Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Dilazep”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1982

Effects of dilazep on fibrinolytic system in animals. I. Enhancement of fibrinolytic activity by administered dilazep in ex vivo experiment.

The effects of dilazep on blood fibrinolytic system were studied in ex vivo experiment. Fibrinolytic activity in plasma was determined by the fibrin plate method at designed times after the administration of dilazep in guinea pigs, rabbits and mongrel dogs. In guinea pigs, fibrinolytic activity of euglobulin (plasminogen activator level, 1.10+/-0.08 CU/ml in control animals) rose to 1.53+/-0.24, 1.92+/-0.13 and 2.35+/-0.15 CU/ml 2 h after the p.o. administration of 30, 100 and 300 mg/kg of dilazep, respectively. Plasminogen levels in euglobulin were unchanged, however, plasmin inhibitory activities were lowered following the increase of plasminogen activator levels. About 2-fold increase of plasminogen activator level was also observed in rabbits 60 min after the p.o. administration of 300 mg/kg dilazep and returned to the initial level (0.054 CU/ml) within 3 h after the administration. A rapid increase of plasminogen activator level was observed in a case of the i.v. administration of dilazep into rabbits and mongrel dogs. In in vitro experiment, dilazep added to whole blood or plasma of guinea pigs ranging 0.1 to 1000 microgram/ml did not reveal any effects on plasminogen activator level or plasmin inhibitory activity in plasma.

Animals↗
PubMed1995

A study on dilazep: I. Mechanism of anti-ischemic action of dilazep is not coronary vasodilation but decreased cardiac mechanical function in the isolated, working rat heart.

In the isolated, perfused working rat heart, ischemia (15 min) decreased the mechanical function and the tissue levels of adenosine triphosphate and creatine phosphate and increased the levels of lactate and free fatty acids. Reperfusion (20 min) did not restore the mechanical function, but restored incompletely the levels of metabolites, with the exception of free fatty acids, which increased further during reperfusion. Dilazep was given 5 min before starting ischemia until the end of ischemia. Dilazep at 5 or 10 microM decreased the cardiac mechanical function, but did not affect coronary flow in the pre-ischemic heart. Dilazep at 5 or 10 microM accelerated the recovery of mechanical function and coronary flow during reperfusion, and it attenuated metabolic changes induced by ischemia and reperfusion. Dilazep at 1 microM neither decreased the pre-ischemic mechanical function nor restored the mechanical function during reperfusion, although it attenuated the accumulation of free fatty acids during reperfusion. These results suggest that dilazep attenuates both ischemia- and reperfusion-induced myocardial damage and that the anti-ischemic action of dilazep is not due to coronary vasodilation but probably due to an energy-sparing effect and other effects that remain to be studied.

Animals↗
PubMed1995

A study on dilazep: II. Dilazep attenuates lysophosphatidylcholine-induced mechanical and metabolic derangements in the isolated, working rat heart.

The effects of dilazep, d-propranolol and lidocaine on the mechanical and metabolic changes induced by lysophosphatidylcholine (LPC) were studied in isolated, perfused working rat heart. After a stabilization period, the heart was perfused for 5 min with LPC (10 microM) alone, LPC plus dilazep (5, 10 or 20 microM), LPC plus d-propranolol (30 or 50 microM) or LPC plus lidocaine (30 or 100 microM) and then perfused with normal Krebs-Henseleit bicarbonate (KHB) buffer for a further 20 min. Perfusion with LPC for 5 min followed by KHB for 20 min irreversibly decreased cardiac mechanical function, decreased the tissue levels of adenosine triphosphate and creatine phosphate significantly, and increased the tissue levels of lactate and free fatty acids including arachidonic acid. Dilazep or d-propranolol significantly attenuated the mechanical and metabolic changes induced by LPC, but lidocaine did not. These results indicate that the exogenous LPC causes ischemia-like changes, suggesting that LPC is one of the important factors in producing ischemia-reperfusion derangements in terms of mechanical and metabolic functions, and that both dilazep and d-propranolol can prevent the LPC-induced myocardial damage.

