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Biomedical subjects

J Dow

Publications and source records attributed to J Dow.

16 recordsLinked to original sources

Dendritic processing: using microstructures to solve a hitherto intractable neurobiological problem.

In vivo, intracellular recordings of mammalian brain stem motoneurones, followed by peroxidase staining and tridimensional reconstruction, suggest that the shape of the dendritic tree plays an important role in the processing of neural information. To test this hypothesis attempts were made to guide, in culture, the growth of neuritic branches of neurones dissociated from the hypoglossal nucleus of rat brain stem. This was performed using topographical and adhesive microstructures which were designed to control the shape of the neuritic tree. Guidance of the neuritic processes can be observed with small grooves engraved on quartz and plastic substrates, and simple shapes with few processes and bifurcations on each neurite could be obtained using adhesive microstructures. These procedures, which allow the shape of a neurone to be controlled, are very promising in the study, by means of classical electrophysiological methods as well as optical recordings, of the involvement of dendritic architecture in the processing of neural information.

Animals

Effect of a cardioselective alpha-tocopherol analogue on reperfusion injury in rats induced by myocardial ischaemia.

Free radicals may cause some of the irreversible injury which occurs during myocardial ischaemia and reperfusion. In the present study the effects of a cardioselective, free radical scavenger, MDL 74270, which is an analogue of alpha-tocopherol, on myocardial infarct size in an anaesthetised rat model of coronary artery ligation (60 min) and reperfusion (30 min) has been evaluated. Infusion of MDL 74270 (0.3-3.0 mg/kg per h) commencing 10 min before occlusion until the end of reperfusion significantly reduced infarct size. The highest dose also caused a significant reduction in serum creatine phosphokinase levels. Similar findings have been obtained with the bromide salt of MDL 74270. Tissue distribution studies with 14C-labelled MDL 74270 and its tertiary amine analogue (MDL 74366) showed heart/blood ratios of total radioactivity, 1-6 h after i.v. administration, greater than 20 after MDL 74270 and around 1 after MDL 74366. The importance of accumulation of total radioactivity in the heart after MDL 74270 is supported by the fact that MDL 74366 was 30 times less potent as a myocardial protector in the ligation/reperfusion studies. It is concluded that MDL 74270 has potential for cardioprotective use in conditions of acute reperfusion.

Animals

A cardioselective, hydrophilic N,N,N-trimethylethanaminium alpha-tocopherol analogue that reduces myocardial infarct size.

The alpha-tocopherol analogue 3,4-dihydro-6-hydroxy-N,N,N,2,5,7,8- heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate (1a, MDL 73404) and its O-acetate 1b (MDL 74270) were synthesized. Compound 1a was found to be hydrophilic (log P = -0.60) and to prevent lipid autoxidation in rat brain homogenate with an IC50 of 1.7 +/- 0.9 microM. Tissue distribution studies with [14C]-1b in rats (1 mg/kg iv) showed that radioactivity accumulates in the heart (ratio 20:1 vs blood after 1 h). Infusion of 1 mg/kg per h of 1b bromide reduced infarct size by 54% in rats subjected to coronary artery occlusion for 60 min followed by reperfusion for 30 min, compared to saline-infused controls. By comparison, the tertiary amine analogue 5 was found not to accumulate in heart tissue, to be an equally effective free-radical scavenger in vitro, but to require a higher dose to reduce infarct size in rats. This shows that the cardioselectivity of compound 1 contributes to its potency in salvaging myocardial tissue in rats after ischemia and reperfusion.

Animals

Ethanol oxidizing enzyme activites in liver disease.

1 The activites of hepatic alcohol dehydrogenase, catalase and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) dependent ethanol oxidizing system were determined in liver biopsies from nine patients with liver disease and seven control subjects with non evidence of liver disease. 2 Alcohol dehydrogenase and catalase activites were significantly lower in the patients with liver disease. 3 The activity of the NADPH dependent ethanol oxidizing system was significantly greater in the patients with liver disease, when its activity was expressed in terms of mg protein or g wet weight liver. 4 It is suggested that the greater activity of the NADPH dependent system may compensate for the low alcohol dehydrogenase activites found in patients with liver disease and maintain normal rates of ethanol metabolism.

Alcohol Oxidoreductases

Relation between hepatic alcohol dehydrogenase activity and the ascorbic acid in leucocytes of patients with liver disease.

1. Hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content was measured in thirty-five patients with liver disease and in ten control subjects with duodenal ulcer. The patients with liver disease were divided into three groups consisting of non-drinkers, moderate drinkers and alcoholic/heavy drinkers. 2. There was no significant difference in hepatic alcohol dehydrogenase activity between the groups with liver disease, but all patients had less than half the hepatic alcohol dehydrogenase activity of the control subjects (P less than 0-001). 3. The ascorbic acid in leucocytes was significantly lower in the alcoholic/heavy drinker group than that in the control subjects (P less than 0-02) when the Student's t-test was applied, but no significant difference was found when the Mann-Whitney U-test was used. 4. A correlation coefficient of r = 0-77 (P less than 0-001) was observed among the thirty-five patients with liver disease when hepatic alcohol dehydrogenase activity was compared with leucocyte ascorbic acid content. An insignificant correlation (r = 0-332) was found in the control subjects with no liver disease. 5. This comparison was also significant among non-drinkers with liver disease (r = 0-873; P less than 0-001), moderate drinkers (r = 0-739; P less than 0-02) and alcoholic/heavy drinkers (r = 0-702; P less than 0-005). 6. The addition of ascorbic acid in vitro (0-5-10 mmol/1) had no effect on the activity of alcohol dehydrogenase. 7. The relation between hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content is probably a consequence of liver disease, as opposed to any specific effect of ascorbic acid deficiency of alcohol consumption on alcohol dehydrogenase activity.

Alanine Transaminase

Fate of coronary collateral circulation after aorto-coronary saphenous vein bypass grafts.

The pre- and postoperative patterns of coronary artery collateral circulation have been studied in 34 patients who had saphenous vein bypass grafting. When the graft remained patent homocoronary collaterals could not be visualized after operation, but new intercoronary anastomoses frequently developed to other diseased arteries. When the graft and the bypassed artery were both obstructed there was a high incidence (5 out of 11) of myocardial infarction despite good preoperative collaterals.

Aorta, Thoracic

Cardioselectivity of alpha-tocopherol analogues, with free radical scavenger activity, in the rat.

MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals