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Dipyridamole alone or combined with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo.

1. In a randomized, double-blind trial we compared the inhibition of the platelet-vessel wall interactions in whole blood ex vivo. There were four groups of 24 healthy volunteers each of whom were treated orally for 3.5 days with either 200 mg dipyridamole (sustained release preparation), 25 mg acetylsalicylic acid, both drugs combined or placebo twice daily. 2. The mean area of all platelets/aggregates was reduced by 6.2% +/- 4.2% (+/- s.e. mean) by placebo (n = 23), 19.8% +/- 6.7% by dipyridamole (n = 22), 53.7% +/- 4.9% by acetylsalicylic acid (n = 23) and 71.4% +/- 3.7% by the combination of both drugs (n = 24), when compared with total inhibition of aggregation by EGTA. Thus, low-dose acetylsalicylic acid inhibited aggregation (P less than 0.001). 3. Dipyridamole reduced the size of platelet aggregates (P less than 0.01, two-fold analysis of variance). The reduction was correlated with the individual dipyridamole plasma levels (P less than 0.05, analysis of covariance). The subgroup of large and very large thrombi being formed was also reduced by dipyridamole (P less than 0.05). 4. This ex vivo study demonstrates that dipyridamole alone inhibits formation of thrombi on subendothelial matrix and enhances the inhibitory effect of low dose acetylsalicylic acid in this model of thrombosis.

Adult↗

Adenosine and dipyridamole: actions and interactions on the contractile response of guinea-pig ileum to high frequency electrical field stimulation.

The action of adenosine on the myenteric plexus-longitudinal muscle strips from guinea-pig ileum to high frequency electrical field stimulation (10 Hz) was investigated. Electrically induced contractions were reduced markedly by tetrodotoxin (0.2 microM) and atropine (1 microM), and partially by noradrenaline (3 microM) and morphine (3 microM). Adenosine, adenosine 5'-monophosphate (AMP) and adenosine triphosphate (ATP) produced a concentration-dependent inhibition of the high frequency contractions over the range of 0.1-100 microM, the most potent being adenosine. The concentration-response curve for adenosine was significantly shifted to the left by dipyridamole (10 nM), while dipyridamole at higher concentrations (30 nM-10 microM), depressed the contraction markedly by itself. Dipyridamole decreased [3H]-adenosine uptake into strips of ileum in a concentration-dependent manner. There was a significant correlationship between the reduction of adenosine uptake and the inhibition of the contraction induced by dipyridamole (r = 0.970). In strips desensitized to adenosine or treated with adenosine deaminase, the inhibitory effect of dipyridamole was significantly reduced. The present investigation revealed that adenosine depressed responses of guinea-pig ileum to high frequency electrical stimulation and suggested that the inhibitory effect of dipyridamole may be closely associated with the behaviour of endogenous adenosine or related compounds.

Adenosine↗

Actions of dipyridamole on endogenous and exogenous noradrenaline in the dog mesenteric vein.

1. In the isolated mesenteric vein of the dog, dipyridamole inhibited both the excitatory junction potential (e.j.p.) and the slow depolarization evoked by perivascular nerve stimulation, to 60-70% of control, with no change in the postjunctional membrane potential. These inhibitory actions of dipyridamole were not modified by 8-phenyltheophylline or phentolamine, suggesting that the inhibition did not involve either the actions of endogenous adenosine or the prejunctional alpha-autoregulation mechanism. 2. Dipyridamole did not produce any detectable effects on either the facilitation process of the e.j.ps or the postjunctional membrane depolarization produced by exogenously applied noradrenaline (NA). 3. Dipyridamole reduced the outflow of both the NA and the 3,4-dihydroxyphenylglycol (DOPEG) evoked by perivascular nerve stimulation to below 10% of control, the effect being much greater than that of exogenously applied adenosine (to about 90% of the control). 4. Exogenously-added NA was degraded by incubation with a segment of the vein. Dipyridamole itself produced degradation of NA and accelerated the NA-induced degradation. By contrast, pyrogallol, but not pargyline or imipramine, prevented the NA-induced degradation. 5. It is suggested that dipyridamole degrades NA directly, and also indirectly through activation of catechol-O-methyl transferase, with no alteration of the activity of monoamine oxidase or of the uptake mechanisms of NA into nerve terminals.

