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PubMed1995

Effects of trapidil and suramin on growth factor-induced calcium response and tyrosine phosphorylation in human glioma cells.

Platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) induce the proliferation of glioma cells in vitro. Trapidil and suramin inhibit this growth factor-stimulated glioma cell growth, but the mechanisms are not fully understood. The effects of trapidil and suramin on PDGF- and EGF-induced early biochemical events in T98G cells were studied. PDGF induced a rapid increase of intracellular free calcium concentration ([Ca2+]i) in fura-2/acetoxymethyl ester-loaded single glioma (T98G) cells. This increase was completely inhibited by removal of extracellular Ca2+ with ethylene glycol bis(beta-aminoethyl ether)-N,N,N,N-tetraacetic acid but not by an L-type calcium channel blocker (nicardipine), suggesting that PDGF may cause calcium influx through voltage-independent calcium channels in T98G cells. Trapidil and suramin blocked the PDGF-induced calcium response and inhibited the PDGF-initiated tyrosine phosphorylation of the PDGF receptor as detected by Western blot analysis using an antibody specific for phosphotyrosine. Trapidil and suramin also inhibited EGF-initiated calcium response in T98G cells, but only partially inhibited EGF-initiated tyrosine phosphorylation at the same concentrations. Our results suggest that trapidil and suramin inhibit PDGF- and EGF-initiated early biochemical events, and thus suppress growth factor-induced cell proliferation.

Antineoplastic Agents↗
PubMed1990

[Effects of lung volume levels and trapidil on transdiaphragmatic pressure in young healthy subjects].

Effects of lung volume levels, and effect of intravenous administration of Trapidil on the maximal force developed by the diaphragm were investigated by the measurement of transdiaphragmatic pressure (Pdi) in 10 healthy young subjects. To evaluate transdiaphragmatic pressure, delta Pdimax was used. delta Pdimax was calculated by the subtraction of the transdiaphragmatic pressure at FRC (Pdi FRC) from the maximal transdiaphragmatic pressure (Pdimax) at each lung-volume level. Regardless of the administration of Trapidil, delta Pdimax was highest at FRC in each subject. When Trapidil was administered, Pdimax increased in cases where absolute Pdimax FRC was initially low. The relation between changes of delta Pdimax at FRC after Trapidil administration and delta Pdimax showed significant linear correlation (r = -0.85, p less than 0.002). These results suggest that FRC is the most adequate lung volume level to produce an effective transdiaphragmatic pressure, and that Trapidil increases the muscle force of the diaphragm in cases where the force is initially low in young healthy subjects.

Adult↗
PubMed1987

[The effectiveness of trapidil and some derivatives on heart function under in vitro and in vivo conditions].

Cardiac and coronary effects of trapidil (Rocornal) and some derivatives were investigated in isolated heart preparations and rabbit hearts in vivo. All substances showed a comparable increase of the coronary flow. Contrary to the cardiotonic influence of trapidil the trapidil derivates induced a negative inotropic effect, possibly due to a weak calcium antagonism. Heart rate was slightly diminished, but in some cases higher doses caused an acute tachycardia. I.v. application of the substances to rabbits in doses of 10 mg/kg and 30 mg/kg induced an initial depression of blood pressure normalizing within 3-5 min. An increase of the myocardial prostacyclin biosynthesis is only demonstrable under trapidil. The results indicate that the cardiac effects of trapidil derivatives are possibly caused by a direct influence on the contractile system and the membrane potential of the cardiac muscle cell.

Anesthesia↗
PubMed1986

Effects of trapidil on diltiazem-induced changes of mechanical and electrical properties in isolated rabbit myocardium.

