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PubMed1983

The effects of ATP-MgCl2 and dipyridamole in cold-storage preservation.

The effects of ATP-MgCl2 and dipyridamole were evaluated in a canine model. Twenty-five adult mongrel dogs were divided into five equal groups. All dogs underwent left nephrectomy and 30 min of warm ischemia followed by Collins' C-4 flush and 24 hr of cold-storage preservation. Heterotopic autotransplantation and immediate contralateral nephrectomy were then performed. Group A served as controls; Group B was pretreated with intravenous ATP-MgCl2 (2.5 mM); Group C with intravenous dipyridamole (10 mg), and Group D with both ATP-MgCl2 (2.5 mM) and dipyridamole (10 mg). Group E was treated with ATP-MgCl2 (2.5 mM) at the time of transplantation. All kidneys underwent cortical biopsies at the end of preservation and 1 hr after restoration of blood flow for determinations of AMP, ADP, and ATP. In Groups A and E there were no survivors, whereas Groups B, C, and D had 40, 60, and 40% graft survival. In Groups B and D, ATP and energy charge (EC) were greater than that of controls after 24 hr of preservation, with Group D values being significantly greater (P less than 0.01). AMP and ADP levels were significantly greater (P less than 0.02) in Group C when compared to Group A. One hour posttransplantation biopsies demonstrated greater ability to regenerate cortical nucleotides in the surviving animals, but no absolute value could be identified as a predictor of viability. In conclusion, pretreatment with ATP-MgCl2 or dipyridamole maintains intracellular nucleotide levels and has a beneficial effect on graft survival in ischemically injured kidneys undergoing cold-storage preservation.

Adenine Nucleotides↗
PubMed1991

Hypolipidemic activity of dipyridamole: effects on the main regulatory enzyme of cholesterogenesis.

The in vivo dipyridamole treatment for 16 days produced a significant decrease in chick plasma cholesterol, mainly due to the esterified form. This effect was especially patent in the VLDL + LDL fraction. Similar results were observed in triglyceride content. To our knowledge, this is the first report on this hypolipidemic effects of dipyridamole. Total and esterified cholesterol increased after the same treatment in chick liver, while brain cholesterol content was not affected. Hepatic 3-hydroxy-3- methylglutaryl-CoA reductase activity was drastically reduced, while other secondary regulatory enzymes such as mevalonate kinase, mevalonate 5-phosphate kinase and mevalonate 5-pyrophosphate decarboxylase did not change significantly. No significant differences were found in cholesterol and lipidic phosphorus from liver microsomes, so that the effect of dipyridamole on reductase activity cannot be due to modifications in cholesterol/lipidic phosphorus molar ratio. Neither of these enzyme activities was affected in vitro by dipyridamole.

Animals↗
PubMed1983

Effect of dipyridamole on experimental disseminated intravascular coagulation in rats.

Experimental disseminated intravascular coagulation (DIC) can be induced by 4-h sustained infusion of endotoxin in a dose of 100 mg/kg in rats. The experimental model of DIC in rats was used to study the preventive effect of dipyridamole against DIC. Before the infusion of endotoxin, 0.5, 5.0 or 50.0 mg/kg of dipyridamole was injected intraperitoneally. The preventive effect against DIC was noted in all the parameters, such as fibrinogen and fibrin degradation products, fibrinogen level, prothrombin time, partial thromboplastin time, platelet count, and the number of renal glomeruli with fibrin thrombi, in rats treated with 5.0 or 50.0 mg/kg of dipyridamole. From these results, it was shown that dipyridamole inhibited the aggravation of endotoxin-induced experimental DIC in rats.

Animals↗
PubMed1983

Mechanism of action of dipyridamole.

Dipyridamole appears to act in vivo by synergistically modifying several biochemical pathways, including: a) inhibition of platelet cAMP-phosphodiesterase; b) potentiation of adenosine inhibition of platelet function by blocking reuptake by vascular and blood cells, and subsequent degradation of adenosine; and possibly, c) potentiation of PGI2 antiaggregatory activity and enhancement of PGI2 biosynthesis. These independent processes inhibit platelet function by increasing platelet cAMP through both a reduction in enzymatic cAMP-degradation, and stimulation of cAMP formation via activation of adenylcyclase by adenosine and possibly PGI2. Only the inhibition of cAMP phosphodiesterase appears to be involved in the dipyridamole inhibition of isolated platelets in vitro, since adenosine and PGI2 originate in vivo from tissues other than platelets and any blood concentrations existing in vivo will disappear before platelet-rich plasma has been prepared for in vitro platelet studies. The antithrombotic effects of dipyridamole in a baboon model of arterial thromboembolism are unaffected by simultaneous administration of dazoxiben, a specific thromboxane synthetase inhibitor, but are optimally potentiated by the simultaneous addition of aspirin in doses of 20 mg/kg/day. Since this dose of aspirin has no detectable antithrombotic effects when used alone, but blocks vascular PGI2 synthesis, the antithrombotic effects of dipyridamole, at least in this model, appear to be independent of prostacyclin.