Adenosine↗

Dipyridamole echocardiography as a useful and safe test in the assessment of coronary artery disease in the elderly.

We prospectively studied the sensitivity, specificity, feasibility, and safety of high-dose dipyridamole echocardiography, compared to exercise electrocardiography in 130 subjects (67 younger and 63 elderly patients) referred for angiographic evaluation of suspected or proven coronary artery disease. Sensitivity, specificity, and feasibility of dipyridamole echocardiography were respectively 75.5%, 100%, and 88.0% in younger patients and 82.9%, 100%, and 79.4% in elderly patients (P = NS). The sensitivity of exercise electrocardiography was 72.7% in young and 66.6% in elderly patients (P = NS); specificity 66.0% vs 60.0% (P = NS); feasibility 83.6 vs 63.5 (P = 0.05). Forty-nine younger and 38 elderly patients performed both tests. Sensitivity of dipyridamole echocardiography compared to exercise electrocardiography was 76.2% vs 73.8% in young patients and 83.3% vs 70% in the older group (P = NS). The feasibility of the two tests was significantly different in the elderly group only (dipyridamole echocardiography 79.4% vs exercise electrocardiography 63.5%; P less than 0.01). The incidence of side effects during dipyridamole echocardiography was similar in the two groups, except for dyspnea which was observed in 20% of older and 5% of younger patients (P less than 0.05). Our data demonstrate that the dipyridamole test combined with echocardiographic monitoring of regional myocardial contractility may be considered a valid non-invasive method for evaluating coronary artery disease in the elderly and that this test is a satisfactory alternative to the exercise stress test.

Aged↗

Beneficial hemodynamic effects of dipyridamole on portal circulation in cirrhosis.

OBJECTIVE: Dipyridamole is a vasodilator that inhibits the cellular uptake of adenosine, which physiologically reduces the resistance to hepatic arterial flow inside the liver. This study aims at assessing the acute effect of dipyridamole on functional liver plasma flow (measured as the extrarenal sorbitol clearance) and on the Doppler US Congestion Index of the portal vein (the ratio between the cross-sectional area of this vein and the mean velocity of portal flow), which correlates with the severity of portal hypertension. METHODS: We have determined the extrarenal sorbitol clearance (14 cases) and the Congestion Index (seven cases) before and at 30, 60, and 90 min after the oral administration of 25 mg dipyridamole in patients with liver cirrhosis. We also measured the effect of dipyridamole on functional liver plasma flow in six healthy subjects. RESULTS: Dipyridamole increased the extrarenal sorbitol clearance in controls (+17%, p < 0.01) and in cirrhotic patients (+15%, p < 0.01). The drug decreased the portal Congestion Index in all patients, averaging -24% (p < 0.05) 90 min after its oral administration. CONCLUSIONS: This result was due both to a mean decrease of the portal sectional area and to a mean increase in portal flow velocity. In conclusion, these data suggest that dipyridamole should decrease the vascular resistance to portal flow in cirrhosis; this effect may be mediated by an adenosine-dependent vasodilation in the intrahepatic site or along the portosystemic collaterals.

Administration, Oral↗

Dipyridamole in vitro suppresses the generation of T-cell cytotoxic functions: synergistic activity with cyclosporine.

