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PubMed1983

Arachidonic acid metabolism in isolated aorta and lung of the rat: effects of dipyridamole, nifedipine, propranolol, hydralazine and verapamil.

Effects of some vasodilating (dipyridamole, nifedipine and verapamil) and antihypertensive (propranolol, hydralazine) drugs on arachidonic acid metabolism in isolated rat aorta and lung have been studied. Dipyridamole significantly increased the formation of PGI2 in aorta and lung. Nifedipine and verapamil decreased the formation of PGI2 in aorta, these drugs though significantly increased the formation of PGI2 in lung. Nifedipine showed no appreciable effect on the generation of TxA2 in rat aorta but in lung both nifedipine and verapamil reduced TxA2 formation though significantly only in the latter case. Dipyridamole showed no effect. The beneficial effect of dipyridamole, seems, at least in part, to be due to its ability to enhance the production of PGI2 both in the aorta and lung, and probably in other tissues as well. Nifedipine and verapamil may show their antianginal effect by a combined effect of enhanced PGI2 and reduced TxA2 formation in lung. In lung, whereas hydralazine reduced the formation of both PGI2 and TxA2, propranolol increased the formation of PGI2. Hydralazine reduced the formation of TxA2 and increased PGI2 formation in aorta. The effect of the drugs on the ability of rat aorta to inhibit collagen induced platelet aggregation of human blood platelets was also examined.

Animals↗
PubMed1983

Effect of prolonged treatment with acetylsalicylic acid and dipyridamole on platelet thromboxane A2 production in atherosclerotic subjects.

We evaluated the effect of four weeks treatment with 90 mg and 1500 mg of acetylsalicylic acid (ASA), 990 mg of ASA together with 225 mg of dipyridamole and 225 mg of dipyridamole daily on the production of thromboxane A2 (TxA2) by platelets of atherosclerotic subjects. All doses of ASA studied inhibited 99% or more of TxA2 production from the third day to the end of the treatment, whereas dipyridamole did not have any effect. After the treatment, TxA2 production recovered in two weeks. Our results argue against the clinical relevance of the recent suggestions that salicylate accumulating during prolonged treatment with ASA could reduce the effect of the parent drug on the synthesis of TxA2 by platelets. Our data also dispute the inhibition of TxA2 synthesis as an antithrombotic mechanism of dipyridamole.

Aged↗
PubMed1994

Investigations on the ethanol-induced flushing reaction: effects of propranolol and dipyridamole on acetaldehyde and prostacyclin metabolism.

Disulfiram, an aldehyde dehydrogenase (ALDH) inhibitor, induces a flushing reaction upon the ingestion of ethanol, exerting aversion against alcohol that has been used in the treatment of alcoholism. This unpleasant response has been associated with an accumulation of acetaldehyde, and more recently, with an increase in vascular prostacyclin (PGI2) production. To evaluate the possibility of evoking the flushing reaction with drugs less toxic than disulfiram, we studied the effects of propranolol and dipyridamole on ALDH and PGI2. Acetaldehyde oxidation rate was assessed by gas chromatography in mitochondria from rats treated with these drugs for seven days. Prostacyclin generation was determined in rat aortic rings incubated in Krebs-Ringer with these drugs separately and associated to acetaldehyde, and measured by radioimmunoassay of 6-keto-PGF1 alpha. Propranolol inhibited acetaldehyde oxidation rate whereas dipyridamole did not. Furthermore, propranolol increased blood acetaldehyde levels without affecting ethanol elimination rate. Both drugs stimulated prostacyclin synthesis but only dipyridamole enhanced the stimulatory effect of acetaldehyde on vascular prostacyclin production. These results strongly suggest the possibility of producing a deterrent effect on the consumption of alcohol by using propranolol or dipyridamole. In contrast to disulfiram, these drugs could potentially induce the flushing reaction in humans in the presence of low acetaldehyde concentrations; this new therapeutic approach might have an important clinical and toxicological relevance.

Acetaldehyde↗
PubMed1988

Safety and diagnostic accuracy of dipyridamole-thallium imaging in the elderly.