Effects of trapidil on diltiazem-induced changes of myocardial properties were investigated mechanically and electrophysiologically in tissues isolated from rabbit hearts. Application of diltiazem (10(-6) M) on right atria significantly decreased both force development and contraction rate. Additional administration of trapidil (10(-4) M) in the presence of diltiazem significantly restored the magnitude of force development without changes in contraction rate. Electrical stimulation to left atria and papillary muscles with varying frequencies produced a frequency-dependent increase in force developments (Bowditch's staircase). Diltiazem (10(-6) M) caused a depression of contractile force hence inhibited the staircase upon increasing frequency of stimulations. Additional application of trapidil (10(-4) M) partially but significantly restored the staircase. Intracellular recordings with microelectrodes clarified that trapidil increased the amplitude of slow responses which was being depressed by the treatment of diltiazem. Our findings suggest that trapidil, when applied successively to diltiazem, may diminish the inhibitory effects of diltiazem on hearts.

Animals↗
PubMed1986

Electrophysiological effect of trapidil on rabbit sinoatrial node cells.

Effects of trapidil on the membrane potentials and currents of rabbit sinoatrial node cells were investigated by means of conventional microelectrode and double microelectrode voltage clamp methods. Trapidil (1 X 10(-4) M) increased the spontaneous firing frequency, the maximum rate of rise, action potential amplitude and the slope of the pacemaker depolarization. Action potential duration was shortened by the drug application. Voltage clamp experiments showed that trapidil increased both the slow inward current (isi) and the potassium outward current (iK). Trapidil fastened the recovery time constant of isi, while the drug did not change the time course of the outward current tail. The hyperpolarization-activated current (ih) was also increased by the drug. The results obtained indicate that at relatively high concentration trapidil produces a positive chronotropic effect on the sinoatrial node cells by mediating an increase in isi, iK and ih.

Animals↗
PubMedDate not supplied

[Inhibition of thrombocyte spreading and the formation of thrombus-like aggregates bound with substrate by the anti-anginal agent trapidil].

Effects of trapidil (rocornal) on interaction of human thrombocytes, purified by gel filtration, and the surface covered with fibrillar collagen from calf skin (CCS) were studied using scanning electron microscopy. When the soluble inductors were absent, trapidil did not affect the thrombocyte adhesion. At the same time, trapidil inhibited the shape alterations of laminated thrombocytes, induced by CCS-substrate with simultaneous increase in the ratio of disc-shaped cells and a decrease in laminated thrombocytes. Soluble inductors of the thrombocyte activity (arachidonic acid, stable derivative of prostaglandin endoperoxides U46619 and thrombin) stimulated the cells mass-scale lamination as well as formation of thrombus-like aggregates bound with CCS-substrate. Trapidil prevented completely the effects of exogenous arachidonic acid and of U46619 on interaction of thrombocytes and the substrate but inhibited only by 40-50% the synthesis of thromboxane A2 in the cells induced by arachidonic acid. The drug blocked also an aggregation of thrombocytes in suspension, lamination and formation of aggregates bound with the surface, induced by low but not by high concentrations of thrombin. Possible use of trapidil is discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1983

Suppression of fibroblast proliferation in vitro and of myointimal hyperplasia in vivo by the triazolopyrimidine, Trapidil.

Platelet derived growth factor (PDGF) is a mitogen capable of stimulating the proliferation of both vascular smooth muscle cells (SMC) and fibroblasts in tissue culture. Recently, it was reported that this in vitro stimulatory effect is significantly reduced by Trapidil, a triazolopyrimidine. We confirm this, and also that similar inhibition occurs in vivo, in balloon catheter deendothelialized aorta of male, Sprague-Dawley rats treated with Trapidil. Two groups of rats, of 8 animals each, were treated daily with oral doses of either 45 mg or 90 mg Trapidil. A third group of 9 control animals were treated identically, but received only the diluent used to dissolve the drug. ADP or collagen-induced platelet aggregation, and endothelial cell regrowth were unaffected by Trapidil administration, but the degree of myointimal hyperplasia was significantly reduced in all animals receiving the drug. Thus, Trapidil seems to possess the selective ability to alter the SMC proliferative response which normally follows deendothelialization.

Animals↗
PubMed1983

Possible antiarrhythmic activities of trapidil.

