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Dose-dependent inhibition of the hemodynamic response to dipyridamole by caffeine.

We investigated the effects of the adenosine antagonist caffeine on the hemodynamic response to dipyridamole infusion (0.4 mg/kg for 4 minutes). According to a randomized, placebo-controlled double-blind protocol, eight normotensive volunteers each participated in five tests: placebo after placebo, dipyridamole after placebo, and dipyridamole after 1, 2, and 4 mg/kg caffeine. Infusion of caffeine alone (4 mg/kg) induced an increase in mean arterial pressure of 6.1 +/- 0.5 mm Hg versus 1.5 +/- 0.9 mm Hg after placebo (p less than 0.05). Infusion of dipyridamole alone exerted a characteristic hemodynamic response with an increase in systolic blood pressure (+8.4 +/- 2.4 mm Hg), pulse pressure (+7.0 +/- 2.4 mm Hg), heart rate (+25.7 +/- 3.8 beats/min) and calculated rate-pressure product (+3419 mm Hg x beats per minute), all being significantly different from the changes induced by placebo. Caffeine induced a dose-dependent attenuation of the response to dipyridamole, with a significant negative correlation between the dose of caffeine on the one hand (0, 1, 2, and 4 mg/kg) and the dipyridamole-induced increments in systolic blood pressure (r = -0.53), pulse pressure (r = -0.50), heart rate (r = -0.95), and rate-pressure product (r = -0.93) on the other hand. We conclude that caffeine attenuates the hemodynamic response to dipyridamole infusion in humans in a dose-dependent fashion. Because of the wide-spread use of caffeine, this pharmacologic interaction may be of clinical importance, for example, in the diagnostic use of dipyridamole in thallium-201 myocardial imaging.

Adult↗

Dipyridamole inhibits PDGF-stimulated human peritoneal mesothelial cell proliferation.

BACKGROUND: It has been proposed that proliferation of human peritoneal mesothelial cells (HPMCs) accompanied by collagen synthesis may contribute to the development of peritoneal fibrosis (PF) in patients of long-term continuous ambulatory peritoneal dialysis (CAPD). However, the precise molecular mechanism regulating HPMC proliferation has never been reported. Dipyridamole has been reported to have potential as an antiproliferative and antifibrotic agent. We investigated the mechanism and effect of dipyridamole in regulation of HPMC proliferation. METHODS: HPMCs were cultured from human omentum by an enzyme digestion METHOD: Cell proliferation was measured by the methyltetrazolium assay and intracellular cAMP was measured using an enzyme immunoassay kit. Cell-cycle distribution of HPMC was analyzed by flow cytometry. Extracellular signal-regulated protein kinase (p44/p42 ERK) activity and expressions of cell-cycle proteins (cyclin D(1), CDK4, pRB and p27(Kip1)) were determined by Western blotting. RESULTS: The addition of DP suppressed PDGF-stimulated HPMC proliferation by cell-cycle arrest at the G1 phase. The antimitogenic effect of dipyridamole was mediated through the cAMP pathway. PDGF (25 ng/mL) increased the ERK1/2 activity of HPMC within 15 minutes, which maximized at 30 minutes, and the pretreatment with dipyridamole (17 microg/mL) substantially reduced the ERK response to PDGF by approximately 78.5%. PDGF induced elevated protein levels of cyclin D(1), but the CDK4 protein level did not change. Dipyridamole and DBcAMP had no effect on the levels of cyclin D(1) and CDK4 in PDGF-stimulated HPMC. PDGF decreased p27(Kip1) and induced pRB phosphorylation of HPMC. In contrast, dipyridamole prevented PDGF-induced p27(Kip1) degradation and attenuated PDGF-stimulated pRB phosphorylation. CONCLUSION: Dipyridamole appears to inhibit PDGF-stimulated HPMC proliferation through attenuated ERK activity, preservation of p27(Kip1), and decreased pRB phosphorylation. Thus, dipyridamole may have therapeutic efficacy to prevent or alleviate PF.

Bucladesine↗

Dipyridamole in chronic stable angina pectoris; a randomized, double blind, placebo-controlled, parallel group study.

