Tsunemi Sakai

Effect of 1,1,1-Trichloroethane Inhalation on Heart Rate and Its Mechanism: A Role of Autonomic Nervous System

The response of heart rate to acute 1,1,1-trichloroethane (1,1,1-TCE) inhalation and its mechanism via the autonomic nervous system were studied in anesthetized dogs in acute inhalation experiments. Concentrations of 1,1,1-TCE in inspired air of 1.32 +/- 0.14% (mean +/- S.E.) increased heart rate, but 2.79 +/- 0.24% decreased heart rate. Opposite reactions of heart rate were observed when blood pressure decreased to 70-80 mm Hg following inhalation. Moreover, both tachycardia from relatively low concentrations and bradycardia from higher concentrations were blocked by pre-administration of adrenergic beta blocker, but were only slightly affected by vagotomy. It is suggested that both tachycardia and bradycardia following 1,1,1-TCE inhalation may be controlled by the sympathetic nervous system.

Neural Control of Blood Pressure following 1,1,1-Trichloroethane Inhalation: A Role of Sympathetic Nervous System

The effects of 1,1,1-trichloroethane (1,1,1-TCE) inhalation on arterial blood pressure and renal sympathetic nerve activity were investigated in anesthetized dogs. In acute inhalation experiments, the threshold concentration of 1,1,1-TCE required to produce a decrease in blood pressure was 0.4 to 0.5% in inspired air; moreover, a dose-response relationship between the decrease in blood pressure and 1,1,1-TCE concentration which exceeded the threshold level was observed. In addition, renal nerve activity increased and was associated with a slight decrease in blood pressure following inhalation of relatively low concentrations of 1,1,1-TCE. Following inhalation of relatively high concentrations of 1,1,1-TCE, however, renal nerve activity decreased and was accompanied by a marked decrease in blood pressure. Opposite reactions of renal nerve activity were observed when blood pressure decreased to 70-80 mm Hg following inhalation. It is suggested that systemic hypotension resulting from 1,1,1-TCE inhalation may be controlled by two different reactions of sympathetic nerve activity.

Acute effects of 1,1,1-trichloroethane, trichloroethylene, and toluene on the hematologic parameters in dogs

Mature cross-bred dogs were acutely exposed to 1,1,1-trichloroethane, trichloroethylene, and toluene. The changes in hematologic parameters, during and after exposure, are reported. A marked but temporary decrease in leukocytes was noted 30 min after the initation of exposure; no changes were observed in erythrocyte counts, hematocrit values, or thrombocytes counts with all three solvents. The decrease in the amount of neutrophils was particularly prominent. Based upon leukocyte differential counts, all types of leukocytes snowed a decrease. The decrease in leukocyte counts was the largest with exposure to trichloroethylene, followed by 1,1,1-trichloroethane, and toluene, respectively. A dose-response relationship was noted between exposure concentrations and decreased leukocyte counts,i.e., 1,1,1-trichloroethane and toluene from 200 to 700 ppm; trichloroethylene from 0 to 700 ppm.

Extrahepatic organs metabolism of inhaled trichloroethylene

An extrahepatic circulation system for dogs was developed using a portal vein to right femoral vein bypass procedure. This system maintained nearly normal biochemical and physiological parameters, i.e. arterial blood pressure, heart rate, electrocardiogram, leukocyte and erythrocyte count, hematocrit, alkaline phosphatase, blood urea nitrogen, ammonia and creatinine, for 2 h. Thus, the system appears to be a valid technique for investigating extrahepatic metabolism. Dogs were exposed for 1 h to 500, 700 and 1500 ppm of trichloroethylene. Free-trichloroethanol, trichloroacetic acid and conjugated-trichloroethanol appeared in the blood and urine after 30 min of exposure. The amounts of metabolite formed by dogs with hepatic bypass were less than by similarly exposed dogs without hepatic bypasses, specifically 50-80%, 10% and 10-20% for free-trichloroethanol, trichloroacetic acid and conjugated-trichloroethanol, respectively. In addition, trichloroethylene exposure produced a smaller decrease in leukocyte counts in the hepatic bypass dogs than in the non-bypass dogs. This observation may indicate that the liver itself played some role in the elimination or increment of leukocyte counts in the blood.

Peripheral Vasodilatation following 1,1,1-Trichloroethane Inhalation: Peripheral Vessels as a Site of Action

The effects of 1,1,1-trichloroethane (1,1,1-TCE) inhalation on total peripheral vascular resistance and the possibility of the peripheral vessels being a site of action for 1,1,1-TCE were investigated in anesthetized dogs. In acute inhalation experiments, a decrease in total peripheral vascular resistance was observed following inhalation of 1,1,1-TCE concentrations sufficient to induce systemic hypotension. The threshold concentration of 1,1,1-TCE required to produce a decrease in perfusion pressure of the isolated hindlimb was approximately 0.4-0.5% in inspired air. A dose-response relationship between the decrease in perfusion pressure and 1,1,1-TCE concentration, which exceeded the threshold level, was observed. It is suggested that the decrease in total peripheral vascular resistance is related to systemic hypotension following 1,1,1-TCE inhalation; further, this vasodilator effect may be induced in the peripheral vessels, which is one of the sites where 1,1,1-TCE acts.

