cardiovascular-agents and mioflazine

Topics: Adenosine; Animals; Biological Transport; Cardiovascular Agents; Cells, Cultured; Formycins; Guinea Pigs; Kinetics; Lidoflazine; Myocardium; Piperazines

The in vivo nucleoside transport inhibitory effects of 6-[(4-nitrobenzyl)-mercapto]purine ribonucleoside (NBMPR), used as its 5'-monophosphate derivative (NBMPR-P), dilazep, mioflazine and its derivatives soluflazine, R57974 and R75231, were investigated in BALB/c mice. The extent and duration of action were followed by assaying adenosine transport in blood cells sampled at time intervals following i.p. administration (ca. 20 mg/kg). Dilazep and R57974 were found to be short-acting inhibitors, while NBMPR-P and R75231 were similar in their action and caused essentially full inhibition of adenosine transport over a 4- to 5-h period. Mioflazine and soluflazine were rather ineffective, causing only partial inhibition. R75231 was also active after oral administration which, when repeated three times in 4-h intervals, resulted in essentially full transport inhibition up to 20 h following the initial dose. Effects of NBMPR-P, R57974 and dilazep on adenosine transport in blood cells were also measured in blood cells of hamsters after i.p. administration of the same doses. All three drugs caused full transport inhibition, but the action of dilazep and R75231 showed reversal within about 30 min and 2 h, respectively, while NBMPR-P caused full inhibition for at least 3-4 h. These results demonstrate the potential of the mioflazine derivative R75231 to be useful in vivo, possibly even after p.o. administration, for host protection against the actions of cytotoxic nucleosides used in experimental antiparasitic therapy or other studies requiring suppression of nucleoside transport.

Topics: Adenosine; Administration, Oral; Animals; Biological Transport; Cardiovascular Agents; Cricetinae; Dilazep; Injections, Intraperitoneal; Mesocricetus; Mice; Mice, Inbred BALB C; Piperazines; Species Specificity; Thioinosine

The zero-trans influx of uridine in human erythrocytes is inhibited by lidoflazine and analogs thereof. The concentrations required for inhibition of nucleoside transport were higher when the compounds were simultaneously added with uridine than upon preincubation of the inhibitors with the erythrocytes. R70380 proved to be the most active compound in this respect, its IC50 value being 13 nM after preincubation. Even the reference compounds nitrobenzylthioinosine and dilazep were remarkably more potent with preincubation; dipyridamole, however, was not.

Topics: Biological Transport, Active; Cardiovascular Agents; Erythrocytes; Humans; In Vitro Techniques; Kinetics; Lidoflazine; Ligands; Nucleosides; Piperazines; Uridine

The sensitivity of facilitated-diffusion and Na(+)-dependent nucleoside transporters to inhibition by a series of novel compounds related to lidoflazine and mioflazine was investigated. Uridine transport by rabbit erythrocytes, which proceeds solely by the nitrobenzylthioinosine (NBMPR)-sensitive facilitated-diffusion system, was inhibited with apparent Ki values of less than 10 nM by lidoflazine, mioflazine, soluflazine and R73-335. These compounds also blocked site-specific [3H]NBMPR binding to rabbit erthrocyte membranes in a competitive fashion. The NBMPR-sensitive system in rat erythrocytes was also inhibited by lidoflazine, mioflazine, soluflazine and R73-335 but was two to three orders of magnitude less sensitive to inhibition than the system in rabbit erythrocytes (apparent Ki 7.3, 2.4, 5.7 and 0.1 microM, respectively). Lidoflazine, mioflazine and R73-335 exhibited a similar potency for the NBMPR-sensitive and -insensitive nucleoside transporters in rat erythrocytes. In contrast, soluflazine was 20- to 100-fold more potent as an inhibitor of the NBMPR-insensitive nucleoside transport component in rat erythrocytes (IC50 of 0.08-0.2 microM) compared to the NBMPR-sensitive nucleoside carrier in these cells (IC50 approximately 10 microM). None of the test compounds were potent inhibits of Na(+)-dependent uridine transport in bovine renal brush-border membrane vesicles. These results indicate that lidoflazine, mioflazine, soluflazine and R73-335 are selective inhibitors of nucleoside transport in animal cells and that the potency of these compounds as nucleoside transport inhibitors is species dependent.

Topics: Affinity Labels; Animals; Biological Transport; Cardiovascular Agents; Cattle; Cells, Cultured; Erythrocytes; Humans; Kidney; Lidoflazine; Nucleosides; Piperazines; Placenta; Rabbits; Rats; Sodium; Thioinosine; Uridine

The influence of nifedipine (20 nM) and mioflazine (300 nM), i.e. concentrations inducing a 60-70% recovery of cardiac function during reperfusion of globally ischaemic guinea-pig working hearts, on the mitochondrial calcium content was investigated in normoxic, globally ischaemic and reperfused globally ischaemic guinea-pig working hearts. Mitochondrial calcium was determined electronmicroscopically with oxalate-pyroantimonate method. In normoxic hearts both nifedipine and mioflazine reduced the mitochondrial calcium content. Global ischaemia for 45 min and subsequent reperfusion for 25 min resulted in a pronounced mitochondrial calcium overload and damage to the cellular structure. In ischaemic and in reperfusion hearts the drugs maintained mitochondrial calcium at pre-ischaemic levels and decreased the damage to the cellular structure.

