Lethality In Rats Research Articles

Some Studies on the Rodenticidal Action of Indomethacin

ABSTRACTThe oral LD50 of indomethacin for a seven-day observation was found to be 12.58μpM1.15 mg/kg. At LD10 of 6.61 mg/kg, a dose to weight ratio of 28 was obtained for a 240g rat, while at a maximum single dose of 3 mg/kg in man it is only 0.04. Neither diazepam nor phenobarbital influenced death at the doses of both drugs used. However, cholestyramine 2g/kg/day was found to protect by 50% from the LD100 of indomethacin. Gross pathological studies showed dose-dependent ulceration and perforation (P < 0.001, 12 vs 24 mg/kg) and such lesions occurred in starved rats, were low in bile duct-ligated compared to sham-operated rats (P < 0.001) and were also low in cholestyramine-treated rats. Indomethacin-induced lethality in rats was found to be dose-dependent.

Role of Kinetics in Acute Lethality of Nonreactive Volatile Organic Compounds (VOCs)

The role of kinetics in the acute inhalation toxicity of nonreactive, volatile organic compounds (VOCs), including lipophilic and hydrophilic compounds, was analyzed with a physiologically based pharmacokinetic (PB-PK) model for the rat. For 15 VOCs, a total of 23 LC50 values were retrieved from the literature. It was observed that the external exposure parameter (LC50·exposure length; in ppm · h), varied approximately 60-fold Concentrations of compounds in the lipoid brain fraction were simulated using a kinetic model. This lead to a more than 10-fold reduction in the toxic range of the 15 VOCs. The average value for this simulated dose surrogate was 70±31 mM for all VOCs. These observations support the presumption that nonspecific, acute narcotic lethality is directly related to the extent of VOC distribution into lipoid brain constituents. The present results can be used for estimation of the acute lethality of nonreactive VOCs on the basis of kinetic simulations. In addition, the presently calculated dose surrogate for VOC lethality in rats is found to be very similar to the reported internal lethal concentrations of so-called “baseline toxicity compounds” in fish. This indicates a common mechanism of acute VOC toxicity among mammalian and aquatic species.

Antagonism to noradrenaline-induced lethality in rats is related to affinity for the α 1a-adrenoceptor subtype

The potency of several α 1-adrenoceptor antagonists in preventing the noradrenaline-induced lethality in conscious rats, their binding affinity for the native α 1A- and α 1B-adrenoceptors, the recombinant animal α 1a-, α 1b- and α 1d-adrenoceptor subtypes, as well as their functional affinity for the α 1L-adrenoceptor subtype were evaluated The potency of the tested compounds as antagonists of noradrenaline-induced lethality was correlated with the affinity for the α 1A- (and α 1a-) adrenoceptor subtype, but not with the affinity for the other subtypes. On the contrary, the hypotensive effects of the compounds, assessed in anesthetized rats, were not clearly related with the affinity for any of the α 1-subtypes. These results suggest that the α 1A-subtype plays a determining role in preventing lethality induced by noradrenaline in the rats, and that this activity is unrelated to the hypotensive effect of the compounds, which cannot be clearly correlated with affinity for a particular α 1-adrenoceptor subtype.

The attenuating effect of carteolol hydrochloride, a beta-adrenoceptor antagonist, on neuroleptic-induced catalepsy in rats.

