Possible carcinogenic effects of X-rays in a transgenerational study with CBA mice.
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A lifetime experiment using 4279 CBA/J mice was carried out to investigate whether the pre-conceptual exposure of sperm cells to X-ray radiation or urethane would result in an increased cancer risk in the untreated progeny, and/or increased susceptibility to cancer following exposure to a promoting agent. The study consisted of four main groups, namely a control group (saline), a urethane group (1 mg/g body wt) and two X-ray radiation groups (1 Gy, 2 Gy). At 1, 3 and 9 weeks after treatment, the males of these four parental groups were mated with untreated virgin females. The offspring of each parental group was divided into two subgroups: one received s.c. urethane (0.1 mg/g body wt once) as a promoter, the other saline, at the age of 6 weeks. All animals were evaluated for the occurrence of tumours. K-ras oncogene and p53 tumour suppressor gene mutations were investigated in frozen lung tumour samples. The female offspring of male parents exposed to X-rays 1 week before their mating showed a trend towards a higher tumour incidence of the haematopoietic system than the F1 controls. In addition, a higher percentage of bronchioloalveolar adenocarcinomas in male offspring born to irradiated paternals mated 1 week after X-ray treatment points to a plausible increased sensitivity of post-meiotic germ cell stages towards transgenerational carcinogenic effects. On the other hand, no increased tumour incidence and malignancy were observed in the offspring born to irradiated paternals mated 3 and 9 weeks after X-ray treatment. Paternal urethane treatment 1, 3 and 9 weeks prior to conception did not result in significantly altered incidence or malignancy of tumours of the lung, liver and haematopoietic tissue in the offspring. K-ras mutations increased during tumour progression from bronchioloalveolar hyperplasia to adenoma. Codon 61 K-ras mutations were more frequent in lung tumours of urethane-promoted progeny from irradiated parents than from control parents. P53 mutations were absent from these lung alterations. (+info)
Long-term potentiation in the dentate gyrus is not linked to increased extracellular glutamate concentration.
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Long-term potentiation (LTP) of excitatory transmission is a likely candidate for the encoding and storage of information in the mammalian brain. There is a general agreement that LTP involves an increase in synaptic strength, but the mechanisms underlying this persistent change are unclear and controversial. Synaptic efficacy may be enhanced because more transmitter glutamate is released or because postsynaptic responsiveness increases or both. The purpose of this study was to examine whether increased extracellular glutamate concentration was associated with the robust and well-characterized LTP that can be induced in the rat dentate gyrus. To favor the detection of any putative change in extracellular glutamate associated with LTP, our experimental strategy included the following features. 1) Two separate series of experiments were carried out with animals under pentobarbital or urethan anesthesia; 2) changes in extracellular concentration of glutamate were monitored continuously by microdialysis coupled to enzyme amperometry; and 3) dialysate glutamate levels and changes in the slope of excitatory postsynaptic potential evoked by activation of the perforant path were recorded precisely at the same site. Tetanic stimulation of the perforant path increased persistently test-evoked responses in the dentate gyrus (by 19 and 14% in barbiturate and urethan group, respectively), but there was no glutamate change either during or after LTP induction and no indication of increased glutamate efflux when low-frequency stimulation was applied. The results do not rule out a possible contribution of enhanced glutamate exocytosis to LTP induction and/or maintenance because such a presynaptic change may not be detectable extracellularly. However, our findings and other data supporting the notion that neurotransmitter glutamate may hardly leak out of the synaptic cleft conflict with the hypothesis that LTP could also involve a broad synaptic spillover of glutamate. (+info)
Acid-base disturbance during hemorrhage in rats: significant role of strong inorganic ions.
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The present study tests the hypothesis that changes in the strong inorganic ion concentrations contribute significantly to the acid-base disturbance that develops during hemorrhage in the arterial plasma of rats in addition to lactate concentration ([Lac-]) increase. The physicochemical origins for this acid-base disorder were studied during acute, graded hemorrhage (10, 20, and 30% loss of blood volume) in three groups of rats: conscious, anesthetized with ketamine, and anesthetized with urethan. The results support the hypothesis examined: strong-ion difference (SID) decreased in the arterial plasma of all groups studied because of an early imbalance in the main strong inorganic ions during initial hemorrhagic phase. Moreover, changes in plasma [Lac-] contributed to SID decrease in a later hemorrhagic phase (after 10% hemorrhage in urethan-anesthetized, after 20% hemorrhage in ketamine-anesthetized, and after 30% hemorrhage in conscious group). Inorganic ion changes were due to both dilution of the vascular compartment and ion exchange with extravascular space and red blood cells, as compensation for blood volume depletion and hypocapnia. Nevertheless, anesthetized rats were less able than conscious rats to preserve normal arterial pH during hemorrhage, mainly because of an impaired peripheral tissue condition and incomplete ventilatory compensation. (+info)
Modulation of receptive field properties of thalamic somatosensory neurons by the depth of anesthesia.