Possible antiarrhythmic activities of 5-methyl-7-diethylamino-s-triazolo(1,5-a)pyrimidine (trapidil, Rocornal) were investigated in vitro and in vivo. Trapidil significantly increased the amount of aconitine or ouabain needed for production of ventricular arrhythmias in rats and guinea pigs. Trapidil also produced a significant increase in threshold current of electrical stimuli which induced ventricular tachycardia in dogs under acute myocardial ischemia. Electrophysiological examinations on effects of trapidil on isolated rabbit ventricular muscle cells showed shortening of the action potential duration (APD) and prolongation of the effective refractory period (ERP), resulting in an increase in the ratio of ERP/APD. The results indicate that trapidil will have a possible effectiveness in inhibiting ventricular arrhythmias.

Aconitine↗
PubMed1982

Relaxant effect of trapidil on isolated dog bronchus.

Relaxant effects of trapidil on dog bronchi were pharmacologically analyzed in vitro. Trapidil concentration-dependently relaxed bronchial strips contracted with methacholine, histamine or potassium. In the strips under methacholine-contracture, theophylline, papaverine, isoproterenol and atropine produced concentration-dependent relaxations. Propranolol significantly decreased isoproterenol-induced relaxations of bronchial strips under methacholine-contracture, but did not trapidil-induced relaxations. Prostaglandin (PG) E1 and PGE2 in high doses slightly relaxed bronchial strips under methacholine-contracture, but PGI2 hardly affected them. Tranylcypromine did not influence relaxant responses of the strips to trapidil. The results indicate that trapidil produces relaxations of bronchial smooth muscle through a non-specific action other than adrenergic beta-receptor activation or endogenous prostaglandin biosynthesis.

Animals↗
PubMed1980

Analysis of relaxant effects of trapidil in isolated dog coronary artery.

Effects of 7-diethylamino-5-methyl-s-triazolo [1,5-a]pyrimidine (trapidil, Rocornal) on dog coronary arteries were investigated in vitro. Trapidil produced dose-dependent relaxations of isolated arteries which were contracted with potassium or prostaglandins F2 alpha. These effects of trapidil were not affected by atropine and propranolol. 5-Hydroxytryptamine (5-HT) and phenylephrine dose-dependently increased the tension of isolated coronary arteries. Trapidil could inhibit these effects of 5-HT or phenylephrine. The results indicate that trapidil has not a muscarinic action and an adrenergic beta-receptor stimulating action, but it has a 5-HT receptor and an adrenergic alpha-receptor blocking action.

Acetylcholine↗
PubMed1981

Effect of trapidil on mechanical and electrical activity of isolated rabbit atrium.

Actions of trapidil on mechanical and electrical activities of rabbit right atria were investigated in vitro. Isolated atria had spontaneous contractions. Ca++ (2.7-4.5 mM) concentration-dependently increased force and frequency of atrial contractions, and trapidil (10(-5)-10(-4) g/ml) also did. Trapidil (10(-5)-10(-4) g/ml) showed a tendency to augment the positive inotropic action of Ca++ and significantly enhanced the positive chronotropic action of Ca++. In experiments using conventional microelectrode techniques, trapidil (10(-5)-10(-4) g/ml) concentration-dependently increased the slope of slow diastolic depolarization, the maximal diastolic potentials and the peak potentials in pacemaker potentials of sinoatrial nodal cells, and shortened the cycle length of them. The results indicate pharmacodynamically and electrophysiologically that trapidil produces a positive inotropic and chronotropic effect on isolated rabbit right atria.

Animals↗
PubMed1993

[Trapidil after one year].