The noninvasive diagnosis of coronary artery disease in the elderly can occasionally be difficult. Intravenous dipyridamole-thallium imaging is a potentially useful diagnostic test to determine presence and severity of coronary disease; however, the safety of the procedure has not been determined in an older population. The side effect profile and frequency of severe ischemic responses after 0.56 mg/kg of intravenous dipyridamole were compared in 101 patients greater than or equal to 70 years old and 236 patients less than 70 years old. There were no side effects in 64% and 62% of patients greater than or equal to 70 and less than 70 years old, respectively (p = NS). Among the 337 patients tested, there were no complications of myocardial infarction or death. The most common cardiac side effect was chest pain, which occurred in 21 (21%) of the 101 patients aged greater than or equal to 70 years and in 64 (27%) of the 236 patients less than 70 years (p = NS). Aminophylline was required to reverse cardiac or noncardiac side effects in 15 (15%) and 36 (15%) of the patients greater than or equal to 70 and less than 70 years old, respectively (p = NS). A severe ischemic response occurred in 2% and 2.5% of patients greater than or equal to 70 and less than 70 years old, respectively (p = NS). The sensitivity of intravenous dipyridamole-thallium imaging for obstructive coronary artery disease was 86% (25 of 29) and 83% (68 of 82) in older and younger patients, respectively (p = NS); the specificity was 75% (6 of 8) and 70% (16 of 23), respectively (p = NS). Thus, intravenous dipyridamole-thallium imaging is a safe noninvasive method for assessment of older patients with obstructive coronary disease; its side effect profile and diagnostic accuracy are similar to those seen in younger patients. The technique is associated with severe ischemic responses in only a small minority of patients.

Adult↗
PubMed1990

Alterations in endocardial vascular resistance after reperfusion in a low flow, high demand model of ischemia: effects of dipyridamole and WEB-2086, a platelet-activating factor antagonist.

To determine if alterations in regional coronary vascular resistance could occur in the type of myocardial ischemia present in severe angina pectoris, regional perfusion and function were studied in 35 conscious sedated dogs. A stenosis producing severe hypokinesia of the perfused segment was created for 2 h on the left anterior descending coronary artery and 10 episodes of 1 min of high demand ischemia (atrial pacing at a rate sufficient to induce dyskinesia in the hypoperfused segment) were superimposed before reperfusion. The dogs were randomized into three treatment groups: control (n = 13), dipyridamole (n = 10) or WEB-2086 (n = 12), an antagonist of the effects of the endogenous platelet-activating factor. During stenosis, residual endocardial blood flow in the ischemic but nonnecrotic area averaged 0.72 +/- 0.14, 0.38 +/- 0.13 and 0.68 +/- 0.17 ml/min per g in the control, WEB-2086 and dipyridamole groups, respectively. Twenty-four hours after reperfusion, endocardial blood flow in the ischemic area was significantly lower in control dogs (1.04 +/- 0.15 ml/min per g) than in dogs treated with WEB-2086 (1.44 +/- 0.28 ml/min per g; p less than 0.03) or dipyridamole (3.00 +/- 0.83 ml/min per g; p less than 0.01). Accordingly, in control dogs, endocardial coronary vascular resistance in the ischemic area was increased after reperfusion from 85 +/- 11 to 124 +/- 27 mm Hg/(ml/min per g) (p less than 0.05) after 24 h. In contrast, coronary vascular resistance in the ischemic area remained unchanged in dogs receiving WEB-2086 (77 +/- 8 to 79 +/- 9 mm Hg/(ml/min per g); p = NS) and it decreased significantly in dogs receiving dipyridamole (72 +/- 8 to 44 +/- 8 mm Hg/(ml/min per g); p less than 0.01). Regional function after 24 h remained depressed in all three groups. These data indicate that low flow, high demand ischemia induces alterations in the subendocardial microvasculature. Such alterations in regional coronary vascular resistance might play a role in several forms of ischemic heart disease such as in severe angina, but they appear susceptible to improvement by therapeutic interventions that influence granulocyte and platelet activation.

Adenosine↗
PubMed1992

Prognostic value of dipyridamole thallium-201 imaging in elderly patients.