The pharmacological activity of dipyridamole has been related to its ability to increase intracellular cAMP. Elevated cAMP concentrations can tone down T-cell effector functions. The aim of this study was to evaluate the dipyridamole effect in vitro on the generation of alloreactive cytotoxic and lymphokine-activated killer cells in normal T-cell subpopulations. Dipyridamole suppressed T-cell cytotoxic functions in a dose-dependent way. The kinetics of suppression showed that dipyridamole prevented the first step of cytotoxicity, i.e. activation of the lytic program following allogeneic or interleukin-2 stimulation. The ability of dipyridamole to interact with the immunosuppressive activity of cyclosporine was also investigated. By itself, cyclosporine suppressed the generation of alloreactive cytotoxicity, but not the generation of lymphokine-activated killer cells. A synergistic immunosuppressive activity between dipyridamole and cyclosporine was observed on the generation of alloreactive cytotoxic T lymphocytes.

Cell Cycle↗

Dipyridamole and RA-642 inhibit the production of superoxide anion and free radical damage to rat lens.

We studied the effects of dipyridamole and RA-642 on the production of superoxide anions and on oxygen radicals-induced lipid peroxidation in lens tissue homogenates from normal rats and rats given dipyridamole or RA-642 intraperitoneally. Superoxide production was evaluated by phenazine methosulphate (PMS)-induced nitroblue tetrazolium (NBT) reduction and lipid peroxidation by ferrous sulfate and ascorbic acid (FeAs)-induced malondialdehyde (MDA) production. Dipyridamole and RA-642 showed an inhibitory effect on both assays in the experiments with lens tissue homogenates from untreated or treated rats. The extent of inhibition, however, was significantly higher in pyrimidopyrimidinic-treated rats (range of inhibition at different times of incubation was 18% versus 23-57% for dipyridamole and 14% versus 73-80% for RA-642 in the assay of MDA production, and 10% versus 33-37% for dipyridamole and 2.5% versus 11-32% for RA-642 in the assay of NBT reduction). Concentrations of dipyridamole and RA-642 in lens tissue from treated animals could not be determined (less than 0.001 micrograms/mg of tissue). Although both compounds inhibited lipid peroxidation induced by oxygen free radicals, the mechanism of action might include the role of adenosine as a mediator.

Animals↗

Residue 33 of human equilibrative nucleoside transporter 2 is a functionally important component of both the dipyridamole and nucleoside binding sites.

Human equilibrative nucleoside transporters 1 and 2 (hENT1 and hENT2) differ functionally in that hENT2 generally displays lower affinity for its nucleoside permeants and is less sensitive to inhibition by the coronary vasodilators dilazep and dipyridamole. In previous work, we demonstrated that mutation of residues 33 (Met versus Ile) of hENT1 and hENT2 altered sensitivity to dilazep and dipyridamole and that the hENT2 mutant (I33M) displayed a K(m) value for uridine that was lower than that of hENT2 and similar to that of hENT1 (J Biol Chem 277:395-401, 2002). In this study, we report results of an in-depth investigation of the role of residue 33 in hENT2. We found that hENT2-I33M displayed decreased K(m) values for both pyrimidine and purine nucleosides and increased V(max) values for purine nucleosides. Cys or Ser at position 33 had similar effects on the kinetic parameters of hENT2 as Met, indicating that hydrophobic (Met and Cys) or hydrogen-bonding energy (Ser) contributed to permeant binding by these residues. hENT2-I33M and I33C displayed increased sensitivities to dipyridamole compared with wild-type hENT2, hENT2-I33A, and hENT2-I33S, suggesting interaction of the sulfur atom of Met and Cys with aromatic moieties on dipyridamole. hENT2-I33C was inhibited by the membrane-impermeant sulfhydryl reactive reagent p-chloromercuribenzyl sulfonate, and uridine, adenosine, and dipyridamole protected against inhibition. Our results indicated that residue 33 resides in an extracellular domain as predicted by the current hENT2 topology model and suggested that it is a functionally important component of both the permeant and dipyridamole binding sites.

Adenosine↗

Dipyridamole reversibly inhibits mengovirus RNA replication.