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Modulation of receptive field properties of thalamic somatosensory neurons by the depth of anesthesia. The dominant frequency of electrocorticographic (ECoG) recordings was used to determine the depth of halothane or urethan anesthesia while recording extracellular single-unit responses from thalamic ventral posterior medial (VPM) neurons. A piezoelectric stimulator was used to deflect individual whiskers to assess the peak onset latency, magnitude, probability of response, and receptive field (RF) size. There was a predictable increase in the dominant ECoG frequency from deep stage IV to light stage III-1 anesthetic levels. There was no detectable frequency at stage IV, a 1- to 2-Hz dominant frequency at stage III-4, 3-4 Hz at stage III-3, 5-7 Hz at stage III-2, and a dual 6- and 10- to 13-Hz pattern at stage III-1. Reflexes and other physical signs showed a correlation with depth of anesthesia but exhibited too much overlap between stages to be used as a criterion for any single stage. RF size and peak onset latency of VPM neurons to whisker stimulations increased between stage III-4 and III-1. A dramatic increase in RF size and response latency occurred at the transition from stage III-3 (RF size approximately 2 whiskers, latency approximately 7 ms) to stage III-2 (RF size approximately 6 whiskers, latency approximately 11 ms). Response probability and magnitude decreased from stage III-4 to stage III-3 and III-2. No responses were ever evoked in VPM cells by vibrissa movement at stage IV. These changes in VPM responses as a function of anesthetic depth were seen only when the nucleus principalis (PrV) and nucleus interpolaris (SpVi) trigeminothalamic pathways were both intact. Eliminating SpVi inputs to VPM, either by cutting the primary trigeminal afferent fibers to SpVi or cutting axons projecting from SpVi to VPM, immediately reduced the RF size to fewer than three whiskers. In addition, the predictable changes in VPM response probability, response magnitude, and peak onset latency at different anesthetic depths were all absent after SpVi pathway interruption. We conclude that 1) the PrV input mediates the near "one-to-one" correspondence between a neuronal response in VPM and a single mystacial whisker, 2) in contrast, the SpVi input to VPM is primarily responsible for the RF properties of VPM neurons at light levels of anesthesia and presumably in the awake animal, and 3) alterations in VPM responses produced by changing the depth of anesthesia are due to its selective influence on the properties mediated by SpVi inputs at the level of the thalamus. (+info)
Cognition-enhancing drugs increase stimulated hippocampal theta rhythm amplitude in the urethane-anesthetized rat.
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Synchronous hippocampal electroencephalographic activity occurring in a frequency range of 3 to12 Hz (i.e., hippocampal theta rhythm) has been associated with mnemonic processes in vivo. However, this link is tenuous and theta rhythm may be secondary to processes that underlie mnemonic function. If theta rhythm is associated with mnemonic or cognitive function, cognition-enhancing drugs should enhance theta rhythm regardless of their primary biological target. In the current study, we evaluated several drugs that were shown to have cognition-enhancing properties in preclinical behavioral models and that vary with respect to their primary biological target: 1) the nootropic piracetam (250 and 500 mg/kg); 2) the small-conductance calcium-activated potassium-channel blocker apamin (0.1 and 0.4 mg/kg); and 3) the acetylcholinesterase inhibitor donepezil (0.1-10.0 mg/kg). All of the cognition-enhancing drugs produced dose-dependent increases in hippocampal theta rhythm amplitude elicited by stimulation of the brainstem reticular formation at doses that did not affect peak theta frequency in the urethane-anesthetized rat. These increases were reversed by the muscarinic receptor antagonist scopolamine, suggesting a common final cholinergic action of these compounds. The use-dependent N-methyl-D-aspartate antagonist dizocilipine maleate and scopolamine reduced theta amplitude (both) and frequency (dizocilipine maleate only). These data demonstrate that hippocampal theta rhythm is sensitive to cognition-modulating compounds, suggesting that theta rhythm may be closely associated with cognitive function. (+info)
Pulmonary oedema produced by scorpion venom augments a phenyldiguanide-induced reflex response in anaesthetized rats.
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1. The involvement of pulmonary oedema produced by scorpion venom in augmenting a phenyldiguanide (PDG)-induced reflex response was evaluated in urethane-anaesthetized rats. 2. PDG-induced bradycardiac, hypotensive and apnoeic responses, expressed as time-response area, exhibited similarities before or after venom treatment. Hence, the time-response area of bradycardia was taken as a reflex parameter. Pulmonary oedema was determined by physical evaporation and histological methods. 3. Exposure to Indian red scorpion (Buthus tamulus, BT; i.v.) venom for 30 min increased the pulmonary water content (P < 0.05; Student's t test) and augmented the PDG-induced bradycardiac reflex response by more than 2 times (P < 0.001). The increase of pulmonary water content was maximal with 100 microg kg-1 of venom and the augmentation was maximal with 10 microg kg-1. In a separate series of experiments, the venom (100 microg kg-1)-induced pulmonary oedema was confirmed by histological and physical methods. In this group also, the venom augmented the reflex to the same magnitude. 4. Pulmonary oedema (physical and histological) and augmentation of the bradycardiac reflex response after BT venom (100 microg kg-1; i.v.) were absent in animals pretreated with aprotinin, a kallikrein-kinin inhibitor (6000 KIU; i. v.). 5. Ondansetron (10 microg kg-1; i.v.), a 5-HT3 receptor antagonist, failed to block the venom-induced pulmonary oedema (physical and histological) but blocked the venom-induced augmentation of the reflex. 6. The results of this study indicate that the venom-induced augmentation of the PDG reflex is associated with pulmonary oedema involving kinins utilizing 5-HT3 receptors. (+info)
The p53 heterozygous knockout mouse as a model for chemical carcinogenesis in vascular tissue.
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Heterozygous p53 knockout mice were investigated as a potential model for vascular tumor carcinogenesis. Groups of 20 male mice were exposed by gavage for 6 months to the vascular carcinogen urethane at 1, 10, or 100 mg/kg body weight/day. Wild-type and heterozygous p53 knockout control groups were exposed by gavage to the vehicle alone. Another group of 20 male mice received d-limonene by gavage (d-limonene is noncarcinogenic in mice). The high dose of urethane caused early mortality in the majority of mice associated with histopathologic evidence of toxicity and tumors, including a high incidence of benign and malignant vascular tumors, in all animals. At the intermediate dose, toxicity was less marked and 3 of 20 mice had tumors; mice that received the low dose did not have signs of toxicity or neoplasia. The two control groups had no tumors and the d-limonene group had one tumor of the prostate, which was considered spontaneous. We conclude that the p53 knockout mouse is a useful tool for investigating vascular tumorogenesis. (+info)
Surfactant protein C expression in urethane-induced murine pulmonary tumors.
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Mice injected with urethane develop tumors with distinct histological patterns, which are classified as solid, papillary, or a mixture of these two patterns within the same tumor. Most investigators agree that solid tumors arise from alveolar type II cells, but the cellular origin of papillary tumors is less certain, being attributed to either type II cells or nonciliated bronchiolar epithelial (Clara) cells. To characterize the state of differentiation of these tumors more precisely and to provide additional information on gene expression, we used immunocytochemistry and/or in situ hybridization to determine the cellular localization of surfactant-associated proteins A (SP-A), SP-B, SP-C, and SP-D; Clara cell-associated protein CC-10; and thyroid transcription factor-1. In normal mouse lung, the messenger RNAs (mRNAs) for SP-A, SP-B, and SP-D were expressed in both type II cells and Clara cells. SP-C mRNA, however, was expressed only in type II cells, and CC-10 expression of mRNA was restricted to Clara cells. All tumors examined, both solid and papillary, expressed SP-A, SP-B, SP-C, SP-D, and thyroid transcription factor-1, but not CC-10. However, SP-C expression was slightly diminished in larger (older) papillary tumors. These results demonstrate that urethane-induced murine lung tumors express the type II cell phenotype. (+info)