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PubMed2001

Glucose-insulin-potassium treatment in combination with dipyridamole inhibits ischaemia-reperfusion-induced damage.

AIMS/HYPOTHESIS: Treatment with intravenous glucose-insulin-potassium has beneficial effects in reperfused patients, reducing mortality in patients with myocardial infarction by 28 %. We hypothesized that insulin response to glucose-insulin-potassium infusion might lead to vasodilation in ischemia/reperfusion (I/R). Hyperglycaemia and hyperinsulinaemia determine oxidative stress. We therefore investigated the microcirculatory changes following I/R after glucose-insulin-potassium or in association with glucose-insulin-potassium dipyridamole in hamster cheek pouch. METHODS: The control (I/R), glucose-insulin-potassium groups with and without dipyridamole were treated with saline, 300 g/l, 50 U/l insulin and 80 meq/l KCl infused at 0.2 ml. 100 g-1. h-1, and GIK plus dipyridamole (0.084 mg. 100 g-1 intravenously) at beginning, 30 min before ischaemia, and continuing through reperfusion. We measured microvessel diameter changes, arteriolar red blood cell velocity, permeability increase, capillary perfused length, leukocyte and platelet adhesion. RESULTS: Hyperglycaemia and hyperinsulinaemia did not cause vasodilation whereas in the glucose-insulin-potassium group with dipyridamole there was a marked arterial vasodilation with increased red blood cell velocity and perfused capillary length at reperfusion. Glucose-insulin-potassium infusion reversed the arterial vasoconstriction caused by I/R at reperfusion. Adhering leukocytes to venules decreased by 56 and 86 % while platelets adhering to microvessels was reduced by 52 and 72 % at reperfusion in glucose-insulin-potassium groups with and without dipyridamole, respectively. The permeability was decreased by GIK and completely suppressed by GIKD after I/R. Conclusion hypothesis: We demonstrated that GIK, when used in combination with dipyridamole, had beneficial effects on the capillary perfusion against I/R-induced injury. There was a marked reduction of leukocyte and platelet adhesion that can be explained by the antioxidant properties of dipyridamole.

Animals↗

PubMed1997

[Intracoronary dipyridamole reduces the incidence of acute coronary vessel occlusion in percutaneous transluminal coronary angioplasty--a prospective randomized study].

Even in the era of coronary stenting, acute coronary artery occlusion continues to represent a significant limitation of percutaneous transluminal coronary angioplasty (PTCA). Despite application of heparin and aspirin, abrupt vessel closure still occurs in 2-8%, depending on the definition applied. Especially patients receiving PTCA for acute coronary syndromes are at high risk for abrupt vessel closure. The formation of an intracoronary thrombus plays a central role in the pathogenesis of abrupt vessel closure. Dipyridamole induces dilatation of coronary arteries and prevents platelet aggregation by a mechanism that differs from that of aspirin. The primary purpose of the study was to evaluate whether adjunctive local intracoronary therapy with dipyridamole could reduce the incidence of coronary artery occlusion following PTCA. Secondary endpoints were defined as myocardial infarction, necessity for bypass grafting, and death. In 939 PTCA procedures performed for stable angina and in 155 angioplasty procedures for acute coronary syndromes (unstable angina, acute myocardial infarction), patients were randomized to receive conventional pretreatment consisting of heparin 15,000 I.E. and aspirin 500 mg i.v. or additional intracoronary infusion of dipyridamole (0.5 mg/kg body weight). Dipyridamole was applied in 550 interventions (455 interventions in men, 95 interventions in women, age = 59.2 +/- 8.4; 74 emergency procedures); conventional pretreatment was performed in 544 interventions (444 interventions in men, 100 interventions in women, age 58.3 +/- 7.9; 81 emergency procedures). Intracoronary application of dipyridamole resulted in a significant reduction in the incidence of abrupt vessel closure following PTCA. This significant reduction was observed in patients presenting with stable ischemia as well as in patients receiving PTCA for acute coronary syndromes. Concerning secondary end points, intracoronary application of dipyridamole did not affect the need for bypass grafting or the incidence of death following PTCA. Intracoronary application of dipyridamole was associated with a reduction in the incidence of myocardial infarction following PTCA which, however, failed to reach significance.