Dipyridamole is an effective inhibitor of cardiovirus growth in cell culture. The effects of dipyridamole on mengovirus replication in vivo and in vitro were examined in the hope the drug could be used as an experimental analog of the poliovirus inhibitor guanidine. Guanidine selectively inhibits poliovirus RNA synthesis but not RNA translation, and as such, has been a valuable research tool. Although guanidine does not inhibit cardiovirus infection, a compound with similar discriminatory characteristics would be experimentally useful for parallel work with these viruses. We found that mengovirus plaque formation in HeLa or L cells was inhibited nearly 100% by the presence of 80 muM dipyridamole. The inhibitory effect was reversible and targeted an early step in the replication cycle. Studies with luciferase-expressing mengovirus replicons showed that viral protein synthesis was unaffected by dipyridamole, and rather, RNA synthesis was the step targeted by the drug. This assessment was confirmed by direct analyses of viral translation and RNA synthesis activities in a Krebs-2-derived in vitro system that supported complete, infectious cardiovirus replication. In Krebs extracts, dipyridamole specifically inhibited viral RNA synthesis to more than 95%, with no concomitant effect on viral protein translation or polyprotein processing. The observed inhibition reversibly affected an early step in both minus-strand and plus-strand RNA synthesis, although inhibition of plus-strand synthesis was more profound than that of minus-strand synthesis. We conclude that dipyridamole is a potent experimental tool that readily distinguishes between cardiovirus translation and RNA replication functions.

Animals↗

Pharmacodynamic effect of dipyridamole on thallium-201 myocardial perfusion in progressive systemic sclerosis with diffuse scleroderma.

We evaluated the effect of dipyridamole on thallium-201 myocardial perfusion in 23 patients with progressive systemic sclerosis (PSS) with diffuse scleroderma. Thallium-201 single photon emission computed tomography (SPECT) was performed at rest and after coronary artery vasodilatation with intravenous dipyridamole (0.14 mg/kg/min for four minutes). The left myocardium was divided into nine segments; each segment was graded as 2.0, 1.5, 1.0, 0.5, 0 (zero represents no activity). Dipyridamole significantly improved resting thallium-201 myocardial perfusion: the mean (SD) number of segments with thallium defects decreased from 6.0 (2.1) at rest to 4.1 (2.5) after dipyridamole (p less than 0.0001); the mean (SD) score in segments with resting defects increased from 0.92 (0.24) at rest to 1.13 (0.38) after dipyridamole (p less than 0.0001); the mean (SD) global score per patient increased from 10.2 (1.8) at rest to 11.4 (2.1) after dipyridamole (p less than 0.02); the global score increased by at least 2.0 in 12 patients and worsened by at least 2.0 in three patients only (p = 0.05). The results of this acute study suggest that some drugs with potent vasodilator activity on small coronary arteries may be beneficial in the treatment of PSS patients with thallium-201 myocardial perfusion abnormalities.

Adult↗

Dipyridamole combined with exercise for thallium-201 myocardial imaging.

A new stress test for thallium-201 myocardial imaging in which pharmacological coronary vasodilatation with dipyridamole is combined with dynamic exercise is described. In 38 patients with coronary artery disease the sensitivity, total number of defects, degree of redistribution, and visual quality of thallium-201 imaging were greater after dipyridamole with exercise testing than after exercise alone. When the data from these 38 patients were combined with the results of dipyridamole-exercise imaging in 49 patients in whom exercise electrocardiography had been inconclusive then the technique gave a sensitivity for coronary disease of 87% and a specificity of 92%. Dipyridamole also increased the sensitivity of the exercise electrocardiogram, so that no patient with coronary disease had a strictly negative dipyridamole-exercise stress test. Only five of 214 patients who have now undergone this test have had complications requiring reversal of vasodilatation with aminophylline. The combined use of dipyridamole and exercise in this simple technique is a reliable and safe improvement on standard thallium-201 imaging tests.