BACKGROUND: Oral dipyridamole induces accumulation of endogenous adenosine, which in a hypoxic milieu exerts experimentally an angiogenic effect on coronary collateral circulation. A meta-analysis of 13 randomized placebo-controlled trials published between 1960 and 1992 showed evidence of benefit for dipyridamole in the treatment of angina pectoris, especially with longer duration of treatment. Aim To assess the efficacy and safety of dipyridamole in the treatment of patients with chronic stable angina in a large scale, international, randomized, placebo-controlled, parallel group study. METHODS: Four hundred patients with chronic stable angina pectoris and a positive treadmill exercise test were randomized to receive either modified release dipyridamole (200 mg b.i.d. p.o., n=198) or corresponding placebo (n=202), for 24 weeks as an add-on to conventional antianginal therapy and for 4 additional weeks as monotherapy--the latter after withdrawal of standard treatment with calcium antagonists and/or beta-blockers and/or long-acting (prophylactic) nitrates. RESULTS: Of the 198 patients randomized to dipyridamole, 134 completed the add-on and only 12 the monotherapy phase. Of the 202 patients randomized to placebo, 162 reached the add-on and only 12 the monotherapy phase. Serious adverse events occurred in 15 patients with dipyridamole and in 12 with placebo (7.6% vs 6.0, P=0.52). Increase over the baseline treadmill exercise test was similar in the treatment groups at each stage of the trial for all the main efficacy parameters: total treadmill exercise test duration; time to first anginal pain (except for a -13 s difference in favour of placebo at week 24;P=0.040); time to ST segment depression >0.1 mVolt (except for a +21 s difference in favour of dipyridamole at week 8;P=0.024; this latter difference was totally attributable to patients with lower exercise tolerance--Bruce stage II at study entry). CONCLUSION: In patients with chronic stable angina treated with regular antianginal background medication, the use of oral dipyridamole is safe and well tolerated. Antianginal and antiischaemic efficacy, as assessed by exercise testing, is comparable to placebo, except for a beneficial effect on time to ischaemia after 2 months, totally attributable to patients with lower exercise tolerance at study entry.

Administration, Oral↗

Patients with stable chronic obstructive pulmonary disease can safely undergo intravenous dipyridamole thallium-201 imaging.

BACKGROUND: Patients with chronic obstructive pulmonary disease are usually excluded from intravenous dipyridamole thallium-201 testing. We developed a nurse-administered protocol to screen and pretreat patients so they could be safely tested. METHODS AND RESULTS: We prospectively screened patients referred for intravenous dipyridamole thallium testing and retrospectively reviewed a comparison group of patients who had undergone intravenous dipyridamole testing before our bronchospasm protocol. We studied 492 consecutive patients referred for intravenous dipyridamole thallium testing, separating those with complete data (n = 451) into two groups: group A (n = 72), patients assessed to be at risk for intravenous dipyridamole-induced bronchospasm who received our bronchospasm treatment protocol; and group B (n = 379), patients assessed to be free of risk, who did not receive our bronchospasm protocol. Group C (n = 89) was a retrospective comparison group of patients who had undergone intravenous dipyridamole testing before initiation of the protocol. Patients were considered at risk for an adverse event if any of the following were present: peak flow < or =400 ml at the time of the test (spirometry by nurse) that increased to >400 ml after bronchodilator treatment, wheezing audible with stethoscope, history of chronic obstructive pulmonary disease or asthma or dyspnea on exertion at less than four blocks, or resting respiratory rate >18 breaths/min. The test was considered contraindicated if resting oxygen saturation was <85%, respiratory rate < or =36 breaths/min, or peak flow measured by peak flowmeter <400 ml after bronchodilator inhalant (albuterol or metaproterenol sulfate by spacer) at a dose of up to six puffs. One minute after injections of thallium-201, patients at risk were given 50 mg aminophylline by slow intravenous injection. We looked for major and minor adverse effects and divided them into three categories: (1) minor events (transient headache, abdominal discomfort, or nausea), wheezing (audible by stethoscope but without marked respiratory distress), (2) marked events (severe bronchospasm or severe ischemia defined as wheezing audible with or without stethoscope, respiratory rate >20 breaths/min or increased by 10 from pretest evaluation, oxygen desaturation to <90%, hypoventilation [reduced respiratory rate with decreased mental status], respiratory arrest, chest pain, horizontal ST-segment depression > or =1 mm on the electrocardiogram in any lead, symptomatic hypotension), or (3) other intravenous dipyridamole-induced side effects (persistent headache, dizziness, flushing, nausea, dyspnea, and ischemic chest pain) or anginal equivalent. The protocol properly identified patients with impaired pulmonary function. There was no difference in the frequency of adverse marked events among groups A, B, or C (1 % vs 4% vs 2%, p = 0.25). Patients in group A had more minor side effects than those in group B (53% vs 35%, p = 0.004). Specifically, patients in group A were more likely to wheeze (39% vs 1 %, p = <0.001), but wheezing in group A was self-limited or responded to treatment as described in the protocol. The prevalence of positive thallium-201 scans in group A (44%) compared with group C (49%) was not different (p = 0.15). CONCLUSIONS: A nurse-administered risk assessment and pretreatment protocol (1) properly identified patients with impaired pulmonary function, (2) permitted completion of intravenous dipyridamole testing in patients at risk for bronchospasm without an increased incidence of marked adverse events, and (3) did not appear to influence the interpretation of the thallium test.

