The aim of this study was to test the effects of the three "classical" methylxanthines, theophylline, caffeine and theobromine, on local cerebral blood flow and glucose utilization. Equimolar doses (1.6 mumol/kg/min i.v.) of theophylline and caffeine produced increases in local cerebral glucose utilization and decreases in local cerebral blood flow. These compounds, therefore, re-set the ratio of cerebral blood flow per unit of glucose utilization at a lower level. These results are interpreted with respect to the known adenosine antagonist properties of caffeine and theophylline. Theobromine, a substance with less significant adenosine antagonist properties, had minimal effects on local cerebral blood flow and glucose utilization at a dose of 1.6 mumol/kg/min i.v. These data may provide supportive evidence for the hypothesis that adenosine plays an important role in cerebral blood flow-metabolism coupling.
Sulphoevernan is a sulphated ~-1 --, 3, 1 -, 4 polyglucan (Mr 20000) with a helical structure. This compound effectively inhibits both human immunodeficiency virus type 1 (HIV-1) and type 2 infection of cells in vitro at concentrations around 0-5 ~tg/ml. Moreover, the compound completely inhibits HIV-l-induced syncytium formation at a concentration of 1 ~tg/ml. Competition experiments with 35S-labelled sulphoevernan revealed that the mannose-specific lectin from Narcissus pseudonarcissus prevented binding of sulphoevernan to HIV-1, whereas the antibody OKT4A did not reduce the amount of sulphoevernan bound to MT-2 cells. These data indicate that the non-cytotoxic polymer sulphoevernan binds to the virus rather than to the host cell. In vivo studies, using Rauscher leukaemia virus in NMRI mice, revealed that, at a daily dose of 20 mg/kg, the animals were protected against virus-induced increases in spleen weight. From these in vitro and in vivo data we conclude that sulphoevernan has potential in the treatment of acquired immunodeficiency syndrome.
The uptake of adenosine is studied in microvessels isolated from a bovine cortex. The KM value for adenosine uptake is 1.92 microM and the Vmax is 1.93 picomole/mg protein/10 min. This high affinity uptake system is very sensitive to inhibition by dipyridamole and papaverine. The uptake of adenosine by microvessels is also inhibited by CuCl2 and by high concentration (2 mM) of adenine nucleotides. Using a series of four xanthines is observed that the adenosine uptake system is most inhibited by 3-methyl-l-(5'-oxohexyl)-7-propylxanthine and the least by caffeine. Theophylline causes a stimulation of adenosine uptake by microvessels. The results obtained agree with the existence of the nucleoside transport system associated with the blood-brain barrier, as previously observed by in vivo studies and experiments with rat brain capillaries.
Stefanovich, V.: Effect of Propentofylline on cerebral metabolism of rats. Drug Dev. Res. 6:327-338, 1985. Propentofylline (HWA 285) [3-methyl-l-(5'-oxohexyl)-7-propylxanthine] is in in vitro experiments a good inhibitor of cAMP and cGMP phosphodiesterases in the rat brain and cerebral microvessels. In in vivo experiments it modulates cAMP and cGMP systems and GABA concentration in four examined structures of rats: cortex, hypothalamus, cerebellum, and striatum. Propentofylline (5 mg/kg i.v.) doesn't influence levels of cerebral energy reserves in normal rats but prevents to a significant degree some of the changes in metabolite levels caused by anoxia (30 s of nitrogen breathing). This antianoxic effect occurs at 5 min and disappears 20 min after administration of the drug. Caffeine (5 mg/kg i.v.) shows a trend toward further aggravation of anoxia. The modulating effect of propentofylline on cAMP and cGMP systems, GABA levels, and especially cerebral energy metabolism in anoxia is possibly related to the potential therapeutic effect of this drug.
It was established that microvessels of a bovine cortex exhibit significant cyclic 3',5'-adenosine monophosphate phosphodiesterase (cAMP PDE) and cyclic 3',5'-guanosine monophosphate phosphodiesterase (cGMP PDE) activities. These activities are dependent on the presence of Mg2+. Absence of Ca2+ was virtually without effect. When both Mg2+ and Ca2+ were absent, PDE activities increased compared with activities observed in the absence of Mg2+. Xanthines (caffeine, theobromine, and theophylline) were better inhibitors of cAMP PDE than of cGMP PDE. Imidazole, in very high concentration (1 X 10(-2) M) only, exhibited PDE stimulatory activity at high concentrations of both substrates. Otherwise, it exhibited PDE-inhibitory properties.
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