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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the brain, the H3 type of histamine receptor has a pre-synaptic autoreceptor inhibitory role which regulates neuronal release and synthesis of histamine. To examine the interaction of the selective H3 receptor antagonist thioperamide with H3 receptors in the brain in vivo, we have used a functional and non-functional measurement of H3 receptor occupancy. In three species (rat, guinea-pig and mouse) peripheral administration of thioperamide caused dose-related increases in histamine turnover in the cerebral cortex (whole brain was examined in the mouse) and, in the same tissues, inhibited the ex vivo binding of the selective H3 receptor agonist [3H](R)-alpha-methylhistamine ([3H]-RAMH). The peak effect of thioperamide to inhibit ex vivo binding of [3H]RAMH was observed approximately 30 min after i.p. administration, whilst the maximum increase in histamine turnover did not occur until after at least 100 min. At a pretreatment time of 30 min, the ED50 of thioperamide to inhibit ex vivo binding of [3H]RAMH binding in the rat, guinea-pig and mouse brain was found to be 2.0 +/- 0.2, 4.8 +/- 0.6 and 2.6 +/- 0.3 mg/kg (mean +/- SEM, N = 4), respectively. We have also examined the effect of peripheral administration of RAMH on ex vivo binding of [3H]RAMH in rat cortex. Qualitatively and quantitatively similar results to those of thioperamide were observed following i.p. administration of RAMH to rats (ED50 = 3.9 +/- 0.4 mg/kg, mean +/- SEM, N = 4). An effect of RAMH on histamine turnover in rat cortex could not be determined as this compound displayed significant cross-reactivity with the antibodies used in the radioimmunoassay to measure histamine and telemethylhistamine. These data indicate that, following peripheral administration, both thioperamide and RAMH penetrate the brain where they can subsequently interact with H3 receptors. It would appear that binding of thioperamide to H3 receptors is linked with a concomitant increase in histamine turnover in the brain. In conclusion, the ex vivo binding technique, particularly when coupled with measurement of histamine turnover, should provide a valuable means for investigating the ability of any peripherally administered compound to cross the blood-brain barrier and subsequently interact with histamine H3 receptors.
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PMID:In vivo occupancy of histamine H3 receptors by thioperamide and (R)-alpha-methylhistamine measured using histamine turnover and an ex vivo labeling technique. 132 64

The in vivo effects of a subcutaneously-administered subcurative dose (200 mg/kg body weight of mouse) of praziquantel on the structure of Schistosoma mansoni was investigated. Worms were collected at varying times post-treatment and processed for both SEM and TEM examination. Praziquantel caused extensive structural changes to both male and female worms within 15 min of treatment although variations in the amount of drug-induced damaged was observed between male and female worms. In female worms although some tegumental vacuolation was observed within 15 min, the major structural change was an often extensive vacuolisation of the subtegumental tissues followed by varying degrees of structural disruption to the subtegumental and gastrodermal musculature. In male worms the initial effects were a vacuolisation of parts of the dorsal tegument and loss of tegumental cytoplasm due to the pinching off of evaginations of the outer surface. With increasing time post-treatment there was an increase in the amount of tegumental damage, particularly in male worms, with total disruption of parts of the outer surface occurring. Also in male worms there was an increase in the amounts of vacuolisation of the parenchymal tissues and in the degree of structural damage to the musculature. In those female worms where subtegumental damage was not extensive changes in the structure of the differentiating vitelline cells were noted.
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PMID:Schistosoma mansoni: the effects of a subcurative dose of praziquantel on the ultrastructure of worms in vivo. 634 Mar 60