Aged↗

The effect of dipyridamole and warfarin on the patency rate of coronary artery bypass grafts.

Seventy consecutive patients who had undergone coronary artery bypass surgery were postoperatively treated with either dipyridamole or warfarin for 6 months. The dipyridamole series consisted of 28 patients given 150 mg dipyridamole 3 times daily and the warfarin series, of 42 patients who received the appropriate daily dose of warfarin needed to maintain the prothrombin time within the therapeutic range. The majority of patients in both series belonged to the NYHA class III. Sixty-one percent of the patients in the dipyridamole series and 66% of those of the warfarin series had triple vessel disease. In all, 70 and 105 coronary artery branches were bypassed in the dipyridamole and warfarin series, respectively. This resulted in 2.5 distal anastomoses per patient in each series. The patency of the grafts was confirmed angiographically. There was no mortality during the 23.6 +/- 2.4 months follow-up period in the dipyridamole series or the 12.8 +/- 2.7 months in the warfarin series. The patency rates were 95.7% and 88.6% in the dipyridamole and warfarin series, respectively. It is apparent that dipyridamole is not less effective than warfarin in preventing postoperative coronary graft occlusion.

Adult↗

Adjunctive intracoronary dipyridamole in the interventional treatment of small coronary arteries: a prospectively randomized trial.

BACKGROUND: Patients undergoing intracoronary stent placement or balloon angioplasty for the treatment of small coronary arteries are at an increased risk of an adverse outcome from a higher incidence of abrupt closure and restenosis. Intracoronary thrombus formation plays a key role in the pathogenesis of abrupt vessel closure and of restenosis. Dipyridamole prevents platelet aggregation by a mechanism that differs from aspirin. The purpose of this study was to investigate the effect of intracoronary dipyridamole on acute complications and restenosis after percutaneous transluminal coronary angioplasty. METHODS: In a prospectively randomized study including 491 dilatations of coronary arteries with a diameter <2.75 mm, additional intracoronary application of dipyridamole was compared with conventional pretreatment consisting of heparin and aspirin. Study end points were defined as incidence of abrupt vessel closure, myocardial infarction, angiographic restenosis, and target vessel revascularization rate. RESULTS: Intracoronary dipyridamole was associated with a significant reduction of abrupt vessel closure (2.8% vs 8.6%; P =.005) and a nonsignificant reduction of myocardial infarction (1.6% vs 4.5%; P =.07) after percutaneous transluminal coronary angioplasty. Net gain 6 months after angioplasty was significantly higher in the dipyridamole group (0.60 +/- 0.35 mm vs 0.42 +/- 0.34 mm; P <.001). However, dipyridamole failed to reduce the incidence of angiographic restenosis (41.6% vs 49.1%; P =.11) and target vessel revascularization rate (20.6% vs 269%; P =.12). CONCLUSIONS: Intracoronary dipyridamole reduces the incidence of adverse cardiovascular events in the first 48 hours after balloon angioplasty of small coronary arteries. Reduction of restenosis rates failed to reach statistical significance. However, a significant increase in net gain was observed. Thus intracoronary application of dipyridamole should be considered in the treatment of small coronary arteries when intracoronary stenting is not appropriate.