The prognostic value of intravenous dipyridamole myocardial perfusion imaging has not been studied in a large series of elderly patients. Patients greater than or equal to 70 years of age with known or suspected coronary artery disease were evaluated to determine the predictive value of intravenous dipyridamole thallium-201 imaging for subsequent cardiac death or nonfatal myocardial infarction. Of the 348 patients, 207 were symptomatic and 141 were asymptomatic; 52% of the asymptomatic group had documented coronary artery disease. During 23 +/- 15 months of follow-up, there were 52 cardiac deaths, 24 nonfatal myocardial infarctions and 42 revascularization procedures (percutaneous transluminal coronary angioplasty in 20; coronary artery bypass surgery in 22). Clinical univariate predictors of a cardiac event included previous myocardial infarction, congestive heart failure symptoms, hypercholesterolemia and diabetes (all p less than 0.05). The presence of a fixed, reversible or combined thallium-201 defect was significantly associated with the occurrence of cardiac death or myocardial infarction during follow-up (p less than 0.05). Cardiac death or nonfatal myocardial infarction occurred in only 7 (5%) of 150 patients with a normal dipyridamole thallium-201 study (p less than 0.001). Stepwise logistic regression analysis of clinical and radionuclide variables revealed that an abnormal (reversible or fixed) dipyridamole thallium-201 study was the single best predictor of cardiac events (relative risk 7.2, p less than 0.001). As has been demonstrated in younger patients, previous myocardial infarction (relative risk 1.8, p less than 0.001) and symptoms of congestive heart failure at presentation (relative risk 1.6, p = 0.02) were also significant independent clinical predictors of cardiac death or myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

The influence of BIBW22BS, a dipyridamole derivative, on the antiproliferative effects of 5-fluorouracil, methotrexate and gemcitabine in vitro and in human tumour xenografts.

Dipyridamole is known as a potent inhibitor of facilitated diffusion-mediated nucleoside transport as well as a modulator of 'classical' multidrug resistance. BIBW22BS, a derivative of dipyridamole, has been found to be 20- to 100-fold more potent in the reversal of multidrug resistance when compared to the parent compound. In parallel, we studied the efficacy of BIBW22BS in the modulation of the antiproliferative effects of 5-fluorouracil, methotrexate and gemcitabine in human cancer cell lines. BIBW22BS, at non-toxic concentrations up to 1.0 microM, increased the antiproliferative effects of 5-fluorouracil 2- to 6-fold in seven of the eight colon cancer cell lines tested in a dose-dependent manner. The addition of 1.0 microM BIBW22BS to methotrexate resulted in a slight increase in the antiproliferative effects, but inhibited the activity of gemcitabine 30- to 100-fold in various cancer cell lines. In vitro, no notable difference was found between BIBW22BS and dipyridamole in their capacity to modulate the activity of the antimetabolites studied. BIBW22BS did not affect the growth inhibition induced by 5-fluorouracil or gemcitabine in human tumour xenografts grown subcutaneously in nude mice. We confirmed the higher potency of BIBW22BS when compared to dipyridamole in the reversal of drug resistance in the Pgp-positive COLO 320 cell line.

Animals↗
PubMed2005

Superior efficacy of clopidogrel plus acetylsalicylic acid compared with extended-release dipyridamole plus acetylsalicylic acid in preventing arterial thrombogenesis in healthy volunteers.

INTRODUCTION: Recent ex vivo platelet aggregometry data indicate that clopidogrel 75 mg/day plus acetylsalicylic acid (ASA) 75 mg/day is a more potent antiplatelet regimen than the marketed combination of dipyridamole+ASA. The present study was designed to assess the antithrombotic effect of both dual antiplatelet regimens using a human ex vivo model of arterial thrombosis. MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled, crossover study. During two 10-day treatment periods separated by a 14-day washout period, 23 healthy male volunteers received once-daily clopidogrel 75 mg plus acetylsalicylic acid 75 mg, or twice-daily extended-release dipyridamole 200 mg plus acetylsalicylic acid 25 mg. Assessments were made at baseline and on Day 10 of each period. Arterial thrombus formation was induced ex vivo by exposing a collagen-coated surface in a parallel-plate perfusion chamber to native blood for 3 min (arterial wall shear rate 2600 s(-1)). Total platelet and fibrin deposition was determined by immunoenzymatic methods. RESULTS: Compared with baseline values, the mean inhibition of total platelet deposition was 63.9+/-5.9% with clopidogrel plus acetylsalicylic acid, compared with 18.4+/-5.6% for extended-release dipyridamole plus acetylsalicylic acid (67% reduction; 95% CI, 49-79%; p<0.0001). Corresponding figures for fibrin deposition were 64.9+/-4.8% and 18.3+/-9.7%, respectively (58% reduction; 95% CI, 45-67%; p<0.0001). Both treatments were well tolerated. CONCLUSIONS: Clopidogrel plus acetylsalicylic acid showed significantly superior antithrombotic efficacy compared with extended-release dipyridamole plus acetylsalicylic acid in preventing arterial thrombogenesis in humans.