Adult↗

PubMed2000

Effect of dipyridamole on serum and urinary phosphate in X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is characterized clinically by rickets, hypophosphatemia and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin D is associated with hypercalcuria and nephrocalcinosis. Recently, intravenous and oral dipyridamole has been reported to decrease fractional excretion of phosphate in adults with idiopathic hyperphosphaturia. Our objective was to determine whether oral dipyridamole therapy reduces urinary phosphate excretion and increases serum phosphate concentration in children with XLH. A prospective study was performed in six children with XLH. The average age of the patients at the start of the study was 12.5+/-1.0 years. The effects of 12 weeks of oral dipyridamole therapy, at 4.4+/-0.4 mg/kg body weight per day, on serum phosphorous, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D, osteocalcin, tubular maximum for phosphate reabsorption (TmP/GFR), urinary calcium excretion, and cyclic adenosine 3',5'-monophosphate (cAMP) excretion, were compared to baseline levels. Our results show that there was no change in serum phosphorous concentration or TmP/GFR after 12 weeks of dipyridamole therapy. Dipyridamole therapy also had no effect on serum PTH, serum 1,25 (OH)2 vitamin D, alkaline phosphatase, osteocalcin levels, urinary calcium or cAMP excretion. We therefore concluded that in children with XLH, a 12-week course of dipyridamole had no effect on serum phosphorous or its urinary excretion. Dipyridamole therapy is unlikely to improve the bone disease in children with XLH.

Adolescent↗

PubMed2005

Antiplatelet and antithrombotic activity of cilostazol is potentiated by dipyridamole in rabbits and dissociated from bleeding time prolongation.

PURPOSE: To determine the antiplatelet effect of cilostazol (Pletal) and its interaction with dipyridamole in in vitro and in vivo rabbit models, and to see if it can be dissociated from bleeding time prolongation. METHODS: In vitro collagen-induced platelet aggregation was measured by an impedance-based aggregometer. The in vivo antithrombotic effect was evaluated in a rabbit carotid artery cyclic flow reduction (CFR) model, in which repetitive thrombosis was induced by mechanical injuries of the artery and stenosis. Template bleeding time was determined in rabbit ear arterioles and hindlimb nail cuticles. RESULTS: In vitro platelet aggregation was slightly inhibited by 4 microM cilostazol (22 +/- 6%), and modestly by 13 microM (57 +/- 3% of aggregation). While dipyridamole itself up to 13 microM had no significant inhibition, it potentiated the effect from cilostazol: in the presence of 4 microM dipyridamole, 4 microM cilostazol inhibited aggregation by 47 +/- 6%. Dipyridamole also potentiated the CFR reducing effect of cilostazol: combination of dipyridamole (no effect by itself) and cilostazol at 1 microM decreased CFRs to levels achieved by 3-4 microM cilostazol alone. Bleeding times were similar in controls and animals treated with cilostazol, or with cilostazol and dipyridamole. In contrast, aspirin (4 mg/kg), while reducing CFRs, significantly increased bleeding time. CONCLUSION: These results suggest that dipyridamole potentiates the antiplatelet effect of cilostazol without prolongation of the bleeding time, implying a potential novel combination antithrombotic therapy.

Animals↗

PubMed1991

Dilatation of the left ventricular cavity on dipyridamole thallium-201 imaging: a new marker of triple-vessel disease.