Angina, Unstable↗

Exercise supplementation to dipyridamole prevents hypotension, improves electrocardiogram sensitivity, and increases heart-to-liver activity ratio on Tc-99m sestamibi imaging.

BACKGROUND: Myocardial perfusion imaging with dipyridamole is an alternative with which to evaluate patients who are unable to exercise. Many patients who undergo dipyridamole testing are limited in their ability, but are not completely unable, to exercise. There are benefits from adding low workload exercise to dipyridamole testing, including a reduction of thallium 201 concentration in the liver, leading to a higher heart-to-liver activity ratio and better image quality. This prospective study was designed to evaluate a protocol of exercise supplementation during dipyridamole technetium 99m sestamibi imaging and to verify whether a higher heart-to-liver activity ratio could be obtained. We also evaluated the potential of this combined protocol to prevent hypotension and induce ischemic changes on the electrocardiogram (ECG). METHODS AND RESULTS: Ninety consecutive patients who were not completely disabled for exercise underwent dipyridamole Tc-99m sestamibi cardiac single photon emission computed tomography with a protocol of exercise supplementation (DipEx). The heart-to-liver activity ratio, hemodynamics, and electrocardiographic changes were studied. The findings were compared with those of a control group (Dip) composed of 99 patients who underwent dipyridamole infusion alone. Patients with left bundle branch block, pacemaker, and atrial fibrillation were excluded. The DipEx patients tolerated the protocol, exercising 4.2 +/- 1.3 minutes on the treadmill (Bruce protocol). Compared with Dip, patients in the DipEx group had a higher heart-to-liver activity ratio (1.3 +/- 0.4 vs 1.6 +/- 0.5, respectively; P =.00001), had no incidence of hypotension (6% vs 0%, respectively; P =.03), and had a higher sensitivity of the ECG to detect ischemia (6% vs 34%, respectively; P =.003). The increase in sensitivity seen in the DipEx group was accompanied by a significant decrease in specificity compared with the Dip group (67% vs 100%, P =.000001). CONCLUSIONS: Our data show that the addition of limited exercise to dipyridamole results in benefits during Tc-99m sestamibi imaging, increasing heart-to-liver activity ratio, preventing vasodilator-induced hypotension, and improving ECG sensitivity for the detection of ischemia. Furthermore, this protocol also provides an estimation of the patient's physical capacity and could be used as an alternative for patients undergoing dipyridamole infusion who are not completely unable to exercise.

Adult↗

Dipyridamole stress echocardiography: state of the art 1996. EPIC (Echo Persantin International Cooperative) Study Group.

Dipyridamole stress is the forerunner and prototype of pharmacological stress echo tests in the diagnosis of coronary artery disease. Among the various stress echo tests, it is probably the least technically demanding to perform and the easiest to interpret. Its accuracy is similar to dobutamine stress echocardiography but its feasibility is higher. The prognostic impact of dipyridamole stress echo has also been proven for presentation of hard end-points such as cardiac death. The safety and prognostic value of this test has been conclusively demonstrated as a result of extensive experience in large scale multicentre projects. Dipyridamole stress is many different tests in one: dipyridamole atropine is best for diagnosis; dipyridamole dobutamine or dipyridamole-exercise is highly sensitive for the detection of minor forms of coronary artery disease; low and high dose dipyridamole is best suited for prognostic stratification; infra-low dipyridamole with low dose dobutamine administration is probably best suited for selective myocardial viability identification. Each patient should have their own test, tailored on the basis of the clinical picture and the diagnostic issue.

Coronary Disease↗

The value of dipyridamole echocardiography in risk stratification before vascular surgery. A multicenter study. The EPIC (Echo Persantine International Study) Group--Subproject: Risk Stratification Before Major Vascular Surgery.