It is known that beta-adrenoceptor antagonists are effective in the treatment of akathisia, one of the extrapyramidal side effects that occur during neuroleptic treatment. Neuroleptic-induced catalepsy, a model of neuroleptic-induced extrapyramidal side effects, was considered suitable as a model for predicting neuroleptic-induced akathisia in humans, although neuroleptic-induced catalepsy was not considered a specific test for neuroleptic-induced akathisia. Therefore, the effects of carteolol, a beta-adrenoceptor antagonist, on haloperidol-induced catalepsy in rats were behaviorally studied and compared with those of propranolol and biperiden, a muscarinic receptor antagonist. Carteolol, as well as propranolol and biperiden, inhibited the haloperidol-induced catalepsy. The inhibitory effect of carteolol was almost comparable to that of propranolol, but was weaker than that of biperiden. Carteolol did not evoke postsynaptic dopamine receptor-stimulating behavioral signs such as stereotypy and hyperlocomotion in rats. Carteolol did not antagonize the inhibitory effects of haloperidol on apomorphine-induced stereotypy and locomotor activity in rats. In addition, carteolol did not evoke 5-HT1A receptor-stimulating behavioral signs such as flat body posture and forepaw treading and did not inhibit 5-hydroxytryptophan-induced head twitch in rats. Finally, carteolol did not inhibit physostigmine-induced lethality in rats. These results strongly suggest that carteolol improves haloperidol-induced catalepsy via its beta-adrenoceptor antagonistic activity and is expected to be effective in the treatment of akathisia without attenuating neuroleptic-induced antipsychotic effects due to its postsynaptic dopamine receptor antagonistic activity.

Progesterone Pretreatment Enhances Cellular Sensitivity to Cadmium Despite a Marked Activation of the Metallothionein Gene

Previously, we found thatin vivopretreatment with progesterone markedly increased cadmium lethality in rats, apparently by enhancing cadmium-induced hepatonecrosis. Therefore, the present study was designed to investigate this phenomenon at the molecular level in anin vitrosystem. TRL-1215 rat liver cells were exposed to various concentrations of progesterone (0, 1, 10, and 100 μm) for 24 hr and subsequently exposed to cadmium (0, 1, 5, 10, and 50 μm; as CdCl2) for an additional 24 hr. Although the levels of progesterone used were essentially nontoxic, progesterone pretreatment resulted in a concentration-dependent increase in sensitivity to cadmium as assessed by loss of mitochondrial enzyme activity (tetrazolium-based dye assay) and loss of cytosolic enzyme activity (glutamic oxaloacetic transaminase). The effects of progesterone treatment on intracellular levels of metallothionein (MT), an inducible metal-binding protein generally associated with cadmium tolerance, were also measured. Progesterone (100 μm) alone increased MT levels 2.4-fold, while cadmium (10 μm) alone resulted in a 7-fold increase over control. Progesterone pretreatment followed by cadmium exposure caused a marked, 16-fold induction in MT synthesis, a level of activity that has been associated with acquired tolerance to cadmium. In addition, progesterone pretreatment clearly induced transcription of theMTgene as evidenced by enhanced cadmium-induced accumulation of cellularMTmRNA. Progesterone pretreatment had no effect on the level of glutathione, a cellular thiol thought to be important in detoxication of cadmium prior toMTgene activation and MT protein accumulation, or on cellular accumulation of cadmium during the initial 3 hr of exposure to the metal. The proportion of total cellular cadmium bound to MT in cells pretreated with progesterone was greater than that in the cells treated with cadmium alone, indicating an enhanced sequestration of the metal by MT after pretreatment. These results indicate that progesterone, at nontoxic levels, markedly exacerbates cadmium toxicity at the cellular level in liver cells. This is in accord with the observed progesterone-induced enhancement of the hepatotoxic effects of cadmiumin vivo.The observed facilitation of cytotoxicity is not based in altered toxicokinetics of cadmium and occurs despite a pronounced activation of theMTgene resulting in an enhanced sequestration of cadmium by MT. The mechanism by which progesterone enhances cadmium toxicity deserves further study.

Stimulatory effects of amphetamine on the development of Walker-256 carcinoma lung metastases in rats

Experiments were performed in order to evaluate the effects of amphetamine (0.4 mg/kg/day) on the development of lung metastases in rats injected i.v. with 10(4) Walker 256 (W-256) carcinosarcoma cells, The number of metastatic nodules on the surface of the lungs, as well as the percentage-area of metastases in the frontal section through pulmonary hilus were increased in rats injected with amphetamine in comparison with those injected with placebo. Survival periods were also assessed and amphetamine was found to increase the lethality of rats.