We have used a sensitive solution hybridization assay that employs a riboprobe obtained from the mouse delta opioid receptor (DOR) coding sequence to quantitate the relative abundance of DOR mRNA in the central nervous system (CNS) of the adult mouse and rat. In brain Poly A+ RNA extracts this riboprobe hybridized to a single 10 kb transcript from mouse and two transcripts, one of 12 and the other of 4.5 kb in size from rat. In mouse CNS the highest levels of DOR mRNA were found in the caudate-putamen at 3.3 +/- 0.1 (SEM) pg/micrograms RNA. DOR mRNA levels in the range from 2.6 to 2.1 pg/micrograms RNA were measured in frontal cortex, nucleus accumbens, whole brain and olfactory tubercle. Spinal cord, periaqueductal gray and hippocampus had DOR mRNA levels in the range from 1.8 to 1.5 pg/micrograms RNA, while medial thalamus and cerebellum had the lowest levels (0.5 pg/micrograms RNA). These results correlate with the reported relative distribution of DOR mRNA in mouse using an in situ hybridization technique. In rat CNS, the highest levels of DOR mRNA were measured in caudate-putamen at 2.3 +/- 0.1 pg equivalents/micrograms RNA. Whole brain, cerebral cortex, olfactory bulb and brain stem had levels in the range from 1.5 to 0.9 pg equivalents/micrograms RNA while the lowest DOR mRNA levels were measured at 0.5 pg equivalents/micrograms RNA or less in thalamus, hippocampus, substantia nigra and cerebellum. This study demonstrates the ability of solution hybridization assays to quantitate homologous (mouse) as well as similar but heterologous (rat) DOR mRNA levels.
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PMID:Quantitative distribution of the delta opioid receptor mRNA in the mouse and rat CNS. 779 21

The effects produced by emissions from coal-fired power plants, including mainly SO2, NOx and particulates, on natural populations and caged specimens of birds and small mammals were studied. The field-captured species used to evaluate these effects were passerine birds: Parus major (coal tit) and Emberiza cia (rock bunting), and the rodent Apodemus sylvaticus (wood mouse). In parallel to this study on animals captured in the field, we used other animals, Mus musculus (house mouse) and Carduelis carduelis (goldfinch) which were placed in cages near the source of pollution. Some of the animals were killed and their tracheas were removed and prepared for conventional optic studies (1000x) and electron microscopy (TEM and SEM). The results show that atmospheric air pollutants from coal-fired power plants produce alterations in the tracheal epithelium. In passerine birds, an increase in the mucus which covers the tracheal epithelium, shortening of the cilia, and increase in the number of secretory granules and vesicles were observed. In mammals, variation of the uniformity of the pseudostratified epithelium with a wide stratum of mucus, shortening of the cilia, and increase in the number of secretory granules were observed.
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PMID:Effects of air pollution on passerine birds and small mammals. 846 92

19F-MRS (magnetic resonance spectroscopy) was used to study the pharmacokinetics of 5-fluorouracil (5-FU) in human (HT29) tumour xenografts, with and without pretreatment of the mice using either thymidine (40 min) or interferon-alpha (2 and 24 h). A 200 mg/kg i.p. bolus dose of 5-FU was eliminated from control tumours with a t1/2 of 25.4 +/- 2 min (mean +/- SEM, n = 11), while both thymidine (500 mg/kg) and interferon (50,000 IU/mouse) significantly increased t1/2 to 36.5 +/- 6.1 (n = 5) and 48.1 +/- 13.6 min (n = 4), respectively (P = 0.04, Gabriel's ANOVA). Thymidine increased 5-FU anabolism to cytotoxic 5-fluoronucleotides, and decreased the amount of tumour catabolites; the latter probably recirculated from liver since isolated HT29 cells did not catabolize 5-FU. These in vivo observations were confirmed by 19F-MRS quantification of tumour extracts. Interferon did not significantly affect 5-FU metabolism in the tumour or liver, nor the 5-FU t1/2 in liver. Treatment of tumours with 5-FU or interferon had no effect on tumour growth, whereas the combination strongly inhibited growth. 31P-MRS of HT29 tumours showed that 2 and 24 h after i.p. injections of interferon there was a significant increase in the pHint of 0.3 +/- 0.04 units (P = 0.002), while pHext and the tumour NTP/Pi ratio were unchanged. The large increase in the negative pH gradient (-delta pH) across the tumour plasma membrane caused by interferon suggest the delta pH may be a factor in tumour retention of 5-FU, as recently shown in isolated tumour cells.
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PMID:A pharmacokinetic and pharmacodynamic study in vivo of human HT29 tumours using 19F and 31P magnetic resonance spectroscopy. 961 92