PURPOSE: Patients undergoing major vascular surgery are at relatively high risk of cardiac events, and pharmacological stress echocardiography is increasingly used for peri-operative risk stratification. PATIENTS AND METHODS: One hundred and twenty-one patients undergoing vascular surgery (age 65 +/- 7 years) were studied by dipyridamole echocardiography testing in six different centres. Of the total 136 patients, 15 were subsequently excluded because surgery was either cancelled (n = 8) or postponed pending cardiac revascularization (n = 7) because of the presence of a 'high-risk' stress echo response (identified 'a priori' as a positive dipyridamole echocardiography testing with a dipyridamole-time < 5 min and/or a peak wall motion score index > 2, upon scoring each segment from 1 = normal to 4 = dyskinetic in an 11-segment model). RESULTS: No major complications occurred during dipyridamole echocardiography testing. Technically adequate images were obtained in all patients; however, in one patient only the low dipyridamole dose (56 mg.kg-1 over 4 min) was given to limit side effects. Of the 121 patients undergoing surgery 28 (23%) had a positive test. Peri-operative events occurred in nine patients (8%): two deaths, two myocardial infarctions, five cases of unstable angina. Sensitivity and specificity of dipyridamole echocardiography testing for predicting cardiac events were 78% and 81%, respectively, with a positive predictive value of 25% and a negative predictive value of 98%. Dipyridamole echocardiography testing effectively singled out patients with, from those without, events, but neither clinical parameters, such as Detsky score, nor baseline echo parameters, such as resting wall motion score index or ejection fraction were able to distinguish between such patients. CONCLUSION: In conclusion, dipyridamole echocardiography testing is safe and well tolerated in patients undergoing major vascular surgery, and provides an effective pre-operative screening test for risk stratification of these patients mainly due to the extremely high negative predictive value. Stress echocardiography is a better discriminator than clinical and rest echocardiographic variables.

Aged↗

Dipyridamole modulated Tc-99m sestamibi lung SPECT in small cell lung cancer.

PURPOSE: In this study, the authors wanted to determine whether dipyridamole-modulated MIBI (dipyridamole-MIBI) could enhance the prediction of the response to chemotherapy in patients with small cell lung cancer. METHODS: Twenty-seven patients with biopsy-proved small cell lung cancer (25 men, 2 women; mean age, 61 +/- 7 years) underwent dipyridamole-MIBI SPECT 3 to 7 days before starting chemotherapy (80 mg/m2 etoposide and 80 mg/m2 cisplatin every 3 or 4 weeks for at least two cycles). Tomographic images before and after dipyridamole (0.84 mg/kg) were acquired 1 hour after injection of 370 (10 mCi) and 1,110 (30 mCi) MBq MIBI, respectively. The response to chemotherapy was grouped as specified as complete response (CR), partial (PR), no change (NC), or progressive disease (PD), according to the change in tumor size on chest roentgenography and CT. Patients showing CR and PR were classified as responders, and those who showed NC and PD were considered nonresponders. RESULTS: Among the 27 patients, 22 were responders (3 CR, 19 PR) and 5 were nonresponders (3 NC, 2 PD). The tumor-to-normal lung ratio (T:NL) of responders was significantly higher than that of nonresponders. The diagnostic accuracy of the T:NL ratio to differentiate responders and nonresponders was 33.3%, with a cutoff value of 2.5, which was significantly improved to 77.8% when an increased T:NL ratio after dipyridamole was assigned to a nonresponder. Furthermore, all patients with CR showed diminished T:NL ratios after dipyridamole, and all patients with NR showed an increased T:NL ratio after dipyridamole. CONCLUSION: Dipyridamole-MIBI SPECT could enhance the prediction of response to chemotherapy in patients with small cell lung cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Usefulness of dipyridamole-thallium imaging in 257 patients with atherosclerotic vascular disease.