Adolescent↗
PubMed2006

Synergistic effect of cilostazol and dipyridamole mediated by adenosine on shear-induced platelet aggregation.

INTRODUCTION: The Cilostazol Stroke Prevention Study found that cilostazol, a phosphodiesterase 3 inhibitor, can reduce the risk of subsequent stroke in Japanese patients with cerebral infarction. Here, we measured the effects of cilostazol in vitro on shear-induced platelet aggregation, an important mechanism of thrombosis at arterial bifurcations or stenotic lesions. We also evaluated the influences of intrinsic adenosine on the ability of cilostazol to inhibit shear-induced platelet aggregation by investigating the effect of dipyridamole, an inhibitor of cellular adenosine reuptake, in combination with cilostazol in vitro. MATERIALS AND METHODS: We measured platelet aggregation induced by a shear rate of 10,800 s(-1) in whole blood and in platelet-rich plasma from healthy volunteers using a cone-plate streaming chamber. RESULTS: Both cilostazol and adenosine dose-dependently inhibited shear-induced platelet aggregation in platelet-rich plasma samples. Adding a low concentration of adenosine (0.3 microM) did not inhibit shear-induced platelet aggregation, but significantly enhanced the inhibitory effect of cilostazol in platelet-rich plasma. Dipyridamole dose-dependently inhibited shear-induced platelet aggregation in whole blood and significantly enhanced the inhibitory effect of cilostazol on shear-induced platelet aggregation, but did not affect shear-induced platelet aggregation in platelet-rich plasma. The inhibitory effects of cilostazol combined with dipyridamole in whole blood were almost completely reversed by adenosine deaminase. CONCLUSIONS: Dipyridamole appears to synergistically enhance the inhibitory effect of cilostazol on shear-induced platelet aggregation by maintaining high plasma levels of adenosine.

Adenosine↗
PubMed2001

Safety, feasibility, and diagnostic accuracy of accelerated high-dose dipyridamole stress echocardiography.

Protocols for dipyridamole stress testing have evolved in the last 16 years in the neverending quest of optimal diagnostic accuracy and user friendliness. Higher dipyridamole dose in a shorter infusion time provides higher sensitivity, but concern over safety is still controversial. An accelerated high-dose (0.84 mg/kg in 6 minutes without atropine) dipyridamole stress test was performed on 1,295 patients in 2 echocardiographic laborotories: Institute of Clinical Physiology of Pisa and Niguarda Hospital of Milan. During testing, there were no deaths and no patients had ventricular fibrillation. Major adverse reactions occurred in 3 cases (1 every 431 studies): 1 myocardial infarction, 1 brief cardiac asystole, and 1 transient ischemic attack. Overall feasibility was 97%. In 66 patients with normal function at rest who were evaluated off therapy, with coronary angiography performed independently of test results, the accelerated high-dose protocol showed a sensitivity of 85% (confidence interval [CI] 73% to 92%) and a specificity of 93% (CI 83% to 97%) for angiographically assessed coronary artery disease (quantitatively assessed diameter reduction > or = 50%). Diagnostic accuracy of the accelerated high dose was 89% (CI 79% to 95%). Thus, accelerated high-dose dipyridamole stress echocardiography was reasonably safe and well tolerated. This protocol is especially appealing for its excellent diagnostic accuracy coupled with the short imaging time and no need for drug cocktails.