Inhibition of nitric oxide formation does not affect endotoxin lethality in rats

Endotoxin causes release of nitric oxide (NO) from different types of cells. A causative role has been suggested for NO in endotoxin-induced hypotension. In order to test the hypothesis that NO may be involved in the high mortality rate following endotoxin challenge, the competitive NO synthase inhibitors Nw nitro-L-arginine methyl ester (L-NAME) and NG methyl L-arginine (L-NMA), or the NOS substrate L-arginine, were administered to rats in the presence and absence of endotoxin. Death rates were examined after drug injection. Urine nitrite concentration and mean arterial blood pressure were examined for 24 h following endotoxin injection. It was found that endotoxin injection increased mortality rates. The mortality rate of rats injected with NOS inhibitors or an NOS substrate concomitantly with endotoxin was similar to that observed in rats treated with endotoxin alone. Endotoxin elicited a decrease in mean arterial blood pressure, whereas treatment with NOS inhibitors prevented this decrease. Treatment with L-arginine markedly exacerbated the endotoxin effects on blood pressure and resulted in hypotension 6 h after the endotoxin injection. The urine nitrite concentration increased after injection of endotoxin or L-arginine alone, or after injection of endotoxin concomitantly with L-arginine. The urine nitrite concentration after injection of endotoxin together with L-NAME was smaller than after injection of endotoxin alone. The effects of L-NAME on the urine nitrite concentration and on the blood pressure were reversed with L-arginine. These results do not support the hypothesis that NO mediates the high mortality rates following administration of endotoxin.

Tissue-specific effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in rats.

Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in TCDD-induced lethality in rats. In this study the toxicological significance of reduced gluconeogenesis was further analyzed by studying dose responses and time courses of effects of TCDD on the activity of PEPCK in liver and two other tissues with high specific activity, viz. kidney and brown adipose tissue (BAT). Liver PEPCK activity was significantly decreased from 1 to 32 days after dosing (60 micrograms/kg). A clear dose response was present 8 days after dosing, beginning at a dose of 1 microgram/kg. In contrast to liver, TCDD treatment increased PEPCK activity in kidney and BAT, but only at the two highest doses administered (30 and 60 micrograms/kg). PEPCK activity in kidney began to increase slowly, reaching a maximum on Day 16 and declining thereafter, whereas in BAT the activity was significantly increased already on Day 1 and maximally on Day 4 after dosing. A likely explanation for these tissue-specific effects is in part related to toxicokinetics and in part to homeostatic responses of the organism to the toxic insult of TCDD. High concentrations of TCDD in liver and BAT combined with early responses (1 day after dosing) suggest a direct effect in these organs/tissues, whereas very low concentration and delayed response in kidney indicate an indirect effect. This interesting enzymatic constellation suggests that the reduction in gluconeogenesis due to decreased PEPCK activity in liver is partially counterbalanced by increased gluconeogenesis in kidney as a result of induction of PEPCK in this organ. Induction of PEPCK in BAT, where it is a glyceroneogenic enzyme, provides for the first time a plausible explanation for the initial accumulation of fat in BAT of TCDD-treated rats.

Biochemical effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and related compounds on the central nervous system

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) and related compounds are an important class of environmental contaminants which induce several types of biochemical alterations. Their effects have been most thoroughly characterized in the liver, especially regarding the Ah receptor-mediated induction of xenobiotic metabolizing enzymes. The behavioral signs exhibited by animals exposed to TCDD (progressive anorexia and body weight loss) suggest a role for the central nervous system (CNS) in TCDD toxicity. At lethal doses, TCDD affects the metabolism of serotonin, a neurotransmitter able to modulate food intake in the brain. This effect is associated with an elevated concentration of free tryptophan in the plasma. There does not appear to be any major changes in catecholaminergic neurotransmitter systems in TCDD-treated rats. Cytochrome P-450 related enzyme activities are induced by TCDD in the brain. As is the case in the liver, this induction does not correlate with susceptibility to TCDD lethality in rats. The involvement of the CNS in TCDD toxicity is still obscure. Elucidation of this role as well as the mechanism of TCDD-induced wasting may well advance our understanding of the regulation of food intake and body weight

Reversal of toxicity using avidin-based hemoperfusion: a model system in rats using biotinylated melittin.