Adult↗

Uses and limitations of high dose dipyridamole stress echocardiography for evaluation of coronary artery disease.

OBJECTIVE: To compare the usefulness of high dose dipyridamole stress echocardiography with dipyridamole stress electrocardiography and exercise electrocardiography for the evaluation of coronary artery disease. DESIGN: Prospective investigation with coronary angiography as the criterion standard and blinded assessment of study data. SETTING: Cardiology unit of a tertiary referral centre. SUBJECTS: Fifty eight patients with suspected coronary disease; three of these were excluded because of poor echogenicity at baseline (test feasibility 95%). Angiography showed normal coronary arteries in 15 and coronary disease (greater than or equal to 70% diameter stenosis) in 40. INTERVENTIONS: Cross sectional echocardiography and 12 lead electrocardiography during dipyridamole stress (up to 1 mg/kg) and exercise electrocardiography on a separate occasion. Wall motion was analysed with an 11-segment model developed at Hammersmith Hospital. MAIN OUTCOME MEASURES: Test sensitivity, specificity, and side effect data. RESULTS: 16 of 40 patients with coronary artery disease had inducible asynergy; all had multivessel disease and a tight stenosis in the vessel that supplied the abnormal segment. Exercise duration and time to 1 mm ST segment depression were significantly shorter in patients with a positive echocardiogram than in those without (both p less than 0.01). The sensitivity and specificity of dipyridamole stress echocardiography were 40% and 93% respectively; sensitivity improved to 60% when baseline (n = 18) or reversible asynergy defined an abnormal study (likelihood ratio = 9). Corresponding figures for stress electrocardiography were 38% and 80% for dipyridamole and 80% and 67% for exercise. Adverse reactions were seen in 67% of patients and included two instances of pronounced hypotension, one episode of prolonged myocardial ischaemia, and one cardiac arrest in a patient who was successfully resuscitated. CONCLUSION: A positive high dose dipyridamole echocardiogram predicts multivessel disease and impaired coronary reserve, but low overall sensitivity and occasionally troublesome side effects limit its clinical usefulness.

Adult↗

Dipyridamole echocardiography: the bedside stress test for coronary artery disease.

Identification of dipyridamole-induced regional wall motion abnormalities by echocardiography has recently been proposed as an alternative diagnostic stress test for coronary artery disease. This study evaluates this new technique by comparing the results obtained (overall, regionally and by abnormality type) with those of thallium-201 myocardial imaging after dipyridamole stress in 25 patients. Acceptable echocardiograms were obtained in 20 patients (80%). Concordance of echocardiographic abnormalities for both overall and regional thallium abnormalities was 85%. Sensitivity, specificity and predictive value of dipyridamole echocardiography for overall and regional thallium defects were 92%, 71% and 85%, and 91%, 81% and 85% respectively. However, concordance between the two for abnormality type (i.e. ischaemia versus infarction) was only 66% and the sensitivity, specificity and predictive value of dipyridamole echocardiography for identifying ischaemia as opposed to infarction were only 43%, 82% and 63%, respectively. There was substantial agreement between thallium and echocardiographic imaging after dipyridamole infusion in the diagnosis of coronary artery disease. Echocardiography appears less well able to distinguish infarction from active ischaemia. Dipyridamole echocardiography provides a highly versatile, noninvasive bedside stress test for the detection and localization of coronary artery disease.

Adult↗

The effect of dipyridamole on the initiation phase of postischemic acute renal failure in rats.