To investigate the significance and mechanism of dilatation of the left ventricular cavity on dipyridamole thallium-201 imaging, we performed both dipyridamole thallium-201 imaging and dipyridamole radionuclide angiography on 83 patients with known angiograms. The dipyridamole/delayed ratio of the left ventricular dimension from the thallium-201 image was defined as the left ventricular dilatation ratio (LVDR). An LVDR greater than the mean + two standard deviations in patients without coronary artery disease was defined as abnormal. Twenty-two of 83 patients showed an abnormal LVDR, and 18 of the 22 patients (82%) had triple-vessel disease. By defect and washout analysis, the sensitivity and specificity for correctly identifying the patients as having triple-vessel disease was 72% and 76%, respectively, whereas LVDR had a sensitivity of 72% and a specificity of 93%. When LVDR was used in combination with the defect and washout criteria, sensitivity increased to 84% without a loss of specificity. In those 22 patients with abnormal LVDRs, end-diastolic volume measured by radionuclide angiography did not change after dipyridamole infusion. Dilatation of the left ventricular cavity on dipyridamole thallium-201 imaging reflected relative subendocardial hypoperfusion induced by dipyridamole rather than actual chamber enlargement. The LVDR was moderately sensitive and highly specific for triple-vessel disease and provided complementary information to dipyridamole thallium-201 imaging.

Adult↗

PubMed1994

Comparison of thallium-201 single-photon emission computed tomographic scintigraphy with intravenous dipyridamole and arm exercise.

In patients who cannot perform treadmill exercise, both intravenous dipyridamole and arm exercise have been used with thallium-201 scintigraphy to detect significant coronary artery disease. However, no study has directly evaluated the results of intravenous dipyridamole and arm exercise thallium scintigraphy as compared with coronary angiography. It was the purpose of this study to compare intravenous dipyridamole and arm exercise thallium-201 single-photon emission computed tomographic (SPECT) scintigraphy for detection of significant coronary artery disease in patients who could not perform treadmill exercise. Data are presented for both intravenous dipyridamole and arm exercise thallium-201 SPECT scintigraphy in 18 men who could not perform treadmill exercise, and results are compared with those of coronary angiography. Ten of 11 (91%) patients with significant coronary artery disease were identified correctly, and the results of intravenous dipyridamole and arm exercise thallium scintigraphy were comparable. In patients without significant coronary artery disease, intravenous dipyridamole thallium images were interpreted correctly. However, initial arm exercise thallium images demonstrated a fixed inferior wall defect in two of seven patients without significant coronary artery disease. Images in one of these patients could not be retrieved from tape for further analysis. Review of the images in the other patient demonstrated relatively high background radioactivity, and when the images were displayed without background subtraction, the inferior wall was correctly interpreted as normal. We conclude that results of intravenous dipyridamole and arm exercise thallium-201 SPECT scintigraphy are comparable.

Coronary Angiography↗

PubMed1981

Platelet function studies in coronary artery disease. X. Effect of dipyridamole.

To evaluate the effects of dipyridamole on blood platelet function in patients with coronary artery disease, platelet counts and aggregation were examined in aortic and coronary venous blood. Before administration of dipyridamole, platelet counts and aggregation in response to adenosine diphosphate were less (p less than 0.02) in coronary venous than in aortic blood. Dipyridamole administration (100 mg) resulted in an increase in platelet counts and platelet aggregation in coronary venous blood so that the differences in aortic and coronary venous blood values were eliminated. These phenomena were probably related to inhibitory actions of dipyridamole on platelet adhesion to atherosclerotic vessels. To further study the mechanism of action, the direct effects of dipyridamole on in vitro platelet aggregation were evaluated. Although dipyridamole, in the concentrations used, had no effect on in vitro platelet aggregation, it greatly potentiated the aggregation inhibitory actions of exogenous prostacyclin. In vivo potentiation of endogenous prostacyclin and inhibitory actions on platelet adhesion are the most likely mechanisms of the potentially beneficial actions of dipyridamole.

Adenosine Diphosphate↗

PubMed1986

Acute effect of systemic versus intracoronary dipyridamole on coronary circulation.