The high-affinity interaction between avidin and biotin (Kd = 10(-15)M) can be exploited to develop specific protocols for retrieval of biotinylated drugs and toxicants from biological fluids. Melittin, the main toxic component of bee venom, was biotinylated and used as a model toxicant to determine whether avidin-based extracorporeal hemoperfusion could remove biotinylated melittin and thus alter the severity of the toxic response in rats. Melittin was biotinylated using N-hydroxysuccinimide-long-chain biotin. Biotinylated melittin produced 100% lethality in rats by 120 min following four sequential intravenous injections of 1.7 mg/kg biotinylated melittin (0, 5, 20, and 35 min). An avidin hemoperfusion column was constructed (10 mg avidin/1 ml gel) and connected via the femoral vasculature to rats intoxicated with biotinylated melittin. Controls rats were hemoperfused using avidin columns blocked with d-biotin. None of the 6 rats hemoperfused using the biotin-blocked avidin column control survived, whereas 5 of 9 of the experimental rats survived to 120 min. The difference between the two survival rates was statistically significant (p < 0.0048). Thus, avidin-based hemoperfusion improved survival following biotinylated melittin toxicity and strengthens the concept that avidin-based hemoperfusion can reverse the toxicity of biotinylated toxicants.

Role of superoxide and nitric oxide in platelet activating factor-induced acute lung injury, hypotension and lethality in rats

Role of superoxide and nitric oxide in platelet activating factor-induced acute lung injury, hypotension and lethality in rats

Synthesis and evaluation of n-substituted 1-(5-fluoro-2-pyrimidinyl)piperazine derivatives as potential anti-ischemic agents

A number of N-substituted 1-(5-fluoro-2-pyrimidinyl)piperazine derivatives were prepared and evaluated for binding to sigma and serotonin 5-HT 1A and 5-HT 2 receptor subtypes as well as for their protection against nitrogen anoxia-induced lethality in rats. Although various compounds exhibited good binding affinity and/or anti-anoxic effects, there was no obvious correlation between their receptor binding and in vivo effects.

Influence of glucocorticoids and activated charcoal on the lethality of rats after acute poisoning with T-2 toxin, diacetoxyscirpenol, or roridin A.

Lethal doses of the trichothecene mycotoxins T-2 toxin (1.5 mg/kg), diacetoxyscirpenol (DAS; 2.3 mg/kg) or roridin A (1.3 mg/kg) were intravenously administered to rats. When rats were treated with either activated charcoal (Superchar liquid, Norit A; 1 g/kg, po) or dexamethasone (8 mg/kg, iv) 30 min after poisoning with one of the trichothecenes, lethality was only marginally reduced. However, when the combination of activated charcoal (Superchar liquid or Norit A) and dexamethasone was administered, the survival rate of animals after 30 days was significantly enhanced by up to 50%. Comparison between 2 preparations of activated charcoal, Norit AR with a surface area of 1,000 m2/g and Superchar liquidR with a surface area of 3,000 m2/g, each in combination with dexamethasone, revealed no difference in their therapeutic efficacy. Prednisolone (60 mg/kg) was as effective as dexamethasone (8 mg/kg), each administered with activated charcoal, in preventing death in acute T-2 toxicosis.

Mechanism of lithium lethality in rats

Lithium inhibits inositol monophosphatase and thereby lowers inositol levels and raises inositol-1-phosphate levels. Many of lithium's biological effects are reversible by inositol replacement. However, lethality caused by high dose lithium was not found to be reversible by intracerebroventricular inositol in various dosages or schedules. Moreover, inositol-1-phosphate, given alone or in the presence of sublethal Li doses to inhibit its degradation, did not show toxic or lethal effects. Therefore inositol depletion or inositol-1-phosphate accumulation are probably not related to lithium lethality.

