maturational influences in the developing rat.

Toluene and benzene inhalation influences on ventricular arrhythmias in the rat.

We have previously found that toluene did not share the capacity of benzene for increasing the arrhythmogenic action of epinephrine in the rat, but appeared to elicit the opposite effect. The present experiments were carried out to verify this observation in rats subjected to more severe ventricular arrhythmias. In animals previously inhaling either air, toluene or benzene and anesthetized with pentobarbital, arrhythmias were produced by coronary ligation or aconitine. In both models, toluene decreased and benzene increased the number of ectopic ventricular beats in the 30 min following induction of arrhythmia. Gas chromatographic measurement of toluene levels in the heart during and after inhalation revealed essentially constant concentrations at the time of arrhythmia evaluation, equivalent to approximately one-third the peak levels observed at the end of inhalation. Although the mechanism of the effect of toluene on arrhythmia could not be ascertained, nonspecific membrane stabilization or central serotonergic stimulation were considered as possible explanations. Since both mechanisms could be operant also in the case of benzene, the opposite effects of the solvents on arrhythmia could not be readily accounted for.

Electrocardiographic effects of toluene in the anesthetized rat.

The influence of inhalation of near lethal quantities of toluene on some ECG parameters, as well as the possible cardiac sensitizing effect of the solvent, were determined in chloralose-anesthetized rats. These actions were compared with those of its close analogue benzene. Both solvents produced tachycardia; toluene increased the duration of QRS and specially PR, while benzene decreased P wave duration. No other systematic changes in ECG morphology or evidence of arrhythmia were observed. Toluene appeared to decrease the number of ectopic beats induced by epinephrine, in contrast to benzene, which increased it markedly. These results suggest that toluene administered by inhalation up to near lethal doses is devoid of untoward ECG effect in the chloralose-anesthetized rat, its only action being a decrease in intraventricular and particularly AV conduction. It does not share the myocardial sensitizing properties of benzene and in fact appears to elicit some protection from the arrhythmogenic effects of epinephrine, although no definite conclusions as to this action can be derived due to limitations in the experimental model used.

Effects of neonatal toluene exposure on the development of evoked and spontaneous cortical activity in the rat.

The effects of neonatal toluene exposure on the development of cortical evoked responses to sciatic nerve and light stimulation, as well as the spontaneous Electrocorticogram (ECoG) of frontal and occipital regions, were studied in rats at different developmental ages. The major findings following the solvent exposure were a significant prolongation in the mean peak latencies of both primary and secondary cortical evoked responses the effects being more severe in the sensorimotor area than in the visual cortical region. Additionally the experimental animals did not show significant differences in the average frequencies histograms of the ECoG in both neocortical areas when compared with control littermates. The data suggest that early toluene exposure was primarily affecting those brain structures underlying locomotor abilities than those related with the functionality of the CNS visual centers.

Neonatal effects of toluene on the locomotor behavioral development of the rat.

Rats were exposed to toluene twice a day for a period of 15 minutes on Days 2 through 32 of postnatal life. The subsequent effects upon swimming ability, escape latency from water, locomotor activity and physical development were evaluated. Maturation of swimming behavior and physical development were delayed about 3-4 days in experimental animals. Moreover, escape from water showed prolonged mean latencies until 24 postnatal days and the locomotor activity was increased during the 60 minutes following toluene exposure, compared with non-exposed littermate controls. The data of these experiments suggest that neonatal toluene exposure appears to be primarily interfering with the development of those cortical and brain stem structures underlying swimming and locomotor activities.

Effects of neonatal exposure to paint thinner on the development of swimming in rats.

Rats were exposed to paint thinner twice a day for a period of 10 minutes on Days 1 through 30 of postnatal life. The subsequent effects upon physical development, swimming ability and escape latency from water were evaluated. Maturation of swimming behavior and general physical development were delayed about 2-4 days in the experimental animals compared with non-exposed littermate controls. The results of these experiments suggest that exposure to this organic solvent during the early postnatal period interferes with the development of the cortico-subcortical neural structures underlying swimming and locomotion.

Toward a behavioral toxicology of paint thinner.

Few experiments have been carried out to evaluate the effects of toxic industrial substances such as the solvents on operant behavior. Laboratory rats trained in a mult FR DRL reinforcement schedule showed a differential impairment in performance when exposed to various doses of paint thinner in the experimental chamber, the FR performance being more sensitive to the solvent than DRL responding. Another study of rats working under a FI schedule suggested that the effects of paint thinner are rate-dependent, a finding which suggests a similarity of thinner with the amphetamines in regard to the behavioral effect. Two other experiments addressed to the behavioral effects of chronic exposure to the solvent showed a decrease in locomotor activity and an impaired acquisition of a complex temporal discrimination task in laboratory rats exposed to paint thinner during four, eight of sixteen weeks. These findings are suggestive of brain dysfunction associated with thinner inhalation but further experiments are needed for more definite conclusions.

Effects of solvents on schedule-controlled behavior.

Operant conditioning techniques have been shown to be sensitive to the acute effects of industrial solvents. In the first experiment, five rats trained in a multiple schedule with a fixed-ratio (FR) 10 component and a differential reinforcement of low rates (DRL) 20-sec component, with a time out 60-sec between reinforcement periods, were exposed to 0.25, 0.50, 1 and 2 ml of toluene in the experimental chamber. The effects were dose-dependent, with an increase in rate in the DRL component and a decrease in FR responding. A second experiment assessing the effects of chronic exposure to thinner in the acquisition of a timing behavior in rats showed an impairment in DRL learning after 4, 8 or 16 weeks of exposure to the solvent: however, rats having a resting period did not differ from control animals. Whereas this finding suggests a reversible impairment in the acquisition of a complex behavior, further research is needed to achieve more definitive conclusions.