Dipyridamole has been proposed as an ideal agent to evaluate coronary vascular reserve because it produces selective coronary vasodilation without systemic hemodynamic effect. The actions of intracoronary (IC) and intravenous (IV) dipyridamole on coronary blood flow and systemic hemodynamics were compared in 15 patients with chest pain syndrome and normal coronary arteries. They received IC dipyridamole, followed 10 minutes later by 0.5 mg/kg of IV dipyridamole. IC dipyridamole produced a 73% increase in coronary sinus flow without hemodynamic changes, except for a slight increase in pulmonary systolic and diastolic pressures. IV dipyridamole administration produced an additional 88% increase in coronary sinus flow, reaching 172% over baseline; it was also associated with a significant (p less than 0.01) increase in heart rate (78 +/- 14 vs 102 +/- 19 beats/min), cardiac index (4 +/- 0.7 vs 6.3 +/- 1.7 liters/min/m2), and pulmonary artery systolic (27 +/- 5 vs 34 +/- 7 mm Hg) and diastolic pressures (12 +/- 4 vs 19 +/- 7 mm Hg). These data suggest that the coronary vasodilatory effect seen after IV dipyridamole administration is related to mechanisms other than direct coronary vasodilation.

Adult↗

PubMed1989

Comparison of dipyridamole-Doppler echocardiography to thallium-201 imaging and quantitative coronary arteriography in the assessment of coronary artery disease.

This study was undertaken to determine whether Doppler measurements of systolic aortic and diastolic mitral blood flow velocities could reliably detect the presence of reversible myocardial perfusion defects during intravenous dipyridamole-thallium-201 imaging. In addition, the ability of dipyridamole-Doppler echocardiography to predict the presence of significant coronary artery disease (CAD) was evaluated. Baseline and post-dipyridamole Doppler studies were performed in 10 normal control subjects and 23 patients with CAD. Aortic peak velocity and acceleration increased from baseline to post-dipyridamole in normal subjects by 0.07 +/- 0.07 m/s (p = 0.016) and 2.1 +/- 2.0 m/s2 (p = 0.009), respectively. The ratio of early to late peak transmitral velocities decreased slightly in normal subjects, by 0.18 +/- 0.72 (difference not significant), whereas the ratio of early to late transmitral velocity-time integrals increased by 0.07 +/- 0.93 (difference not significant). The response of aortic velocity and acceleration to intravenous dipyridamole was not significantly different between normal subjects, patients without reversible thallium-201 perfusion defects and patients with reversible thallium-201 perfusion defects. Furthermore, only 3 of 14 subjects with reversible thallium-201 perfusion defects had abnormal (greater than 2 standard deviations from the mean) responses of aortic velocity or acceleration to intravenous dipyridamole. No patient had an abnormal response of the early to late mitral peak velocity ratio. In addition, the response of Doppler aortic and mitral indexes to intravenous dipyridamole was not able to identify the presence of significant CAD as assessed by quantitative coronary arteriography.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗

PubMed1990

Effect of dipyridamole at the usual oral dose on exercise-induced myocardial ischemia in stable angina pectoris.

A randomized, double-blind, placebo-controlled study was performed to investigate the effect of dipyridamole at a usual oral dose of 150 mg/day on 18 patients with angina pectoris and positive treadmill exercise electrocardiography. After their angina pectoris was stabilized in phase 1, the patients were randomly assigned to sequence group A or B. Group A received a placebo 3 times daily in phase 2 and then 50 mg of dipyridamole 3 times daily in phase 3. Group B received the treatment in the reverse order. The degree of ST depression and the threshold for angina pectoris in treadmill exercise electrocardiography, which was performed on the last days of phases 2 and 3, were compared. The mean duration of exercise was 5 minutes and 23 seconds during dipyridamole and 5 minutes and 13 seconds during placebo administration, with no significant difference. Dipyridamole caused an aggravating effect on the ST change (earlier appearance of ST depression and/or deeper total sum of ST depression at the end of the exercise) in 3 patients, a salutary effect in 5 and no effect in 10. Dipyridamole decreased the threshold for angina pectoris in 5 patients, increased it in 6 and did not change it in 7. To summarize, dipyridamole showed adverse effects (aggravative effects on the ST change and/or on the threshold for angina pectoris) in 6 patients, beneficial effects in 8 and no effect in 4. A usual oral dose of dipyridamole induced myocardial ischemia during exercise in some patients while it improved it in a similar number of patients.