Induction of cytochrome P-450, cytochrome b-5, nadph-cytochrome c reductase and change of cytochrome P-450 isozymes with long-term trichloroethylene treatment

Several reports have described the effects of trichloroethylene (TCE) on the microsomal mixed function oxidase system (MFOS). These studies suggest that repeated TCE administration induces MFOS, especially cytochrome P-450 and NADPH-cytochrome c reductase. However, it is uncertain what isozymes are induced by TCE treatment, and it is not clear how microsomal enzymes or cytochrome P-450 isozymes are altered when TCE is administered for a duration longer than 28 days. We investigated the changes of MFOS by long-term TCE treatment. Male Wistar rats were injected with TCE, 1.0 g/kg body weight once a day for 5 continuous days or 2.0 g/kg body weight twice a week for 15 days. The mean body weight of the rats treated with TCE for 15 weeks was slightly, but not significantly, less than that of the control rats. Relative liver weights (liver wt/body wt) of the TCE-treated group were however significantly larger (21%) than those of the control group. The weights of the other organs were not changed by long-term TCE treatment. Trichloroethylene treatments for 5 days and 15 weeks caused significant increases in microsomal protein, cytochrome P-450, cytochrome b-5 and NADPH-cytochrome c reductase. TCE treatments produced an increase in a polypeptide band at 52,000 molecular weight range observed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This increase in similar to, but less pronounced than that induced by phenobarbital (PB) treatment. There were no remarkable changes at 56,000 molecular weight range where a band appeared after the treatment with 3-methylcholanthrene (MC). It is likely that the induction of cytochrome P-450 by TCE is relatively similar to that by PB.

Biliary excretion of trichloroethylene and its metabolites in dogs

To examine the biliary excretion of trichloroethylene (TRI) and its metabolites, we carried out various experiments with TRI and its metabolites, i.e., chloral hydrate (CH), free-trichloroethanol (F-TCE) and trichloroacetic acid (TCA), using anesthetized dogs. The amount of biliary excretion was significantly increased with the administration of CH and F-TCE, whereas it remained at control levels with the administration of TRI and TCA. The substances excreted into bile were conducted in the form of conjugated-TCE (Conj-TCE) in over 90% of the CH, F-TCE and TRI administration groups. About 95% of these Conj-TCE were conjugated with glucuronic acid. The cumulative excretion ratios of substances and metabolites to dose were 20% for CH and F-TCE, and about 1% for TCA and TRI 2 h after administration.

Experimental study on the pulmonary absorption and excretion of toluene

SummaryThree exposure levels of toluene were inhaled by dogs for 1h. Toluene concentrations in expired air, arterial blood and venous blood were repeatedly measured. Absorptions of toluene within one hour of exposure were 25, 56 and 74 mg/kg at 700, 1500 and 2000 ppm respectively (absorption ratio = 27%). The cumulative excretion one hour after exposure was 63% of the absorped material at all three exposure levels. Multiple regression analyses were performed to interconnect the independent variables.

Influence of Heart Rate on Left Ventricular dp/dt Following 1,1,1-Trichloroethane Inhalation

The effect of acute 1,1,1-trichloroethane (1,1,1-TCE) inhalation on left ventricular contractility and influence on heart rate were investigated in anesthetized dogs. In the acute inhalation experiment, a decrease in the maximum left ventricular dp/dt (peak dp/dt) was observed following inhalation of higher 1,1,1-TCE contentrations. The threshold concentration of 1,1,1-TCE that decreased peak dp/dt was approximately 0.2% in inspired air. A dose-response relationship was observed between the decrease in peak dp/dt and 1,1,1-TCE concentration. Heart rate recorded simultaneously increased with relatively low concentrations and decreased with higher concentrations. Increase or decrease in peak dp/dt was observed to be dependent on changes in heart rate induced by right atrial pacing. Thus, the degree of the decrease in peak dp/dt during pacing experiments was compared with those of nonpacing experiments. At low concentrations, peak dp/dt during pacing decreased more than in nonpacing experiments. With higher concentrations, the decreases in peak dp/dt during pacing was slightly less than in the nonpacing experiments. Heart rate may be important in regulating peak dp/dt for relatively low 1,1,1-TCE concentrations. However, the effect of heart rate on peak dp/dt is slight at higher concentrations.

Metabolism of chloral hydrate in the anoxic perfused liver

The metabolism of chloral hydrate (CH) under anoxic conditions was investigated in the non-recirculating, hemoglobin-free liver perfusion system. CH uptake in the anoxic liver decreased to about 80% of that in the oxygen-supplied liver. The reduction of CH to trichloroethanol (TCE) increased and the oxidation of CH to trichloroacetic acid (TCA) decreased. The TCE/TCA ratio increased; however, the total trichloro compounds, that is TCE and TCA, were not significantly altered by anoxia. Though approximate 14% of the CH infused into the oxygen-supplied liver was changed to substances other than TCE or TCA, the unknown part was a very small portion in the anoxic liver. The decrease in CH uptake, by the anoxic liver, is thought to be equivalent to the decrease of the unknown metabolites. The TCE/TCA ratio under anoxia was also altered by pyruvate or lactate infusion.