An excessive amount of neutrophil elastase (NE) released from neutrophils accumulated in the lung can cause tissue damage, despite its importance to host defense against microbial pathogens in severe pneumonia. Therefore, NE inhibitors may reduce tissue damage in lungs with severe pneumonia. In this study, the efficacy of a specific NE inhibitor, sivelestat sodium hydrate (sivelestat), was examined using a murine model of severe pneumonia with Streptococcus pneumoniae. Male mice (CBA/JNCrj, aged 5 weeks) were inoculated intranasally with penicillin-susceptible S. pneumonia (1.0 x 10(5) CFU/mouse). Sivelestat (3 mg/kg) or physiological saline was administered every 12 hours beginning at 12 hours after inoculation. Survival was primarily evaluated. Bronchoalveolar lavage fluid (BALF) and blood were collected at 30 hours after inoculation. Thus, cell counts in BALF and numbers of viable bacteria in blood were determined. Histopathological analysis was also performed. Sivelestat significantly prolonged survival when compared with the control group (P < .05), although all animals died within 4 days. Cell count and histopathological analysis indicated that sivelestat prevented the progression of lung inflammation, such as alveolar neutrophil infiltration and hemorrhage. Furthermore, the number of viable bacteria in blood was significantly lower in the sivelestat group than in the control group (5.69 +/- 0.27 and 6.75 +/- 0.32 log CFU/mL, respectively; mean +/- SEM, P < .01). Sivelestat prolonged survival in this model. A possible explanation for the improved survival is that sivelestat prevents tissue damage by inhibiting NE activity in the lung. Therefore, NE inhibitors may be useful for treating with patients with severe pneumonia.
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PMID:Effects of specific neutrophil elastase inhibitor, sivelestat sodium hydrate, in murine model of severe pneumococcal pneumonia. 1745 3

There is considerable evidence to support a role for lipotoxicity in the development of diabetic cardiomyopathy, although the molecular links between enhanced saturated fatty acid uptake/metabolism and impaired cardiac function are poorly understood. In the present study, the effects of acute exposure to the saturated fatty acid, palmitate, on myocardial contractility and excitability were examined directly. Exposure of isolated (adult mouse) ventricular myocytes to palmitate, complexed to bovine serum albumin (palmitate:BSA) as in blood, rapidly reduced (by 54+/-4%) mean (+/-SEM) unloaded fractional cell shortening. The amplitudes of intracellular Ca(2+) transients decreased in parallel. Current-clamp recordings revealed that exposure to palmitate:BSA markedly shortened action potential durations at 20%, 50%, and 90% repolarization. These effects were reversible and were occluded when the K(+) in the recording pipettes was replaced with Cs(+), suggesting a direct effect on repolarizing K(+) currents. Indeed, voltage-clamp recordings revealed that palmitate:BSA reversibly and selectively increased peak outward voltage-gated K(+) (Kv) current amplitudes by 20+/-2%, whereas inwardly rectifying K(+) (Kir) currents and voltage-gated Ca(2+) currents were unaffected. Further analyses revealed that the individual Kv current components I(to,f), I(K,slow) and I(ss), were all increased (by 12+/-2%, 37+/-4%, and 34+/-4%, respectively) in cells exposed to palmitate:BSA. Consistent with effects on both components of I(K,slow) (I(K,slow1) and I(K,slow)(2)) the magnitude of the palmitate-induced increase was attenuated in ventricular myocytes isolated from animals in which the Kv1.5 (I(K,slow)(1)) or the Kv2.1 (I(K,slow)(2)) locus was disrupted and I(K,slow)(1) or I(K,slow2) is eliminated. Both the enhancement of I(K,slow) and the negative inotropic effect of palmitate:BSA were reduced in the presence of the Kv1.5 selective channel blocker, diphenyl phosphine oxide-1 (DPO-1).Taken together, these results suggest that elevations in circulating saturated free fatty acids, as occurs in diabetes, can directly augment repolarizing myocardial Kv currents and impair excitation-contraction coupling.
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PMID:Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents. 1985 98