Several previous observations support the hypothesis that increased adenosine production and release mediate, at least in part, the reductions in renal blood flow and glomerular filtration rate in ischemic acute renal failure (ARF). If this hypothesis is correct, dipyridamole should potentiate these changes, since it blocks cellular adenosine uptake, thereby increasing the concentration and potentiating the effects of extracellular adenosine. Moreover, theophylline should block the effects of dipyridamole, since it is an adenosine receptor antagonist. These predictions were tested in three groups of anesthetized rats. All rats were subjected to 30 min of left renal artery occlusion; 30 min after relieving the occlusion, a 45-min clearance period was begun. The control group was given saline i.v.; the two experimental groups received either dipyridamole (24 micrograms X min-1 X kg-1) or dipyridamole plus theophylline i.v. (111 mumol/kg as a prime, 1.1 mumol X min-1 X kg-1 as an infusion). In the control group, the previously ischemic left kidneys exhibited decreased clearances of para-aminohippurate and inulin (CPAH and CIn), filtration fraction (FF), and urine/plasma inulin concentration (U/PIn), and increased urine flow (V), Na excretion (UNaV), and fractional Na excretion (FENa) in comparison with the contralateral right kidney. Dipyridamole pretreatment did not affect the right kidney, but it intensified the reductions in left kidney CPAH, CIn, and FF. Theophylline blocked all these effects of dipyridamole on the left kidney, and increased renal plasma flow (CPAH/PAH extraction), despite a decrease in systemic arterial blood pressure. These results are further support for the hypothesis that adenosine mediates, at least in part, the hemodynamic changes in postischemic ARF in rats.

Acute Kidney Injury↗

Inhibition of glucose uptake in murine cardiomyocyte cell line HL-1 by cardioprotective drugs dilazep and dipyridamole.

Inhibition of adenosine reuptake by nucleoside transport inhibitors, such as dipyridamole and dilazep, is proposed to increase extracellular levels of adenosine and thereby potentiate adenosine receptor-dependent pathways that promote cardiovascular health. Thus adenosine can act as a paracrine and/or autocrine hormone, which has been shown to regulate glucose uptake in some cell types. However, the role of adenosine in modulating glucose transport in cardiomyocytes is not clear. Therefore, we investigated whether exogenously applied adenosine or inhibition of adenosine transport by S-(4-nitrobenzyl)-6-thioinosine (NBTI), dipyridamole, or dilazep modulated basal and insulin-stimulated glucose uptake in the murine cardiomyocyte cell line HL-1. HL-1 cell lysates were subjected to SDS-PAGE and immunoblotting to determine which GLUT isoforms are present. Glucose uptake was measured in the presence of dipyridamole (3-300 microM), dilazep (1-100 microM), NBTI (10-500 nM), and adenosine (50-250 microM) or the nonmetabolizable adenosine analog 2-chloro-adenosine (250 microM). Our results demonstrated that HL-1 cells possess GLUT1 and GLUT4, the isoforms typically present in cardiomyocytes. We found no evidence for adenosine-dependent regulation of basal or insulin-stimulated glucose transport in HL-1 cardiomyocytes. However, we did observe a dose-dependent inhibition of glucose transport by dipyridamole (basal, IC(50) = 12.2 microM, insulin stimulated, IC(50) = 13.09 microM) and dilazep (basal, IC(50) = 5.7 microM, insulin stimulated, IC(50) = 19 microM) but not NBTI. Thus our data suggest that dipyridamole and dilazep, which are widely used to specifically inhibit nucleoside transport, have a broader spectrum of transport inhibition than previously described. Moreover, these data may explain previous observations, in which dipyridamole was noted to be proischemic at high doses.

Adenosine↗

Effects of dipyridamole on myocardial adenosine and active hyperemia.

Dipyridamole, a vasodilator that potentiates the actions of exogenous adenosine, is known to inhibit cellular uptake of adenosine, but its effects on cellular adenosine release, and thus interstitial adenosine levels, are disputed. We used the accumulation of adenosine in pericardial infusates (PCI) as an index of interstitial adenosine concentration and observed the effects of dipyridamole on relationships among coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and PCI adenosine concentrations during steady-state alterations of cardiac work. Dipyridamole increased CBF and PCI adenosine concentration without altering MVO2. The relationship between PCI adenosine and CBF was unaltered, supporting a cause and effect relationship between interstitial adenosine concentration and CBF. In addition, we determined that unlike previous studies in isolated perfused hearts the washout of adenosine by coronary plasma was unaffected by dipyridamole. The results support previous suggestions that, whereas dipyridamole inhibits adenosine uptake, it does not alter cellular adenosine release, and therefore interstitial adenosine levels are increased. The constant relationship between PCI adenosine and CBF supports hypotheses that attribute the hyperemias associated with increased cardiac work or with dipyridamole to increased interstitial adenosine.