Adenosine↗
PubMed1983

Clinical pharmacokinetics of dipyridamole.

The pharmacokinetics off dipyridamole were studied in six normal subjects and 20 patients. The normal subjects received 20 mg IV each and five also took a 50 mg oral dose. Concentrations after the intravenous dose showed a tri-exponential decline with a terminal half-life of 11.6 +/- 2.2 hr (mean +/- S.D.). Total plasma clearance was 138 +/- 30 ml/min and the apparent volume of distribution was 141 +/- 51 l. Peak concentrations after oral dipyridamole occurred 2--2.5 hr after the dose. Systemic availability of the oral dose was 52 +/- 23%. Plasma protein binding was 99.13 +/- 0.24%. Twenty patients, admitted for coronary artery bypass grafting, received total daily doses of 150 mg, either as 50 mg tid or 75 mg bid. Based on drug cumulation during chronic dosing, the terminal half-life averaged about half a day. There was wide interpatient variability, averaging about 10-fold, in observed plasma concentrations for both dosage regimens. The bid regimen was not associated with lower trough concentrations of the drug than the tid regimen. These results indicate that dipyridamole concentrations vary widely in patients receiving the drug, and suggest that it could be administered twice a day, and that dipyridamole levels should be monitored for the antithrombotic effect in clinical studies.

Administration, Oral↗
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↗
PubMed1990

Relationship between vessel wall 13-HODE synthesis and vessel wall thrombogenicity following injury: influence of salicylate and dipyridamole treatment.

We performed studies to determine the relationship between injured vessel wall thrombogenicity, vessel wall 13-hydroxyoctadecadienoic acid (13-HODE) synthesis and cAMP levels in rabbit treated with salicylate or dipyridamole. Injured vessel wall thrombogenicity was measured as the number of 3H-adenine labelled platelets adhered to the subendothelial basement membrane exposed by air injury in carotid arteries of rabbits treated orally with salicylate or dipyridamole. Vessel wall 13-HODE was measured by HPLC and vessel wall cAMP was measured by RIA. Vessel wall thrombogenicity was increased two-fold in rabbits treated with salicylate and decreased by half in rabbits treated with dipyridamole. The levels of vessel wall cAMP levels were correlated both with the plasma dipyridamole levels and increases in 13-HODE synthesis. cAMP levels were unaffected by salicylate treatment, but 13-HODE synthesis was decreased. We conclude that there is a significant relationship between vessel wall cAMP levels and 13-HODE synthesis, which in turn, influences subsequent vessel wall thrombogenicity.

Animals↗
PubMed1990

Dipyridamole inhibits O2- release and expression of tissue factor activity by peripheral blood monocytes stimulated with lipopolysaccharide.

Monocytes can be induced to synthesize and express tissue factor procoagulant activity. They can also be stimulated to release a broad spectrum of inflammatory agents including superoxide anion (O2-) that are thought to contribute to the pathogenesis of inflammatory diseases. Dipyridamole, an inhibitor of platelet aggregation blocks the lipopolysaccharide (LPS)-induced increase in monocyte-associated tissue factor activity and phorbol myristate acetate (PMA) stimulated O2- release from monocytes and polymorphonuclear leukocytes (PMN). Dipyridamole inhibition of O2- release can be reversed by increased glucose in the culture media, whereas dipyridamole inhibition of tissue factor can not be reversed by increased glucose in the culture media. These results reveal that dipyridamole influences monocytes by at least two distinct mechanisms. Further, it may serve as an anti-thrombotic agent by virtue of its effect on both platelet aggregation and monocyte tissue factor activity.

Biological Transport↗
PubMed1990

Dipyridamole--evaluation of an established antithrombotic drug in view of modern concepts of blood cell-vessel wall interactions.

The effect of dipyridamole on the local antithrombotic activities of endothelium has been evaluated. Human whole blood was allowed to flow over an endothelial cell-derived extracellular matrix partially covered by human endothelial cells. Half-maximal suppression of platelet aggregate formation occurred with approximately 5 microM dipyridamole. Similarly, a pronounced inhibition of thrombus formation was observed by in vivo microscopy and computer-assisted morphometric analysis, after oral treatment of non-anesthetized hamsters with dipyridamole, 5 mg/kg. This strong suppression of thrombus formation was maintained in animals on a long-term cholesterol-supplemented diet. The antithrombotic potential of dipyridamole has been clearly demonstrated, both in vitro and in vivo using these more complex approaches employing quantitative microscopy.