We evaluated the usefulness of dipyridamole-thallium imaging for the detection of ischaemic heart disease in 257 patients with atherosclerotic vascular disease (80 patients with arteriosclerosis obliterans, 81 patients with aneurysm of the abdominal aorta, 60 patients with aneurysm of the thoracic aorta and 36 patients with dissecting aortic aneurysm). Clinical evidence of ischaemic heart disease was found in 69 of 257 (27%) patients, including 32 patients with arteriosclerosis obliterans, 23 with aneurysm of the abdominal aorta, 9 with aneurysm of the thoracic aorta and 5 with dissecting aortic aneurysm. Dipyridamole-thallium imaging identified myocardial ischaemia in 49 of 69 (71%) patients with clinical evidence of ischaemic heart disease. Dipyridamole-thallium imaging showed positive results in 67 of 81 (83%) patients with aneurysm of the abdominal aorta. In patients with no clinical evidence of ischaemic heart disease, the results of dipyridamole-thallium imaging were positive in 39 of 188 (21%) patients. Dipyridamole-thallium imaging was positive in 90 of the 257 (35%) patients as a whole. When we combined the patients with positive dipyridamole-thallium imaging with those with negative dipyridamole-thallium imaging but who had clinical evidence of ischaemic heart disease, 42% of all patients had evidence of ischaemic heart disease. Our findings suggest that atherosclerotic vascular disease is strongly associated with ischaemic heart disease and that dipyridamole-thallium imaging is useful for the detection of ischaemic heart disease.

Aged↗

Comparison of adenosine and high-dose dipyridamole both combined with low-level exercise stress for 99Tcm-MIBI SPET myocardial perfusion imaging.

Intravenously administered adenosine and high-dose dipyridamole, both combined with low-level exercise stress, were compared in a head-to-head fashion using 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI) single photo emission tomography (SPET) myocardial perfusion imaging. Thirty-nine consecutive patients who had undergone coronary arteriography underwent 99Tcm-MIBI (740 Mbq) SPET after dipyridamole (0.84 mg kg-1) and after adenosine (0.84 mg kg-1), both combined with low-level exercise (30 W load), and under resting conditions. Our results demonstrate that adenosine and dipyridamole combined with exercise have comparable haemodynamic effects, with a low incidence of side-effects. The time of recovery from the stress protocol was not significantly different: adenosine, 5.7 +/- 3.9 min; dipyridamole, 6.6 +/- 4.9 min. However, aminophylline was significantly (P < 0.05) more often administered to reverse side-effects using the dipyridamole protocol (36% of patients) compared with the adenosine protocol (8% of patients). The results of 99Tcm-MIBI SPET imaging were highly concordant and demonstrated a high diagnostic accuracy for identifying coronary artery disease (CAD). The sensitivity was 90% (95% confidence intervals 79-100%) with adenosine SPET and 93% (95% confidence intervals 84-100%) with dipyridamole SPET for identifying patients with CAD (i.e. luminal stenosis > 50%); their specificities were both 100% (95% confidence intervals 66-100%). The sensitivity of identifying angiographically diseased vessels was 81% (95% confidence intervals 70-92%) using adenosine SPET and 85% (95% confidence intervals 75-95%) using dipyridamole; the specificity for both stress modalities was 94% (95% confidence intervals 89-100%). The combination of exercise with adenosine and high-dose dipyridamole appears to be a feasible and safe method to alleviate some of the undesirable A1-receptor-mediated side-effects of adenosine. The choice of the pharmacological stress will depend on local expertise and availability.

Adenosine↗

The effects of dipyridamole on the guinea-pig ileal longitudinal muscle-myenteric plexus preparation.

1 The longitudinal muscle-myenteric plexus strip prepared from guinea-pig ileum has been used to study the actions of dipyridamole and its interactions with adenine derivatives. 2 Dipyridamole augmented the inhibitory effects of adenine derivatives on the twitch response induced by 0.1 Hz field stimulation of the preparation. This synergistic effect was apparent with relatively low concentrations of dipyridamole (10 to 100 nM) and after short pretreatment times (1 to 2 min) that did not inhibit the twitch response on their own. Appropriate studies suggested the dipyridamole-adenosine synergism followed a pattern of facilitative agonist competition. 3 Dipyridamole did not inhibit either uptake of [3H]-adenosine by the preparation or adenosine deaminase activity under the same conditions that it exhibited synergism with adenosine. 4 Higher concentrations of dipyridamole inhibited the twitch response, mainly by decreasing acetylcholine release but partly by a direct action on smooth muscle. The direct action of dipyridamole on muscle was not synergistic with adenosine. 5 Fluorescence microscopy showed preferential binding of dipyridamole to the myenteric plexus.