Adenosine↗

Dipyridamole-induced capillary growth in normal and hypertrophic hearts.

Chronic increases in myocardial blood flow have been shown to stimulate capillary proliferation in normal growing hearts. It is unknown, however, if elevated myocardial blood flow stimulates precapillary and/or capillary growth in hearts undergoing hypertrophy. Accordingly, renal hypertension was produced in rabbits (Page, 1-kidney, 1-wrap model) in which one group of Page (n = 9) and one group of normotensive sham (n = 10) rabbits were given dipyridamole (4.0 mg/kg sc) twice daily for 2 mo. Another group of Page (n = 7) and sham (n = 12) rabbits received vehicle injections. In separate acute studies performed on conscious rabbits, this does of dipyridamole increased myocardial blood flow 35-60% over time without altering transmural distribution of flow or systemic blood pressure. Two months later, minimal coronary vascular resistance (MCVR/100 g) was calculated from perfusion during maximal coronary vasodilation in conscious animals. Histomorphometric methods were then utilized to evaluate various indexes of capillarity in perfuse-fixed hearts. Systolic pressure and left ventricle weight-to-body weight ratios were significantly higher in Page vs. sham rabbits; dipyridamole treatment did not alter these parameters within either group. Similarly, dipyridamole treatment did not significantly alter MCVR/100 g values in either normotensive or hypertensive rabbits. In contrast, dipyridamole treatment increased endomyocardial capillary length density by 33% in the hypertensive group (P less than 0.05) and 11% in the sham group (P not significant) compared with the respective vehicle-treated rabbits. In addition, intercapillary distance was significantly reduced in the endomyocardial region of both groups receiving dipyridamole injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Dipyridamole decreases protease-activated receptor and annexin-v binding on platelets of post stroke patients with aspirin nonresponsiveness.

BACKGROUND: Although controversial, the phenomenon of aspirin resistance (AR) has been correlated in some small studies with poor clinical outcomes in patients with coronary artery disease. Even less is known regarding the role of AR in the post stroke population. The reason for and the underlying mechanism of AR is unknown. We hypothesized that excessive formation of thrombin on the platelet surface may contribute to this phenomenon and assessed how dipyridamole affects multiple platelet and thrombin generation biomarkers in AR patients after ischemic stroke. METHODS: Whole blood samples from 20 post stroke AR patients were pretreated with dipyridamole, simulating the therapeutic range, and then incubated for 45 min at 37 degrees C. Platelet characteristics were assessed by aggregometry, cartridge-based analyzer, and receptor expression by flow cytometry. Markers of thrombin generation were measured in the autologous plasma by ELISA. RESULTS: Pretreatment of blood with dipyridamole resulted in 22-26% diminished expression of intact PAR-1 receptor (p=0.021 and p=0.024) and 28-31% decrease of annexin V binding (p=0.031 and p=0.02) after incubation with 2 microg/ml and 4 microg/ml of dipyridamole, respectively. Platelet aggregation and thrombin generation markers were not affected in vitro by dipyridamole. CONCLUSIONS: Dipyridamole may be capable of overcoming increased prothrombinase complex formation and be in part able to compensate for AR in patients with moderate carotid stenosis. This phenomenon may explain the clinical advantages of Aggrenox, known to reduce ischemic events in post stroke patients as proven in clinical trials, though an additional antithrombotic benefit beyond the platelet inhibition by aspirin alone.

Aged↗