Animals↗
PubMed1982

Effects of dilazep on fibrinolytic system in animals. II. Enhancing effect of dilazep on plasminogen activator release in the isolated perfused pig ear.

The influence of drugs on the release of plasminogen activator was studied in the isolated perfused pig ear. The pig ear was perfused with oxygenated Tyrode's solution pH 7 . 4, at 37 degrees C via main artery and perfusate from the veins was collected at 2 min intervals. The drug was injected into a rubber tube connected in the front of arteria cannula, and the fibrinolytic activity of perfusate collected was measured by the fibrin plate method using plasminogen-containing bovine fibrinogen. Under the test condition, dilazep enhanced plasminogen activator release (PA release) in a dose-dependent fashion ranging 10 to 100 microgram, however, it did not affect the perfusion pressure. Hypotensors, namely acetylcholine (0.1-3 microgram), bradykinin (0.1-3 microgram) and histamine (0.1-3 microgram) enhanced also the PA release in a dose-dependent fashion with no effects on perfusion pressure. Vasoconstricting drugs, namely phenylephrine (0.3-10 microgram), norepinephrine (0.1-3 microgram) and serotonin (0.1-3 microgram) exerted hypertensive effects on perfusion pressure in a dose-dependent fashion, however, it did not cause the PA release.

Acetylcholine↗
PubMed1989

Interaction of [3H]dilazep at nucleoside transporter-associated binding sites on S49 mouse lymphoma cells.

Dilazep, a tertiary amine that is greater than 96% protonated at pH 7.4, is a potent inhibitor of facilitated diffusion (equilibrative) nucleoside transport (NT) in animal cells. In this study, saturable reversible binding of [3H]dilazep was demonstrated at sites on S49 mouse lymphoma cells but not in AE1 cells, an NT-deficient mutant of S49 cells. Mass law analysis of dilazep binding under equilibrium conditions revealed two saturable components, representing binding sites that differed about 50-fold in affinity for dilazep (Kd values of 0.21 and 10 nM). At pH 7.4, the low affinity sites were more abundant (Bmax, 3.5 X 10(5) sites/cell) than the high affinity site (Bmax, 3.0 X 10(4) sites/cell). Binding of dilazep was pH dependent; at pH 9.0, binding at the high affinity sites predominated, whereas, at pH 5.0, the low affinity component predominated, suggesting that these components represented binding of nonprotonated and protonated dilazep molecules, respectively. Nitrobenzylthioinosine (NBMPR) and physostigmine selectively blocked binding of nonprotonated and protonated species of dilazep, respectively, at pH 7.4, yielding Scatchard plots that were similar to control plots obtained at pH 5.0 and 9.0. First-order plots of the dissociation of [3H]dilazep-binding site complexes in the presence of excess nonradioactive dilazep at pH 7.4 were nonlinear and were resolved into rapid (rate constant, 3.4-4.7 min-1) and slow (rate constant, 0.13-0.15 min-1) components. In the presence of site-saturating concentrations of NBMPR or high concentrations of nucleoside permeants, dissociation of site-bound [3H]dilazep was incomplete and only the slow component of dissociation was apparent (rate constant, 0.11-0.19 min-1). The combined presence of nonradioactive dilazep and NBMPR yielded time courses of [3H]dilazep-site dissociation equivalent to those obtained in the presence of nonradioactive dilazep alone. These results are consistent with a model in which protonated and nonprotonated species of dilazep bind at separate sites on S49 cells. The absence of both high and low affinity sites on AE1 cells suggests that, in S49 cells, both populations of sites are associated with NT polypeptides. The high affinity sites that bind nonprotonated species of dilazep appear to overlap with NBMPR binding sites on these cells.

Animals↗
PubMed1992

Behavioral effects of dilazep on cholinergic, dopaminergic, and purinergic systems in the rat.