Aged↗
PubMed1983

In vivo quantitation of platelet deposition on human peripheral arterial bypass grafts using indium-111-labeled platelets. Effect of dipyridamole and aspirin.

Indium-111-labeled autologous platelets, injected 48 hours after operation, were used to evaluate the thrombogenicity of prosthetic material and the effect of platelet inhibitor therapy in vivo. Dacron double-velour (Microvel) aortofemoral artery bifurcation grafts were placed in 16 patients and unilateral polytetrafluoroethylene femoropopliteal grafts were placed in 10 patients. Half the patients in each group received platelet inhibitors before operation (dipyridamole, 100 mg 4 times a day) and after operation (dipyridamole, 75 mg, and acetylsalicylic acid, 325 mg 3 times a day); the rest of the patients served as control subjects. Five-minute scintigrams of the graft region were taken with a gamma camera interfaced with a computer 48, 72, and 96 hours after injection of the labeled platelets. Platelet deposition was estimated from the radioactivities of the grafts and expressed as counts per 100 pixels per microcurie injected. Dipyridamole and aspirin therapy significantly reduced the number of platelets deposited on Dacron grafts and prevented platelet accumulation over 3 days. With the small amount of platelet deposition on polytetrafluoroethylene femoropopliteal artery grafts even in control patients, platelet inhibitor therapy had no demonstrable effect on platelet deposition on these grafts. It is concluded that (1) platelet deposition on vascular grafts in vivo can be quantitated by noninvasive methods, and (2) dipyridamole and aspirin therapy reduced platelet deposition on Dacron aortofemoral artery grafts.

Adult↗
PubMed1987

Different degrees of ischemic threshold stratified by the dipyridamole-echocardiography test.

Dipyridamole-echocardiography (echo) testing, exercise stress testing and coronary arteriography were performed in 141 patients with effort chest pain. Patients were separated into 5 groups according to the dose of dipyridamole needed to induce ischemia (0.56 mg/kg over 4 minutes vs 0.84 mg/kg over 10 minutes) and to the time of onset of the asynergy with the small dose (within vs beyond 3 minutes after the end of dipyridamole administration): group 1--early positive response to a small dose (33 patients); group 2--late positive response to a small dose (29 patients); group 3--negative response to a small dose, positive response to a large dose (17 patients); group 4a--negative response to both large and small doses, with significant coronary artery disease (CAD) (32 patients); and group 4b--negative response to small and large doses, without CAD (30 patients). All patients in groups 1, 2 and 3 had significant CAD. The rate-pressure product on exercise stress testing was measured at 0.10 mV of ST-segment shift in patients with a positive response and at peak exercise in patients with a negative response. Rate-pressure product significantly separated group 1 and group 2 from each other (157 +/- 46 and 229 +/- 33 mm Hg X beats/min X 1/100, respectively, mean +/- standard deviation) and from group 3, group 4a and group 4b (284 +/- 40, 290 +/- 51, and 298 +/- 45 mm Hg X beats/min X 1/100); values in the 3 latter groups overlapped.2+ Thus, the dipyridamole-echo test can stratify groups of patients with different levels of ischemia threshold on effort.

Adult↗
PubMed1997

Diagnostic and prognostic value of dipyridamole and dobutamine stress echocardiography in patients with Q-wave acute myocardial infarction.

The aim of this study was to compare dipyridamole and dobutamine stress echocardiography, performed early in patients with acute myocardial infarction (AMI) to evaluate residual ischemia, viability, and prognosis. Fifty patients (mean age 55 +/- 9 years, 47 men, 3 women) with AMI, all treated with thrombolytic therapy, underwent standard dipyridamole and dobutamine tests, within the fifth day of the event. Wall motion score index and the 16 segments model were used to evaluate contractility. Forty-seven patients underwent coronary angiography within the tenth day of the event. The mean follow-up was 24 +/- 12 months. No side effects occurred during both tests. Both dipyridamole and dobutamine tests were positive for ischemia, in 32 and 33 of 47 patients, respectively (sensitivity 73% and 75%; specificity 67% and 67%); these tests induced an improvement of contractility in 23 and 38 of 139 abnormal segments at baseline, respectively (sensitivity 52% and 86%; specificity 100% and 100%). Cardiac events occurred in 26 of 50 patients, 22 with a positive dipyridamole test and 21 with positive dobutamine test. Thus, both tests were feasible, safe, and useful to evaluate residual ischemia, viability, and prognosis. No significant differences were found in sensitivity and specificity between tests.