INHIBITORY EFFECTS OF ALPRAZOLAM ON THE ENHANCEMENT OF LUNG METASTASES INDUCED BY OPERATIVE STRESS IN RATS

Experiments were performed in order to evaluate the effects of alprazolam (I mg/kg s.c.), a central benzodiazepine agonist anxiolytic, on the development of lung metastases in rats subjected to laparotomy and injected (i.v.) with 10(4) Walker 256 (W-256) carcinosarcoma cells. The number of metastatic nodules on the surface of the lungs, as well as the percentage-area of metastases in the frontal section through pulmonary hilus were increased in rats subjected to sham-surgery or laparotomy. Treatment with alprazolam partially reversed those adverse effects of surgery, but the difference was clearer when it was administered before surgery was performed. Survival periods were also assessed and alprazolam was found to decrease the lethality of rats exposed to surgery. Pretreatment with Ro 15-1788, a central benzodiazepine antagonist, suppressed the inhibitory effects of alprazolam on tumor growth.

Study on zwitter-ionization of drugs. II. Synthesis and pharmacological activity of some N-[3-(5H-dibenzo[a, d]cyclohepten-5-ylidene) propyl]-N-methylamino- and N-[3-(6H-dibenz[b, e]oxepin-11-ylidene) propyl]-N-methylamino-alkanoic acid derivatives and related compounds.

A series of N-[3-(5H-dibenzo[a, d]cyclohepten-5-ylidene)propyl]-N-methylamino- (6a) and N-[3-(6H-dibenz-[b, e]oxepin-11-ylidene)propyl]-N-methylamino-alkanoic acid derivatives (6b) and related compounds (6c-f) were synthesized and examined for pharmacological activities in vitro, i.e., inhibitory effect on monoamine [noradrenaline (NA) and 5-hydroxytryptamine (5-HT)] uptake, inhibitory effect on 5-HT-, histamine-, acetylcholine- and NA-induced contraction, and binding affinity for alpha 2-adrenoceptor and dopamine D2-receptor. In vitro tests indicated that zwitter-ionization was capable of maintaining H1-antihistaminic activity while greatly reducing other pharmacological activities. Further, 6a-f showed much stronger inhibitory effects on compound 48/80-induced lethality in rats than did the corresponding N,N-dimethylamines (2a-f). 3-[N-[3-(6H-Dibenz[b, e]oxepin-11-ylidene)propyl]-N-methylamino]- propionic acid (6b-2), selected as a candidate antiallergic agent of a new type, equally potent in rats and guinea-pigs, exhibited strong inhibitory effects on 48 h homologous passive cutaneous anaphylaxis (PCA) in rats (ED50 = 0.019 mg/kg, p.o.) and on histamine-induced bronchoconstriction in anesthetized guinea-pigs (ED50 = 0.0067 mg/kg, p.o.).

Protective effect of antithrombin III in acute experimental pancreatitis in rats

In the present study we investigated the therapeutic action of antithrombin III (AT III) in taurocholate-induced experimental pancreatitis with high lethality in rats. High-dose AT III treatment greatly improved the survival rate not only when given as pretreatment but also when given 2 hr after induction. No favorable effect on survival rate was observed on administration after 5 hr. Both intravascular and intraperitoneal AT III administration locally restored decreased AT III levels in the peritoneal cavity and increased plasma AT III to supranormal levels. The primary pancreatic insult seemed to be unaffected by the treatment, because neither the rise in plasma lipase nor the development of ascites or the extension of the pancreatic necrosis were diminished. Because heparin pretreatment of the rats was also effective, the mechanism of the beneficial action was probably mediated by inhibition of the proteases of the coagulation cascade, thereby preventing intravascular coagulation in the pancreas and distant organs and subsequent systemic complications. The high efficacy of AT III treatment in this experimental model may stimulate clinical studies evaluating the efficacy of AT III treatment in an early stage of acute pancreatitis.