This study examined the effects of 1,4-bis[3-(3,4,5-trimethoxy benzoyloxy)-propyl] perhydro-1,4-diazepine (dilazep; Comelian) on central dopaminergic, cholinergic, and purinergic neuronal systems in rats. Intraperitoneal injections of dilazep (1-5 mg/kg) produced yawning responses, the most effective dose being 2 mg/kg. Dilazep potentiated physostigmine-induced yawning but not pilocarpine- and bromocriptine-induced yawning. Dilazep-induced yawning was not affected by low doses of haloperidol or sulpiride, but was completely inhibited by atropine, a muscarinic M1 receptor antagonist. Dilazep-induced yawning, as well as physostigmine-induced yawning, were markedly inhibited by pretreatment with SK & F 38393, a dopamine D1 receptor agonist, and were potentiated by SCH23390, a dopamine D1 receptor antagonist that alone does not elicit yawning. Caffeine, an adenosine receptor antagonist, inhibited dilazep- and physostigmine-induced yawning responses but N6-cyclohexyl adenosine (CHA) and N6-(L-phenylisopropyl, adenosine (L-PIA), adenosine A1 receptor agonists, were inactive. These results suggest that because the effects of dilazep on central cholinergic neurons are similar to those of physostigmine dilazep may potentiate indirectly the action of endogenous acetylcholine. Cholinergic neurons activated by dilazep may be modulated by postsynaptic dopamine D1 receptor activity but may not be affected by dopamine D2 receptor activity. Furthermore, the stimulatory effects of dilazep on cholinergic neuron may not be due to an inhibition of dopamine D1 receptors via purinergic (adenosine A1 receptor) stimulation by dilazep.

Animals↗
PubMed1986

Effect of dilazep on decrease in myocardial pH during ischemia in dogs.

The present study was undertaken in order to examine whether dilazep (1,4-bis-[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1, 4-diazepine dihydrochloride monohydrate) attenuates myocardial acidosis induced by coronary artery occlusion in dogs. In dogs with nonischemic normal heart, dilazep (300 or 500 micrograms/kg i.v.) increased blood flow in the left anterior descending coronary artery (LAD) with a decrease in heart rate and diastolic blood pressure. In other dogs, LAD flow was reduced by an occluder by 57 to 68% (partial occlusion) for 90 min. Partial occlusion for 30 min decreased myocardial pH by 0.67 to 0.87 pH units, increased ST segment of the surface electrocardiogram, and decreased regional myocardial contractile force. Dilazep was injected i.v. 30 min after partial occlusion. The decrease in myocardial pH induced by partial occlusion was attenuated by the injection of 300 micrograms/kg of dilazep insignificantly and by that of 500 micrograms/kg of dilazep significantly. Restoration of myocardial [H+] induced by dilazep was calculated from the myocardial pH data. Dilazep (500 micrograms/kg) restored myocardial [H+] induced by partial occlusion by 56.7%, and saline solution restored it by 27.4% 60 min after the drug injection, the actual restoration induced by dilazep being 29.3%. Dilazep, however, did not restore the ST segment elevation and contractile force decrease. It is concluded that dilazep attenuates myocardial acidosis during ischemia.

Animals↗
PubMed1989

Therapeutic tolerance, hemodynamic effects, and oral dose kinetics of dilazep dihydrochloride in hypertensive patients.

The oral dose metabolism of dilazep dihydrochloride [tetrahydro-1H-1,4-diazepine-1,4(5H)-dipropanol 3,4,5-trimethoxybenzoate] was examined in six hypertensive patients receiving a single oral dose of 600 mg of dilazep (3-3.8 mg/kg BW). Blood was collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after administration of the dose and urine was collected for three time intervals of 0-4 h, 4-10 h, and 10-24 h. Dilazep concentrations in blood and urine were determined by high-performance liquid chromatography. Dilazep decayed monoexponentially with a mean elimination rate constant of 0.27 +/- 0.13 h-1 and a mean half-life of 3.04 +/- 1.34 h. The mean tmax of absorption was 1.40 +/- 0.82 h. With maximally tolerated chronic doses, the steady-state concentration measured at 1 week was 25.6 ng/mL in a patient receiving 300 mg daily (100 mg TID) for 3 weeks, and dilazep concentration increased with the dose in others for up to a 600-mg dose daily. Dilazep did not produce any significant changes in heart rate and blood pressure after a single oral dose or during chronic dosing. There was no correlation between blood dilazep levels and the changes in heart rate and blood pressure. In three additional patients, oral dilazep dihydrochloride titrated gradually to maximally tolerated doses (900 mg daily) failed to produce significant effects on biochemical and neurohumoral measurements, and hemodynamic parameters as well as ventricular functional indices measured by radionucleide methods. Oral dilazep administration in maximally tolerated doses is devoid of effects on blood pressure and cardiac hemodynamic function.