Topics: Animals; Antimony; Calcium; Cardiovascular Agents; Coronary Disease; Guinea Pigs; Homeostasis; In Vitro Techniques; Mitochondria, Heart; Myocardial Reperfusion; Nifedipine; Oxalates; Piperazines

The binding of [G-3H]-6-(4-nitrobenzylmercapto)purine ribonucleoside [( G-3H]NBMPR) was investigated using a centrifugation assay with membrane preparations from hamster tissues including liver, lung, kidney and heart. Only liver and lung membranes showed high specific binding, with dissociation constants (Kd) values of 2.4 +/- 0.4 and 0.44 +/- 0.05 nM, and maximal binding (Bmax) of 3.7 +/- 0.4 and 1.04 +/- 0.01 pmol/mg, respectively. The binding of [G-3H]NBMPR was inhibited in a concentration dependent manner by unlabelled NBMPR, dilazep and a new group of chemically related nucleoside transport inhibitors, mioflazine, soluflazine and R57974, the latter being the most potent derivative. R57974 displaced bound [G-3H]NBMPR as effectively as unlabelled NBMPR suggesting a common binding site. The assay procedure used appears useful for the rapid screening of the effectiveness of nucleoside transport inhibitors which will be of value for the selection of inhibitors suitable for combination with cytotoxic nucleosides in the treatment of selected cancers or parasitic diseases.

Topics: Animals; Binding Sites; Cardiovascular Agents; Cell Membrane; Cricetinae; Dilazep; In Vitro Techniques; Inosine; Liver; Lung; Male; Mesocricetus; Piperazines; Thioinosine

Topics: Animals; Calcium; Cardiovascular Agents; Coronary Disease; Female; Hemodynamics; In Vitro Techniques; Lidoflazine; Male; Myocardium; Piperazines; Rabbits

Topics: Animals; Cardiovascular Agents; Female; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Piperazines; Rabbits

Intravenous injection of mioflazine, a nucleoside transport antagonist, caused maximal coronary vasodilation in canine hearts. This was completely reversed by intravenous injection of the enzyme adenosine deaminase. Coronary vasodilation was induced again by the adenosine deaminase inhibitor EHNA [Erythro-9(2-hydroxy-3-nonyl)adenine]; however, without previous injection of mioflazine, EHNA did not produce coronary vasodilation. Mioflazine-induced coronary vasodilation was antagonized by theophylline, but it was not associated with increased plasma levels of adenosine. Under the influence of mioflazine, ischemic myocardium contained adenosine and inosine at a ratio of 65:30, which is the reverse of the control ratio. Total nucleoside content following mioflazine showed reduced nucleoside losses as compared with control. A significant amount of the accumulated adenosine is extracellular since it was accessible to exogenous adenosine deaminase. Reperfusion of ischemic myocardium did not result in increased rates of adenosine phosphorylation, another indicator of its extracellular accumulation. The data are best explained by assuming release of adenosine by mioflazine in addition to its known effect of inhibiting nucleoside transport. The adenosine release occurs most probably into the interstitial space where it occupies smooth muscle adenosine receptors. The existence of nonsymmetric transport (uptake is more inhibited than release) is postulated for the myocyte, as well as for the endothelial cell plasma membrane.

Topics: Adenine Nucleotides; Adenosine; Adenosine Triphosphate; Animals; Blood Pressure; Cardiovascular Agents; Chromatography, High Pressure Liquid; Coronary Circulation; Coronary Disease; Dogs; Female; Heart Rate; Hemodynamics; Male; Piperazines

Mioflazine, a nucleoside transport inhibitor, was given PO to dogs at doses of 0.04-10 mg/kg. Sixteen hour polygraphic sleep recordings were made and analysis and sleep stage classification was done by computer. Mioflazine decreased wakefulness and increased slow wave sleep, but did not affect the latencies of either REM sleep or slow wave sleep. This increased sleep was due to an increase in the number of light and deep slow wave sleep epochs. The effect lasted for about 8 h. The decreased wakefulness and increased slow wave sleep could be antagonized by the adenosine antagonist caffeine (2.5 and 10 mg/kg, PO); however, there was not a pure antagonistic effect. It might be that the enhancement of slow wave sleep is due to an activation of brain adenosine receptors. This is the first report of a drug acting on adenosine that given orally improves sleep. Mioflazine might be the prototype of substances worth considering for the treatment of a variety of sleep disorders.

Topics: Administration, Oral; Animals; Caffeine; Cardiovascular Agents; Dogs; Drug Interactions; Electromyography; Electrooculography; Female; Male; Piperazines; Sleep

The effect of mioflazine (R 51 469) on infarct size was studied in anesthetized dogs subjected to 24 h of LAD (left anterior descending) coronary artery occlusion. The myocardium normally supplied by the occluded coronary artery (perfusion area, PA) was delineated by perfusion of the arterial bed distal to the occlusion with colorless fluid while the remainder of the heart was simultaneously perfused with an Evans blue solution. After sectioning the heart, infarct areas (IA) could be visualized by incubation of the slices in triphenyl-tetrazolium-chloride (TTC). Quantification of the areas was performed using a Quantimet 900 image analysis system. The animals either received mioflazine (2.5 mg X kg-1 orally) or a same volume of 20% polypropylene glycol, the solvent of mioflazine 2.5 h before the start of the surgical procedure. For perfusion areas greater than 20% of the left ventricle infarct size was significantly reduced in mioflazine pretreated animals compared with the control group, both expressed as per cent of the left ventricle (10.6 +/- 2.3 vs 19.2 +/- 1.5, p less than 0.005) and as per cent of the perfusion area (35.1 +/- 7 vs 64.4 +/- 5, p less than 0.005).

Topics: Anesthesia; Animals; Cardiovascular Agents; Dogs; Female; Male; Myocardial Infarction; Piperazines