Animals↗
PubMed1990

Dipyridamole specifically decreases platelet-derived growth factor release from platelets.

The authors have previously reported that dipyridamole decreased platelet-derived growth factor levels in human serum by lowering the release of this factor during blood clotting. In the present study, we have shown that this effect is specific to dipyridamole, and does not occur with other antiplatelet drugs such as aspirin, trapidil or ticlopidine. In addition, dipyridamole has been shown to decrease the PDGF level selectively, but not the levels of other factors from alpha granules in platelets (beta-thromboglobulin and platelet factor 4). These data indicate that dipyridamole may be an effective drug for the prevention of PDGF-related disorders.

Blood Platelets↗
PubMed1992

Dipyridamole inhibits platelet aggregation induced by oxygen-derived free radicals.

Pyrogallol (a generator of superoxide anions) caused 50% increase in platelet aggregation induced by 400 microM of arachidonic acid. Dipyridamole did not produce a statistically significant inhibition of arachidonic-acid induced platelet aggregation, but it caused 100% inhibition of pyrogallol-stimulated platelet aggregation. Ferrous salts (Fe2+) induced 34% platelet aggregation which was inhibited (79.6%) by a concentration of dipyridamole of 10 microM. Dipyridamole inhibited ferrous-induced lipid peroxidation with IC-50 values of 17.5 microM. When arachidonic acid was used as aggregating agent, the corresponding IC-50 value was 140.5 microM. These results indicate that dipyridamole prevented platelet activation induced by oxygen-derived free radicals.

Adult↗
PubMed1981

The inactivation of prostaglandin E2 is decreased by dipyridamole and sulfinpyrazone in isolated rat lungs.

The inactivation of prostaglandin E2 (PGE2) was decreased in the pulmonary circulation of isolated rat lungs, when either dipyridamole or sulfinpyrazone was infused into the pulmonary artery at the concentration of 20 microM. After pulmonary injection of 7.1 nmoles of 14C-PGE2 the amount of 15-oxo-metabolites of PGE2 in the effluent was 3.91 +/- 0.19 nmoles from control lungs and 2.05 +/- 0.19 nmoles (2P less than 0.001) in that from 20 microM dipyridamole treated lungs. The corresponding values for control and 20 microM sulfinpyrazone lungs were 4.11 +/- 0.25 and 3.03 +/- 0.14 nmoles (2P less than 0.01), respectively. The amounts of unmetabolized PGE2 were correspondingly increased in the effluents from dipyridamole and sulfinpyrazone (20 microM) lungs. Neither dipyridamole nor sulfinpyrazone had at concentration of 2 microM any significant effect on the amount of 15-oxo-metabolites in the effluent, although the amount of unmetabolized PGE2 was slightly increased in 2 microM sulfinpyrazone experiments.

Animals↗
PubMed1988

Species differences in sensitivity of nucleoside transport in erythrocytes and cultured cells to inhibition by nitrobenzylthioinosine, dipyridamole, dilazep and lidoflazine.

Differences in sensitivity of uridine transport in erythrocytes and cultured cells to inhibition by dipyridamole, dilazep and lidoflazine were largely species-specific; uridine transport in human cells, and probably in pig and rabbit cells, was 2-3- and 10-times more sensitive to inhibition by dipyridamole (IC50 approx. 50 nM) and about 10- and 20-times more sensitive to dilazep inhibition (IC50 approx. 5 nM) than transport in mouse and rat cells, respectively. Uridine transport in human erythrocytes and HeLa cells was strongly inhibited by lidoflazine (IC50 10-140 nM), whereas that in both mouse and rat cells was highly resistant (IC50 greater than 10 microM). Superimposed on species-specific differences were some cell type specific differences in sensitivity of nucleoside transport to these inhibitors. Uridine transport in Walker 256 rat carcinoma cells was more resistant to dipyridamole and dilazep than that of other rat cells. Transport in human Hep-2 cells was more resistant to lidoflazine (IC50 2000 nM) than that of human erythrocytes and HeLa cells, whereas it showed similar sensitivity to dilazep and dipyridamole. Uridine transport in Chinese hamster cells was also more resistant to dilazep than that of baby hamster kidney cells. In addition HeLa cells and clones thereof expressed uridine transporters (about 50% each) with difference of about 1000-fold in sensitivity to inhibition by dilazep (IC50 approx. 5 nM and 5 microM, respectively).

Animals↗
PubMed1989

Electrophysiologic effects of intravenous dipyridamole.