Administration, Oral↗
PubMed1988

Relaxing effects of dilazep and lidoflazine in dog cerebral and renal arteries independent of adenosine.

The adenosine potentiating drugs dilazep and lidoflazine were studied for their relaxing ability in isolated dog cerebral and renal arteries contracted under conditions which induce the opening of potential-dependent calcium channels (using K+ at 30, 50 and 100 mmol/l) and under conditions which induce the opening of receptor-operated calcium channels (prostaglandin F2 alpha, PGF2 alpha; 5-hydroxytryptamine, 5-HT) and compared with those of adenosine and a standard calcium entry blocker, diltiazem. Dilazep, lidoflazine and diltiazem exerted concentration-dependent relaxation in cerebral and renal artery ring strips contracted with 30, 50 and 100 mmol/l K+. However, dilazep was slightly more potent at 100 mmol/l K+. In contrast, whereas the high concentration of adenosine (1 X 10(-5)-3.7 X 10(-4) mol/l) relaxes these arteries only at 30 mmol/l K+, it produced a more pronounced concentration-dependent relaxation when PGF2 alpha or 5-HT was used as a contracting agent. The order of relaxing responses of both cerebral and renal arterial ring strips contracted by PGF2 alpha were: diltiazem greater than adenosine greater than lidoflazine greater than dilazep. On the other hand, the relaxing responses on cerebral and renal arteries contracted with 5-HT were: diltiazem greater than lidoflazine greater than adenosine greater than dilazep and diltiazem greater than adenosine greater than lidoflazine greater than dilazep, respectively. Adenosine deaminase reversed the relaxation produced by adenosine, but was unable to reverse the relaxing responses to diltiazem, lidoflazine and dilazep. These findings suggest that dilazep and lidoflazine have a direct relaxing effect independent of adenosine in cerebral and renal artery ring strips possibly through their calcium entry blocking activity. The data suggest that adenosine is more effective on the receptor-operated contractions, whereas dilazep and lidoflazine are more effective on the potential-dependent contractions.

Adenosine↗
PubMed1976

[Studies on the bioavailability of the individual components from a combination of dilazep and beta-acetyldigoxin (author's transl)].

Original tablets of Cormelian [= 50 mg 1,4-bis[3-(3,4,5-trimethoxybenzoyl-oxy)-propyl]-perhydro-1,4-diazepine (dilazep)] and Cormelian-Digotab (= 50 mg dilazep + 0.2 mg beta-acetyl-digoxin) were produced with 3H-dilazep as prescribed in the special galenic technique. After application of a single oral dose of two tablets dilazep to 9 patients serum concentration was analysed at different times up to 24 h p.a.; the renal excretion rate of dilazep and metabolites was determined up to 48 h. Two tablets of the combination were given to 4 of these patients 4 days after application of dilazep and the corresponding analysis were repeated; in the serum of these patients the concentration of glycoside was determined by radioimmuno assay. The following results were obtained. 1. Differences in serum concentrations and renal excretion rates of dilazep and metabolites were not observed after application of the mono- and combination product. In comparison to results after oral application of pure dilazep in gelatin capsules the serum concentrations 1 h after application of Cormelian and Cormelian-Digotab were statistically significantly higher. With reference to comparable total absorption rates these results may be representative for a possibly retarded absorption rate of dilazep given as pure substance. An influence of the different galenic techniques on the intensity and direction of metabolites could not be substantiated. 2. By large dispersions of the single values high absolute and relative concentrations of beta-acetyl-digoxin were found in the serum of all the 4 patients after application of combination. Contrary to two commercial products, applied to each of 10 test persons under comparable conditions, statistically higher serum concentrations of glycoside were analysed 1 h after application of the combination. The results of these studies confirm a positive influence of the galenics on the biological availability of both the components in the combination drug Cormelian-Digotab.