Adenosine↗

Protection of low density lipoprotein oxidation at chemical and cellular level by the antioxidant drug dipyridamole.

1. The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Natural and synthetic antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Synthetic antioxidants are currently being tested, by they are not necessarily safe for human use. 2. We have previously reported that dipyridamole, currently used in clinical practice, is a potent scavenger of free radicals. Thus, we tested whether dipyridamole could affect LDL oxidation at chemical and cellular level. 3. Chemically induced LDL oxidation was made by Cu(II), Cu(II) plus hydrogen peroxide or peroxyl radicals generated by thermolysis of 2,2'-azo-bis(2-amidino propane). Dipyridamole, (1-10 microM), inhibited LDL oxidation as monitored by diene formation, evolution of hydroperoxides and thiobarbituric acid reactive substances, apoprotein modification and by the fluorescence of cis-parinaric acid. 4. The physiological relevance of the antioxidant activity was validated by experiments at the cellular level where dipyridamole inhibited endothelial cell-mediated LDL oxidation, their degradation by monocytes, and cytotoxicity. 5. In comparison with ascorbic acid, alpha-tocopherol and probucol, dipyridamole was the more efficient antioxidant with the following order of activity: dipyridamole > probucol > ascorbic acid > alpha-tocopherol. The present study shows that dipyridamole inhibits oxidation of LDL at pharmacologically relevant concentrations. The inhibition of LDL oxidation is unequivocally confirmed by use of three different methods of chemical oxidation, by several methods of oxidation monitoring, and the pharmacological relevance is demonstrated by the superiority of dipyridamole over the naturally occurring antioxidants, ascorbic acid and alpha-tocopherol and the synthetic antioxidant probucol.

Antioxidants↗

Effects of dipyridamole on postischemic vasodilation and extracellular adenosine.

Postischemic vasodilation (PIVD) was studied in pump-perfused dog gracilis muscles. The hemodynamic responses to 1, 3, and 5 min of ischemia were evaluated in the presence and absence of intraarterial infusions of dipyridamole in concentrations that inhibit cellular transport of adenosine. Dipyridamole infusion produced concentration-dependent reductions in vascular resistance and increased the time for 50% recovery (t0.5) in vascular resistance by 39% following 5 min of ischemia. The t0.5 for PIVD was unaffected by dipyridamole following 1 and 3 min of ischemia. Dipyridamole elevated tissue adenosine content two- to three-fold at 1, 3, and 5 min of ischemia compared with saline controls. Intra-arterial infusions of adenosine deaminase along with dipyridamole completely prevented the dipyridamole-induced increase in tissue adenosine, demonstrating that dipyridamole increases extracellular adenosine during muscle ischemia. The significance of these findings is analyzed using a two-compartment model for the distribution of adenosine. The data indicate that a severalfold increase in interstitial adenosine content does not alter PIVD and that the hemodynamic effects of dipyridamole following 5 min of ischemia may be due to some mechanism other than enhanced accumulation of adenosine.

Adenosine↗

Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates.

BACKGROUND: Drugs that simultaneously decrease platelet function and inflammation may improve the treatment of cardiovascular disorders. Here, we determined whether dipyridamole and aspirin, a combination therapy used to prevent recurrent stroke, regulates gene expression in platelet-monocyte inflammatory model systems. METHODS AND RESULTS: Human platelets and monocytes were pretreated with dipyridamole, aspirin, or both inhibitors. The cells were stimulated with thrombin or activated by adhesion to collagen, and gene expression was measured in the target monocytes. Thrombin-stimulated platelets increased monocyte chemotactic protein-1 (MCP-1) expression by monocytes. Dipyridamole but not aspirin attenuated nuclear translocation of NF-kappaB and blocked the synthesis of MCP-1 at the transcriptional level. Dipyridamole delayed maximal synthesis of interleukin-8 but did not alter cyclooxygenase-2 accumulation. Adherence to collagen and platelets also increased the expression of matrix metalloproteinase-9 (MMP-9) in monocytes, a response that was inhibited by dipyridamole. In this case, however, dipyridamole did not block transcription or distribution of MMP-9 mRNA to actively translating polysomes, indicating that it regulates the expression of MMP-9 protein at a postinitiation stage of translation. Dipyridamole also blocked MCP-1 and MMP-9 generated by lipopolysaccharide-treated monocytes, indicating that at least part of its inhibitory action is unrelated to its antiplatelet properties. CONCLUSIONS: These results indicate that dipyridamole has selective antiinflammatory properties that may contribute to its actions in the secondary prevention of stroke.