Adult↗
PubMed1998

Risk stratification of patients undergoing peripheral vascular revascularization by combined resting and dipyridamole echocardiography.

Patients with advanced peripheral vascular disease have an increased cardiac morbidity and mortality. The aim of this study was to assess the predictive value of rest and stress echocardiography for perioperative and late cardiac events in 110 patients undergoing limb revascularization. All patients underwent preoperative clinical and echocardiographic evaluation at rest and by dipyridamole stress testing to assess cardiac risk. Patients with > or =3 clinical Eagle markers, low left ventricular ejection fraction at rest, or positive dipyridamole stress test results were considered at high cardiac risk. To record adverse cardiac events, all patients were monitored during and after surgery, and followed for at least 1 year after hospital discharge. Cardiac complications occurred in 10 patients (9.7%) perioperatively (2 fatal myocardial infarctions), and in 13 (13%) at 1-year follow-up (7 fatal myocardial infarctions). Echocardiographic evaluation was the best predictor of early (p <0.00003) and late (p <0.0003) cardiac complications. No patient with a negative dipyridamole stress test result and good left ventricular ejection fraction had cardiac complications, either postoperatively or during follow-up. Clinical evaluation does not appear sufficiently sensitive for predicting perioperative cardiac events, but was valuable in predicting late cardiac complications (p <0.0002). Our data show that echocardiographic evaluation of resting dysfunction and of the ischemic response to dipyridamole is a good predictor of perioperative cardiac risk, and is superior to generally available clinical data. Echocardiographic evaluation is useful in defining a low-risk group of patients who can safely undergo limb revascularization, whichever surgical procedure is proposed.

Aged↗
PubMed1999

Effect of dipyridamole on QT dispersion in vasospastic angina pectoris.

Life-threatening ventricular arrhythmias have frequently been documented in patients with vasospastic angina. Moreover, the incidence of ventricular arrhythmias has been closely associated with increased QT dispersion. However, the underlying mechanism responsible for this arrhythmogenesis has not been clarified. The effects of dipyridamole and subsequent aminophylline administration on QT dispersion were examined in 35 patients with vasospastic angina and 30 patients with atypical chest pain. None of the patients enrolled in this study revealed any significant stenosis in coronary angiography. QT dispersion during dipyridamole followed by aminophylline administration was compared between the 2 groups. The baseline QT dispersion was similar in both groups (vasospastic angina: 27 +/- 8 ms; atypical chest pain: 28 +/- 7 ms). No significant changes in QT dispersion were observed in patients with atypical chest pain by dipyridamole (23 +/- 9 ms) and subsequent aminophylline administration (23 +/- 5 ms). However, the QT dispersion in patients with vasospastic angina increased significantly by dipyridamole administration (53 +/- 14 ms, p <0.0001) and returned to baseline by subsequent aminophylline administration (26 +/- 10 ms). Our data suggest that the disparity of ventricular repolarization in vasospastic angina may be mediated by increased endogenous adenosine.

Adult↗
PubMed1995

Failure of protective effect of captopril and enalapril on exercise and dipyridamole-induced myocardial ischemia.

Fifteen patients with angiographic evidence of significant coronary artery disease, exertional myocardial ischemia, and positive dipyridamole echocardiographic test results at basal conditions and after 7 days of placebo treatment were prospectively studied to see whether captopril (containing sulfhydryl) and enalapril (nonsulfhydryl) modify myocardial ischemia induced by exercise testing and the effects of dipyridamole echocardiographic testing on regional myocardial contractility. Patients were randomized to captopril (150 mg/day in 3 separate doses) or enalapril (20 mg/day) for 1 week. At the end of this period each patient crossed over to the alternate regimen after a washout period of 7 days. Exercise stress testing and dipyridamole echocardiographic testing were repeated at the end of each treatment period. Neither captopril nor enalapril had a significantly greater anti-ischemic effect than placebo in any patient. Exercise duration, time to onset of ST-segment depression, maximal workload, degree of ST-segment depression, and rate-pressure product were not affected by either drug. Neither captopril nor enalapril improved dipyridamole-induced mechanical dysfunction or ST-segment depression.