Azepines↗
PubMed1989

Central nervous system effects and behavioral interactions with ethanol of centrally administered dilazep and its metabolites in mice.

Dilazep (i.p.), a coronary vasodilator and an uptake inhibitor of adenosine, dose dependently potentiated acute ethanol-induced motor incoordination in mice. In view of peripheral cardiovascular depressive effects of dilazep, the effect of i.c.v. dilazep (25, 50 and 75 micrograms), and its metabolites, 1,4-bis(3-hydroxypropyl)perhydro-1,4-diazepine (BHPD) (15, 31 and 62 micrograms) and 1-[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1,4-diazepine (TBPD) (62 and 125 micrograms) on ethanol-induced motor incoordination was studied. Dose-related potentiation of ethanol-induced motor incoordination was noted with dilazep and its metabolites. Whereas dilazep (i.p.) produced no apparent central nervous system (CNS) effects, by i.c.v. route, it caused CNS excitation including tonic-clonic seizures. Adenosine uptake inhibition, Ca2+ entry blockade or direct activation of adenosine receptors was ruled out as the possible mechanism of seizures because dipyridamole, verapamil or N6-(2-phenylisopropyl)-adenosine (R-PIA) administered i.c.v., while potentiating ethanol (i.p.)-induced motor incoordination did not produce seizures. The CNS excitation was minimal with BHPD and none with TBPD. Theophylline pretreatment partially blocked potentiation of ethanol-induced motor incoordination by dilazep and BHPD and not by TBPD. The data suggest dilazep-induced potentiation of ethanol-induced motor incoordination is partially due to central adenosine receptor mechanism and partly due to other yet unknown mechanism(s) and further supported our earlier reports about adenosine involvement in the CNS effects of ethanol. The data also suggest that dilazep (i.c.v.)-induced seizures are due to mechanism(s) other than adenosine uptake inhibition, Ca2+ entry blockade or direct adenosine receptor activation.

Animals↗
PubMed1984

Interaction between dilazep and alpha-adrenoceptors.

Dilazep, 1,4-bis-[3-(3,4,5-trimethoxybenzoyl-oxy)propyl]perhydro-1,4-diazep ine, is a novel antianginal agent with an unusual chemical structure. The drug is a weak calcium antagonist. In pithed rats dilazep (10-100 mg/kg i.v.) caused a transient hypotensive effect which was accompanied by a strong and persistent reduction in heart rate. Similarly as observed for other, more potent calcium antagonists dilazep (10-100 mg/kg) counteracted the vasoconstriction, evoked by the stimulation of postsynaptic alpha 2-adrenoceptors with the selective agonist B-HT 920. The antagonism proved noncompetitive. The vasoconstriction, induced upon selective stimulation of postsynaptic alpha 1-adrenoceptors with methoxamine, however, was hardly influenced by dilazep. These findings are in accordance with the calcium-antagonistic activity of dilazep, demonstrable at relatively high doses. From radioligand-binding studies it was concluded that dilazep is an extremely weak antagonist of alpha 1-adrenoceptors, whereas it does not possess any measurable affinity towards alpha 2-adrenoceptors. It seems unlikely that the antianginal activity of dilazep can be fully explained by its weak calcium-antagonistic potency. However, the bradycardic effect of dilazep is probably relevant to its antianginal activity.

Adrenergic alpha-Agonists↗
PubMed1992

Inhibitory action of dilazep on histamine-stimulated cytosolic Ca2+ increase in cultured human endothelial cells.