Anti-Inflammatory Agents, Non-Steroidal↗

Prevention of early aortocoronary bypass occlusion by low-dose aspirin and dipyridamole. Grupo Español para el Seguimiento del Injerto Coronario (GESIC)

To analyze the efficacy of low-dose aspirin in preventing early aortocoronary vein graft occlusion, 1,112 consecutive patients were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial comparing 50 mg t.i.d. aspirin, 50 mg aspirin plus 75 mg t.i.d. dipyridamole, and placebo. All patients received 100 mg q.i.d. dipyridamole for 48 hours before surgery, and assigned treatment was started 7 hours after surgery. Vein graft angiography was performed in 927 patients (83%) within 28 days of surgery (mean, 10 days). Aspirin plus dipyridamole significantly (p = 0.017) reduced the occlusion rate of distal anastomoses from 18% (placebo) to 12.9%. Occlusion rate in the aspirin group was 14%, which approached statistical significance (p = 0.058). Furthermore, only aspirin plus dipyridamole reduced (p = 0.01) the number of patients with occluded grafts (placebo, 33%; aspirin, 27.1%; aspirin plus dipyridamole, 24.3%). Mediastinal drainage was slightly higher (p = 0.04) in the aspirin plus dipyridamole group (713 +/- 456 ml) than in the other two groups (placebo, 670 +/- 437 ml; aspirin, 629 +/- 337 ml), but hospital mortality (average, 4.6%) and early reoperation (average, 3.9%) rates were similar among the three groups. Thus, low-dose aspirin plus dipyridamole safely improves early saphenous vein aortocoronary graft patency; this effect is an added benefit to a preoperative regimen of dipyridamole.

Aged↗

Dipyridamole echocardiography in essential hypertensive patients with chest pain.

The exercise-electrocardiography test shows limited feasibility and diagnostic accuracy for the noninvasive detection of coronary artery disease in hypertensive patients. Recently, the dipyridamole-echocardiography test (two-dimensional echocardiographic monitoring with dipyridamole infusion, up to 0.84 mg/kg over 10 minutes) has been proposed as an exercise-independent method for the diagnosis of coronary artery disease. The diagnostic usefulness of the exercise-electrocardiography test and the dipyridamole-echocardiography test was evaluated in 63 consecutive inpatients with history of chest pain, essential hypertension, and no previous myocardial infarction. The criterion of positivity for the exercise-electrocardiography test was a horizontal or downsloping ST segment shift exceeding 0.1 mV and for the dipyridamole-echocardiography test, a transient dyssynergy of contraction. Fifteen patients could not perform a diagnostic exercise-electrocardiography test because of an inability to exercise adequately (two patients), severe hypertension in spite of full antihypertensive therapy (six patients), or excessive blood pressure rise at the first step of the exercise-electrocardiography test (seven patients). Five patients could not perform the dipyridamole-echocardiography test because of a poor acoustic window. The overall feasibility was 76% for the exercise-electrocardiography test and 92% for the dipyridamole-echocardiography test (p less than 0.05). All 43 patients who performed both tests underwent coronary angiography; 30 had significant coronary artery disease (greater than 70% lumen reduction of at least 1 major coronary vessel). Sensitivity was 67% for both the exercise-electrocardiography test and the dipyridamole-echocardiography test (p = NS); specificity was 46% for the exercise-electrocardiography test and 92% for the dipyridamole-echocardiography test (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