Adult↗
PubMed1995

Nonlimited exercise test combined with high-dose dipyridamole for thallium-201 myocardial single-photon emission computed tomography in coronary artery disease.

Clinical, electrocardiographic, and thallium-201 single-photon emission computed tomography data were evaluated in 397 consecutive patients divided into 3 groups according to coronary hyperemic stimulation: 186 patients (group I; Ex) had maximal symptom-limited exercise ergometric stress testing, 93 patients (group II; Dip) had intravenous dipyridamole (0.7 to 0.8 mg/kg) stress testing, and 118 patients (group III; Dip+Ex) had dipyridamole (0.7 to 0.8 mg/kg) plus nonlimited (i.e., symptom-limited) exercise stress testing, achieving a maximal workload (mean +/- SD) of 102 +/- 37 W. Clinical tolerance was higher in Ex than in Dip groups (p < 0.01), and tended to be higher in Dip+Ex than in Dip groups (p = NS). Image quality--as judged by signal-to-noise ratios--was superior in Ex and Dip+Ex groups when compared with the Dip group (p < 0.01). Chest pain and electrocardiographic positivity were more frequent in the Dip+Ex group than in the Dip group (p < 0.05), despite more extensive coronary artery disease (CAD) in the Dip group; and reversible scintigraphic defects were more frequent in Dip+Ex versus Dip (p < 0.01) and in Ex versus Dip groups (p < 0.05) in patients with established CAD, as well as for the whole group. We conclude that, in patients unable to achieve 85% of their maximal predicted heart rate, the combination of high-dose dipyridamole plus nonlimited exercise stress testing is superior to dipyridamole stress testing alone, and comparable to maximal exercise testing.

Aged↗
PubMed1997

Chronic oral dipyridamole as a 'novel' antianginal drug: the collateral hypothesis.

Dipyridamole is an adenosine transport blocker that produces elevation of tissue adenosine levels. The oral formulation has long been used as a 'coronary vasodilator', but inappropriate vasodilation can lead to a pro-ischemic effect. However, available evidence linking adenosine to angiogenesis raises the possibility of a therapeutically relevant anti-ischemic effect of the drug. Molecular biology data show that in a hypoxic milieu, increased interstitial adenosine increases proliferation of endothelial cells in culture by stimulating A1 and A2 adenosine receptors and induces vascular endothelial growth factor which leads to angiogenesis. Morphologic data indicate that chronic, intermittent dipyridamole administration increased endomyocardial capillary length density by 33% in hypertensive and 11% in normotensive rabbits. Experimental data suggest that chronic treatment with dipyridamole increases collateral flow and decreases exercise-induced left ventricular dysfunction in the territory dependent upon a critical coronary stenosis. Clinical data indicate that the meta-analysis of all published double-blind, placebo-controlled, randomized trials assessing the effect of dipyridamole as an antianginal agent showed a highly significant drug benefit (odds ratio = 0.299, confidence intervals = 0.202-0.443). Treatment duration (log time in days) was significantly correlated to the observed benefit (log odds) (r = -75, P = 0.0031), consistently with a structural change in the collateral coronary circulation requiring time to emerge. The available data support the 'adenosine collateral hypothesis' (i.e., a beneficial angiogenetic effect of chronic endogenous adenosine accumulation). The angiogenetic effect would be different from the coronary vasodilator effect in several respects: coronary anatomical target (mainly capillaries instead of arterioles); cellular target (mainly endothelium rather than smooth muscle cell); receptor target (A1 and A2 rather than A2 adenosine receptors); time required for effect (weeks or months rather than minutes or hours); clinical use (possibly therapeutic for angiogenesis; mainly diagnostic for vasodilator stress testing). Prospective, properly designed trials are needed to assess convincingly the efficacy of a drug used for 40 years and yet possibly prematurely discarded as an effective antianginal treatment.

Adenosine↗