Using a fluorescent Ca(2+)-sensitive dye, fura-2, and photometric fluorescence microscopy, we measured changes in cytosolic Ca2+ concentration ([Ca2+]i) in cultured human endothelial cells and studied the effect of dilazep on [Ca2+]i elevation induced by histamine. Histamine (1 microM) caused a rapid transient peak in the average [Ca2+]i of a group of cells (approximately 10(2) cells), followed by a decrease to a sustained elevation. Dilazep as well as diltiazem (1.0 to 100 microM) concentration-dependently inhibited the latter sustained elevation, which was eliminated by removal of extracellular Ca2+, while the initial transient response was not changed by dilazep at concentrations up to 100 microM. The IC50 values of dilazep and diltiazem were 16 and 58 microM, respectively. The patterns of the [Ca2+]i elevation responses to histamine were variable among individual cells. Some single cells showed a transient peak and a sustained elevation as observed in a group of cells. Some single cells caused a repetitive spikelike elevation of [Ca2+]i. Dilazep lowered the sustained elevation to the resting level and in some single cells, changed the sustained elevation to the spikelike elevation. The frequency of the spikelike [Ca2+]i elevation was also decreased by dilazep. Decrease in extracellular [Ca2+] showed the same pattern of inhibitory actions as dilazep did. These results indicate that dilazep inhibits the extracellular Ca2+ influx in endothelial cells.

Calcium↗
PubMed1993

The effect of dilazep on urinary protein excretion in spontaneous diabetic Chinese hamster.

The effect of dilazep, an adenosine potentiator and platelet aggregation inhibitor, on experimental diabetic nephropathy was investigated in spontaneous diabetic Chinese hamster. Prediabetic animals, 8 weeks of age, were divided into two groups. In one group, 5 mg/kg dilazep was injected i.p. once a day. In the other group, saline of the same amount was injected. Age- and sex-matched animals from a nondiabetic subline were used as controls. No difference was observed in body weight, mean blood pressure, fasting plasma glucose and glycated hemoglobin level between diabetic animals with and without dilazep administration throughout the entire period of experiment. Urinary protein excretions in untreated diabetic animals increased significantly compared to those of nondiabetic controls at 8 weeks (17.5 +/- 3.5 vs 2.0 +/- 0.1 mg/day), and at 24 weeks (25.3 +/- 5.1 vs 2.7 +/- 0.1 mg/day) of experiment. In diabetic animals with dilazep treatment, urinary protein excretions (4.1 +/- 0.7 at 8 weeks and 13.1 +/- 2.9 mg/day at 24 weeks of experiment) were significantly suppressed compared to those in untreated diabetic animals. Significant thickening of glomerular basement membrane (GBM) was observed in diabetic animals both with and without dilazep administration at 24 weeks of experiment compared to that in nondiabetic controls. The number of anionic sites in GBM, stained by polyethyleneimine, was reduced in untreated diabetic animals, but was not different in dilazep treated animals compared to that in nondiabetic controls. It was concluded that dilazep administration suppressed urinary protein excretion in diabetic Chinese hamster possibly through the preservation of charge barrier of the glomerulus.

Animals↗
PubMed1981

Effect of dilazep on myocardial contractility following acute ischemia and reperfusion in isolated blood-perfused canine left ventricular muscle.

Myocardial protection by dilazep HCl, an antianginal drug and a potent calcium antagonist, against myocardial damage following acute ischemia and reperfusion was studied with respect to myocardial contractility in isolated blood-perfused canine left ventricular muscle. Myocardial function was expressed by percent recovery rate of maximal net developed tension. 1) The coronary infusion of dilazep revealed significant myocardial protection during normothermic ischemic arrest of 45 min and reperfusion. 2) The intravenous administration of dilazep to the support dog and Young's infusion also showed significant myocardial protection during normothermic ischemic arrest of 45 min and reperfusion. Dilazep showed no persistent depression of myocardial contractility due to its calcium antagonistic effect during reperfusion. 3) The combination of intravenous administration of dilazep to the support dog, Young's infusion, and hypothermia showed significant myocardial protection during prolonged ischemia and reperfusion even in hypertrophied ventricle. These results demonstrate that dilazep provides effective myocardial protection during ischemic arrest and reperfusion by preventing abnormal calcium accumulation in myocardial cells during reperfusion. No persistent depression of myocardial contractility during reperfusion may support dilazep's clinical application as a myocardial protective agent in open-heart surgery.