Present knowledge about cerebral limb ischemia has pointed out the importance of a versatile pharmacological approach, which considers not only the hydraulic aspect of the problem through a vasodilating action, but also all the hemorheologic and hemocoagulative implications, which seem to characterize the pathology itself. For about one year Trapidil has been entering the therapeutic treatments for arterio-vascular diseases in Italy; this drug was already known and tested abroad. Trapidil has shown a more complete antithrombocytic activity than other antiaggregating drugs; as a matter of fact it inhibits the formation of TXA2 through a mechanism of receptorial antagonism and at the same time it favours an increase of prostacyclina from the arterial walls. Moreover this drug is provided with a selective inhibition of the mitogenic effects of PDGF, which occurs for the block of the receptorial binding of this factor at the level of the myointimal cells. In conclusion, in some experimental models Trapidil seems to be able to improve the hemoreologic properties of the blood. Some different clinical studies have demonstrated the therapeutic effectiveness of Trapidil. In the treating of claudication and of the pain during the rest in AOCP, we want to report two studies which have shown a general improving either of the free interval of run or a reduction of the pain. In particular the polycentric study of Bonavita has examined 200 patients afflicted with AOCP at II and III stage, who were divided into three treatment groups: Trapidil, ticlopidina and picotamide.

Anticoagulants↗
PubMed1997

The effects of the growth factor-antagonist, trapidil, on remyelination in the CNS.

In this study we describe the effects of trapidil, a putative platelet-derived growth factor-antagonist, on spontaneously occurring remyelination in rat spinal cord. Demyelination was created in the dorsal funiculus of 6- and 11-week-old female rats by the direct injection of 1.0 microliter of 1% lysolecithin. The animals received daily intra-peritoneal injections of either trapidil or saline for 21 days, commencing on the day of lesion induction. The 11-week-old rats receiving trapidil (60 mg/kg) showed a significant decrease in the extent of oligodendrocyte remyelination. Moreover, those axons that were remyelinated by oligodendrocytes tended to have thinner myelin sheaths than axons remyelinated by oligodendrocytes in the control group. In the 6-week-old group, the dose of trapidil which inhibited oligodendrocyte remyelination in the 11-week-old animals had a minimal effect on the extent of oligodendrocyte remyelination and no effect on the quality of myelin sheath formation. A higher dose of trapidil (80 mg/kg) was required before significant impairment of oligodendrocyte remyelination was achieved in the younger age group, implying an age-dependent effect of growth factor-inhibition of CNS remyelination. These results indicate an important role for growth factors, and in particular PDGF, in the orchestration of oligodendrocyte remyelination in the rodent CNS.

Animals↗
PubMed1998

The effect of trapidil on the reactive astrocytic proliferation following spinal cord trauma in rats: light and electron microscopic findings.

Platelet-derived growth factor (PDGF) released from platelets is one of the mitogens in serum, which plays a major role upon the cell biology, namely enhancing cell division and controlling of the maturation, especially upon the glial cell growth and its differentiation. Trapidil, which is an anti-PDGF agent, inhibits the effect of PDGF, especially the proliferative effects on the glial and tumoral cells in vitro. Previous studies suggested that the astrocytic proliferation stimulated by PDGF was inhibited by trapidil via the selective antagonism. Trapidil was not found to have a considerable effect on the prevention of nonpermissive astrocytes in this study. It should be theorized that trapidil, administered immediately even after the trauma, could not reach the injury site in effective measure because of secondary events such as edema and impairment of blood circulation. This suggestion should be another subject for studies concerning trapidil which is administered prior to the trauma.

Animals↗
PubMed1997

Results of a Meta-Analysis of Trapidil, a PDGF Inhibitor Ñ A Sufficient Reason for a Second Look to the Pharmacological Approach to Restenosis.

