PubMed · 5482809
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M Neuman. 1970-10-31. [Drug interactions. 2].. https://pubmed.ncbi.nlm.nih.gov/5482809/
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Hypothermia is a commonly reported thermoregulatory response in rodents acutely exposed to organophosphates (OP); however, our laboratory has recently found a delayed hyperthermic response following the initial hypothermia when exposed to the OP, chlorpyrifos. It is well known that rodents display tolerance to OP-induced hypothermia but little is known about tolerance to OP-induced hyperthermia. Twenty female rats of the Long-Evans strain were made tolerant to chlorpyrifos by administering 0 or 10 mg/g chlorpyrifos by gavage daily for four days. Core temperature (T[c]) and motor activity (MA) were monitored continuously by telemetry. Twenty-four hours after the fourth 10 mg/kg injection, the animals were administered a challenge dose of 25 mg/kg chlorpyrifos or corn oil while the telemetry data were monitored for the next 72 h. Non-tolerant rats displayed an initial hypothermic response with reduced MA followed by a delayed increase in T(c) 24 h after exposure. The tolerant animals displayed a blunted hypothermic response with virtually no change in MA, but a delayed increase in T(c) similar to that of non-tolerant animals. The hyperthermic response of the non-tolerant animals persisted for two days, whereas the tolerant animals recovered by the second day. The data indicate that tolerance to the hypothermic and hyperthermic effects of chlorpyrifos involve separate neurochemical pathways.
The intravenous administration of lipopolysaccharide (LPS) to rats results in liver lesions characterized by the infiltration of both platelets and neutrophils into the liver and by midzonal hepatocellular necrosis. The liver injury is dependent on neutrophils, platelets and the coagulation system, as removal or inhibition of any of these components inhibits the development of hepatocellular necrosis. Platelet activating factor (PAF) and the cysteinyl leukotrienes (LTs) are potent inflammatory lipids that are critical for the development of some LPS-mediated alterations. To test the hypothesis that PAF, alone or in combination with LTs, contributes to the development of liver injury during LPS exposure, we conducted studies with the PAF receptor antagonist, WEB 2086, and the 5-lipoxygenase inhibitor, Zileuton. Female, Sprague-Dawley rats were pretreated with WEB 2086 (10 mg/kg, i.p.) alone or with Zileuton (40 mg/kg, p.o.) 1 h before the administration of LPS (4 mg/kg, i.v.) or its saline vehicle. Treatment with WEB 2086, alone or in combination with Zileuton, did not inhibit LPS-mediated hepatic neutrophil infiltration or liver injury, as assessed by histologic evaluation and increases in plasma alanine aminotransferase activity. Pretreatment with these agents also had no effect on the activation of the coagulation system or on the thrombocytopenia induced by LPS. These results suggest that PAF, alone or in combination with 5-lipoxygenase products, is not a critical mediator of LPS-induced hepatocellular injury in this model.
There are conflicting results in the literature concerning the effect of gavage vehicle, corn oil (CO) versus aqueous suspension, on the toxicity of haloalkanes. The purpose of our study was to assess the influence of oral dosing vehicle on the acute hepatotoxicity of CCl4 and nephrotoxicity of CHCl3. Male Sprague-Dawley rats, fed ad libitum, were treated (po) with single doses of CCl4 or CHCl3 using corn oil (CO), or an aqueous preparation (5%) of Emulphor (EL620) or Tween-85 (Tw-85) as vehicle (10 ml/kg). Rats were killed 48 h after treatment. Blood was collected for plasma alanine aminotransferase (ALT) determination and renal cortical slices were prepared for p-aminohippuric acid (PAH) incorporation. The comparison, between gavage vehicles, of the slopes and ED50 of the dose-response curves, although not significantly different, indicated clear trends for enhanced potency with CO for CHCl3 nephrotoxicity but not for CCl4 hepatotoxicity. However, ALT values, a measure of the severity of effect for CCl4, also indicated that CO, when compared to EL620 and Tw-85, tended to enhance CCl4 hepatotoxicity at low toxicity incidence. Furthermore, CO clearly enhanced the severity of effect for CHCl3 nephrotoxicity, as measured by the slice-to-medium PAH ratios, at high dosage. The greater severity of the lesion produced by exposure to these chemicals, when administered in CO, is consistent with the trends observed for their potency (dose-response curves). Our results agree with an increased toxicity of haloalkanes by the gavage vehicle CO reported in the literature. Thus, CO should be considered a potential confounder in hepato- and nephrotoxicity assays.