We evaluated the electrophysiologic effects of dipyridamole given intravenously to 24 patients during intracardiac electrophysiologic study. Electrophysiologic parameters were measured before and 5 minutes following infusion of 0.5 mg/kg of dipyridamole. The drug significantly shortened the sinus cycle length by 26 per cent (P less than 0.001), sinuatrial conduction time by 15 per cent (P less than 0.01), maximal sinus node recovery time by 21 per cent (P less than 0.001), atrial and atrioventricular nodal effective refractory period by 8 and by 11 per cent, respectively (both P less than 0.01), ventricular effective refractory period by 4 per cent (P less than 0.001), paced cycle length to atrioventricular nodal Mobitz type II block by 5 per cent (P = 0.046), and QT interval during sinus rhythm by 10 per cent (P less than 0.01). After dipyridamole, the PA interval increased by 16 per cent (P less than 0.001), the AH interval by 11 per cent (P less than 0.01), and the corrected QT interval by 5 per cent (P less than 0.01). During retrograde conduction we observed a shortening of the ventriculoatrial interval by 6 per cent (P = 0.036), retrograde atrioventricular nodal effective refractory period by 5 per cent (P less than 0.001), paced cycle length to atrioventricular nodal Wenckebach and atrioventricular nodal Mobitz type II block both by 8 per cent (P less than 0.01). We conclude that intravenous dipyridamole increases sinus node automaticity and reduces atrial, atrioventricular nodal and ventricular refractory periods, prolongs intra-atrial and atrioventricular nodal conduction, but does not produce any changes in His-Purkinje system conduction times.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Angiographic findings in patients exhibiting ischemia after oral dipyridamole.

We have assessed the angiographic features of a group of 37 patients given oral dipyridamole and 37 patients given matching placebo. Both groups represented severe coronary arterial disease and were studied prior to bypass surgery. Six patients (16%) had angina and 13 patients (35%) had electrocardiographic changes after dipyridamole. All the patients in the control group were nonresponders. In the group given dipyridamole the patients responding with angina had significantly more compromised collaterals than the patients without chest pain (P = 0.021). The same applied to the patients with electrocardiographic changes versus those with no electrocardiographic changes (P = 0.034). No differences between responders and nonresponders could be found in terms of the severity of coronary arterial disease, severity of anginal symptoms, exercise tolerance, antianginal medication, number of past myocardial infarctions, and left ventricular ejection fraction. In conclusion, the data strongly suggest that ischaemic responses to dipyridamole originate from myocardial steal accentuated by compromised flow in collateral vessels.

Administration, Oral↗
PubMed1993

Asystole and bradycardia during dipyridamole stress testing in patients receiving beta blockers.

Only rarely have serious side effects been reported with the use of intravenous dipyridamole. We describe two cases of severe bradycardia, of which one led to asystole, in patients undergoing dipyridamole-thallium studies. The association between beta blocker therapy and the seven reported cases of asystole with dipyridamole is discussed and mechanisms postulated. Some caution is advised when patients on beta blockers or similar medications have dipyridamole-thallium studies.

Adrenergic beta-Antagonists↗
PubMed1995

QTc interval prolongation during infusion with dipyridamole or adenosine.

The aim of our study was to discover whether there was a relationship between the QTc interval prolongation on the standard 12-lead electrocardiogram (ECG) and provoked myocardial ischemia. Since the increase of adenosine plasma levels, obtained either with adenosine or dipyridamole (an adenosine reuptake inhibitor) infusion, has been used to test the coronary artery reserve in patients affected by coronary artery disease, the QTc interval modifications during dipyridamole or adenosine echocardiographic stress test were evaluated. Twenty-five patients admitted to our Institute for evaluation of chest pain of suspected myocardial origin underwent an echocardiographic dipyridamole stress test (0.84 mg/kg over 10 min) after discontinuation of antianginal treatment. Of these patients, 10 underwent an echocardiographic adenosine stress test (scalar doses of 50, 75, 100, 140 micrograms/kg/min) after 48-72 h. The Bazett formula was used to evaluate the QTc interval. After dipyridamole and adenosine administration, a significant prolongation of the QTc interval was observed only in those patients who had positive test results. Our data suggested that QTc interval prolongation during pharmacological stress tests might be considered a marker of myocardial ischemia.

Adenosine↗
PubMed1986

Effect of dipyridamole upon thymidine incorporation and capping in human lymphocytes.

Dipyridamole is a potent inhibitor of tritiated thymidine incorporation by PHA-stimulated human lymphocytes. This effect is unrelated to the length of culture, to the level of response in untreated cultures, or to the proliferative index. This suggests that dipyridamole principally effects the membrane transport of thymidine. Dipyridamole inhibits sheep-erythrocyte-capping by E-rosettes. This effect cannot be mimicked by theophylline or cyclic nucleotides and cannot be reverted by adenosine. Pharmacological studies with colchicine and cytochalasin B suggest interference with cytoskeletal functions, probably of microtubules. This could be another site of action of dipyridamole beyond phosphodiesterase inhibition and adenosine metabolism.

Dipyridamole↗