Effect of 3-amino-1,2,4-triazole on ethanol-induced narcosis, lethality and hypothermia in rats

It has been proposed that ethanol can be oxidized in brain via the peroxidatic activity of catalase and that centrally formed acetaldehyde may mediate several of the psychopharmacological actions of ethanol. The present study was designed to investigate the role of brain catalase in the mediation of ethanol-induced narcosis, hypothermia and lethality in rats. Rats were pretreated with the catalase inhibitor 3-amino-1,2,4-triazole (AT) or saline. Five hours later, animals in each pretreatment group received IP injections of ethanol (3 or 4 g/kg). Ethanol-induced narcosis was significantly attenuated in AT-pretreated rats compared to the saline control group. As well, AT pretreatments reduced significantly the lethal effect of these ethanol doses. However, AT-pretreated ethanol-injected animals significantly reduce their body temperature as compared to the saline-ethanol animals. Blood ethanol determinations revealed that AT did interfere with ethanol metabolism. AT inhibits significantly brain catalase activity at all doses used in this study. The results indicate a role for brain catalase in ethanol effects. Furthermore, they suggest that catalase may be involved in the oxidation of ethanol in brain and that centrally formed acetaldehyde may play a role in ethanol-induced narcosis and lethality, but not hypothermia.

Cocaine toxicity: Genetic differences in cocaine-induced lethality in rats

Cocaine produces stimulation, depression, convulsions and death, and binds at several receptor sites. Thus cocaine may produce toxicity through similar or distinct pathways from those associated with stimulation. Genetic differences in stimulant response to cocaine have recently been reported for four inbred rat strains, ACI, F344, LEW and NBR. In the present study, significant genetic differences were found in cocaine-induced lethality, with a two-fold difference in LD 50 values seen between the most sensitive (NBR) and least sensitive (LEW) strains. Sensitivity to lethality was not correlated with sensitivity to stimulation, but was highly correlated with baseline activity. This lack of strong association between stimulant and lethal effects of cocaine may be important in clinical manifestations of the cocaine sudden death syndrome.

Potentiation of halomethane hepatotoxicity by chlordecone: A hypothesis for the mechanism

A major toxicological issue today is the possibility of unusual toxicity due to interaction of toxic chemicals upon environmental or occupational exposures to two or more chemicals, at ordinarily harmless levels individually. While some laboratory models exist for such interactions for the simplest case of only two chemicals, progress in this area has suffered for want of a model where the two interactants are individually nontoxic. One such model is available, where prior exposure to nontoxic levels of the pesticide Kepone R (chlordecone) results in a 67 — fold amplication of CC1 4 lethality in rats. Extensive hepatotoxicity observed in this interaction is characterized by histopathological alterations, perturbation of related biochemical parameters and is followed by complete hepatic failure. This propensity for chlordecone to potentiate hepatotoxicity of halomethanes such as CC1 4, CHC1 3, and BrCC1 3 has been a subject of intense study to unravel the underlying mechanism. Mechanisms such as induction of microsomal cytochrome P - 450 by chlordecone and greater lipid peroxidation are inadequate to explain the remarkably powerful potentiation of halomethane toxicity. Compelling experimental evidence supports the hypothesis that hepatocellular division during early time points after the administration of CC1 4 is an important determinant of the progression (or repair of it) of the liver injury and consequent destruction (or restoration) of the hepatolobular architecture and function. This paper advances a hypothesis for the mechanism of hepatotoxic and lethal effect of CC1 4 as being primarily related to the accelerated progression of liver injury due to suppressed hepatocellular regeneration and hepatolobular restoration. This is in contrast to the widely accepted putative mechannism, one which invokes only bioactivation followed by runaway lipid peroxidation as the events determining the course of the progressive phase of liver injury. The concept being advanced in this paper accepts bioactivation (and perhaps lipid peroxidation) as the primary initiating events of cell injury, but maintains that they are not the determinants of the progressive phase of liver injury. The biological issue of whether the cells are incapacitated from regenerating is the determinant of the progression of liver injury, and therefore, the ultimate outcome of hepatotoxicity and lethality.