Animals↗
PubMed1989

Effects of dilazep on cytoplasmic calcium ion concentrations and arachidonic acid metabolism in activated human platelets.

The effects of dilazep (tetrahydro-1H-1,4-diazepine-1,4(5H)-dipropanol bis(3,4,5-trimethoxybenzoate)-di-hydrochloride monohydrate, Comelian), a coronary and cerebral vasodilator and an antiplatelet drug, on the cytoplasmic Ca2+ concentration ([Ca2+]i) and arachidonic acid (AA) metabolism in activated human platelets were investigated. [Ca2+]i (free calcium ion concentration) of aequorin-loaded platelets was estimated by using the platelet ionized calcium aggregometer. AA metabolism was studied by the determination of AA metabolites, hydroxyheptadecatrienoic acid and 12-hydroxyeicosatetraenoic acid, using reversed-phase high performance liquid chromatography. When platelets were preincubated with dilazep (0-0.5 mmol/l), the drug inhibited both platelet aggregation and [Ca2+]i elevation induced by thrombin, AA and collagen in a concentration dependent manner, while only aggregation was inhibited after stimulation with the Ca ionophore A23187 (calcimycin). Both influx and release of Ca2+ into platelet cytoplasm induced by thrombin or AA were inhibited by dilazep, while neither of them was affected when induced by A23187. Oral ingestion of dilazep as a 100-mg capsule significantly depressed the [Ca2+]i elevation induced by thrombin, AA and collagen after 3 h. Dilazep inhibited endogenous AA metabolism by platelets induced by thrombin, although it enhanced exogenous one. Thus, dilazep inhibited platelet aggregation induced by any agonists including A23187, while [Ca2+]i elevation was inhibited by the drug only when the receptor-mediated agonist was used. Furthermore, it is suggested that dilazep inhibited AA liberation from platelet membrane phospholipids, leading to reduced production of all endogenous AA metabolites after platelet activation although metabolites of exogenous AA could be increased.

Adult↗
PubMed1987

The effect of dilazep on puromycin-induced rat renal mitochondrial dysfunction.

The effect of tetrahydro-1 H-1,4 (5H)-dipropanol bis(3,4,5-trimethoxybenzoate)hydrochloride monohydrate (dilazep, Comelian) on puromycin-induced rat renal damage was investigated. In vivo study: Rats were divided into 3 groups, the control group; untreated, the puromycin group; puromycin (150 mg/kg) was injected intraperitoneally once, the dilazep + puromycin group; puromycin (150 mg/kg) was injected 1 h after intraperitoneal dilazep injection (2 mg/kg), and dilazep (2 mg/kg) was injected every 12 h until the end of the experiment. In each group, 84 h after puromycin injection, kidneys were isolated and renal mitochondria were prepared. The endogenous phospholipase activity in kidney homogenate was determined by high performance liquid chromatography. The activities of three segments (NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome c oxidase) of the electron-transport chain in mitochondria were measured enzymatically. In the puromycin group, phospholipase activity was increased and activities of all of three segments of the electron-transport chain were decreased. In the dilazep + puromycin group, premedication with dilazep prevented activation of phospholipase and maintained mitochondrial electron-transport activity. In vitro study: Mitochondria prepared from intact rat kidney were incubated with phospholipase C. Activities of the mitochondrial electron-transport chain were deteriorated by phospholipase C. These results indicated that activation of endogenous phospholipase, which digests membrane phospholipids, essential components in maintaining mitochondrial electron-transport activity, is responsible for the puromycin-induced renal damage. Premedication with dilazep prevented the damage by inhibition of the activation of phospholipase.

Animals↗