Restenosis in 30%Ð40% of patients remains the major limitation to the long-term success of balloon angioplasty (PTCA) in patients with coronary artery disease. So far, only coronary stent implantation has established its role as an effective strategy to prevent restenosis after PTCA. In contrast to numerous pharmacological strategies that all have failed to demonstrate a convincing reduction in the rate of restenosis, trapidil, a PDGF inhibitor, has shown promising and conclusive results in animal models as well as in three human trials published between 1992 and 1994. Although the results of the human trials showed trapidil to be capable of reducing restenosis after PTCA by 40%Ð53% compared to control patients, the compound is not well known and little used in interventional cardiology. Possible explanations for this situation may include trapidilÕs non-availability in the United States and most European countries, the small number of trapidil trials and treated patients, as well as a probable perception of the medical community that a pharmacological approach to restenosis prevention is unlikely to work. Additionally, clinical expert behavior has often shown not to be synchronized with accumulating evidence of efficacy. The results of this meta-analysis, however, demonstrate trapidilÕs efficacy. The rate of per-patient restenosis in the trapidil group was more than halved as compared to controls (odds ratio 0.44, 95% confidence interval 0.29Ð0.66). Tolerability with trapidil was good, and the rare adverse events observed included gastric intolerance, thrombocytopenia, headache, and increased serum AST and ALT levels which were transient or subsided with cessation of treatment.

Journal Article↗
PubMed1999

A randomized comparison of trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, versus aspirin in prevention of angiographic restenosis after coronary artery Palmaz-Schatz stent implantation.

The aim of the study is to assess the safety of trapidil in the setting of coronary stenting and to evaluate its efficacy in reducing angiographic in-stent restenosis. One hundred eighteen patients undergoing Palmaz-Schatz stent implantation were randomly assigned to receive antiplatelet therapy using either aspirin (325 mg/d) or trapidil (400 mg/d), in combination with ticlopidine (500 mg) for the first month. At entry, both groups were comparable with regard to clinical, angiographic, and procedural characteristics. At 6-month angiographic follow-up, >50% restenosis occurred in 15 of 52 lesions (28.8%) of the aspirin group and in 14 of 47 lesions (29.8%) of the trapidil group (P=not significant, NS). At 6-month clinical follow-up, there was no difference in the two groups in the rate of adverse events (2.0% vs. 2.1%, P=NS), medication side effects (4.0% vs. 4.2%, P=NS), and peripheral vascular complications (4.0% vs. 4.2%, P=NS). In conclusion, treatment with trapidil seems to be associated with a similar incidence of stent restenosis and adverse cardiac events as compared to aspirin and could be a valuable alternative to aspirin in the setting of coronary stenting.

Aged↗
PubMed1984

Decrease of platelet aggregation and spreading via inhibition of the cAMP phosphodiesterase by trapidil.

Trapidil (N,N-diethyl-5-methyl[1,2,4]triazolo[1,5-alpha]pyrimidine-7-amine ) inhibits platelet spreading and aggregation induced by arachidonic acid (AA), a stable analogue of prostaglandin (PG) endoperoxides (U46619), ADP, and low concentrations of thrombin, but not by A23187 and high concentrations of thrombin. Trapidil does not affect platelet adenylate cyclase but inhibits the cAMP PDE by approx. 50%. PDE inhibition proceeds via a competitive mechanism (Ki = 0.52 mM) and is not mediated by calmodulin inhibition. Trapidil does not change the platelet basal cAMP level but potentiates an increase of cAMP induced by the stable prostacyclin analogue (6 beta-PGI1). These results suggest that trapidil antiplatelet effects may be due to the inhibition of platelet PDE.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Effect of the combination of antiplatelet agents in man: combination of aspirin, trapidil, ticlopidine and dipyridamole.

An in vitro study of how platelet aggregation would be inhibited by the combination of aspirin or ticlopidine irreversibly inhibitory to platelet aggregation and trapidil or dipyridamole reversibly inhibitory, was carried out. The measured 50% inhibition concentrations indicated that aspirin was most inhibitory to collagen-induced platelet aggregation, followed by trapidil, ticlopidine and dipyridamole in decreasing sequence of inhibition. The combination of either aspirin or ticlopidine with trapidil inhibited platelet aggregation more intensely than the combination of either agent with dipyridamole. Thus, in clinical use of aspirin or ticlopidine, it may be expected that the lower dosage of aspirin or ticlopidine with lower frequencies of side effects inhibits platelet aggregation effectively with the combination of trapidil rather than dipyridamole.

Aspirin↗