Administration, Oral↗

PubMed1992

Feasibility of high-dose dipyridamole-magnetic resonance imaging for detection of coronary artery disease and comparison with coronary angiography.

To assess the feasibility, safety and usefulness of gradient-echo magnetic resonance imaging (MRI) combined with pharmacologic stress testing for the detection of coronary artery disease, 23 patients without previous myocardial infarction but with significant stenosis (greater than 70% diameter stenosis) of greater than or equal to 1 major coronary artery were selected for dipyridamole-MRI stress testing. Each patient underwent MRI at rest, and high-dose dipyridamole-MRI (0.75 mg/kg over 10 minutes) of corresponding basal and midventricular short-axis tomograms. Additionally, these patients performed symptom-limited exercise stress tests. All short-axis tomograms were evaluated on a standardized segmental basis by grading each segment as normal, hypokinetic, akinetic or dyskinetic. Dipyridamole-MRI was considered pathologic if segmental wall motion deteriorated by greater than or equal to 1 grade after dipyridamole. For comparison with coronary angiography, segmental wall motion gradings were related to the respective coronary artery territories in the short-axis plane. Pathologic dipyridamole-MRI was obtained in 18 of 23 (78%) patients. For 1- and 2-vessel diseases, sensitivity was 69 and 90%, respectively. Exercise stress tests were pathologic in 14 of 23 (66%) patients. For 1- and 2-vessel diseases, sensitivity of exercise stress test was 58% (7 of 12 patients) and 77% (7 of 9), respectively. Sensitivity/specificity of dipyridamole-MRI for the localization of the stenosed coronary artery was 78/100% for left anterior descending, 73/100% for left circumflex, and 88/87% for right coronary artery stenoses. It is concluded that dipyridamole-MRI is a feasible nonexercise-dependent test for detection and localization of functionally significant coronary artery disease.

Aged↗

PubMed1993

Comparison of dobutamine stress echocardiography, dipyridamole stress echocardiography and exercise stress testing for diagnosis of coronary artery disease.

To compare the value of dobutamine and dipyridamole stress echocardiography with exercise stress testing for the diagnosis of coronary artery disease (CAD), 80 patients with chest pain of suspected myocardial ischemic origin (57 with CAD and 23 without significant CAD) underwent dobutamine stress echocardiography (5 to 40 micrograms/kg/min), dipyridamole echocardiography (0.84 mg/kg over 10 minutes) and bicycle exercise electrocardiography after discontinuation of antianginal treatment. Dobutamine echocardiography and exercise testing revealed a higher overall sensitivity than dipyridamole echocardiography (79 vs 60%, p < 0.005; 77 vs 60%, p < 0.05, respectively); this finding was due to a higher dobutamine and exercise sensitivity in 1-vessel CAD (62 vs 33%, p < 0.05 for both tests), whereas sensitivity of the 3 tests was similar in multivessel CAD. Dobutamine and dipyridamole showed a higher specificity than exercise (83 vs 43%, p < 0.01; 96 vs 43%, p < 0.005, respectively). Diagnostic accuracy of dobutamine echocardiography was higher than that of exercise (80 vs 67%, p < 0.05), whereas the difference with dipyridamole (80 vs 70%) was not significant. In the tests that yielded positive results, double product during exercise was significantly higher than that during dobutamine and dipyridamole echocardiography. No major complications occurred during the tests, but adverse effects were more frequent during dobutamine testing. Thus, dobutamine echocardiography may be superior to dipyridamole echocardiography and exercise electrocardiography for the diagnosis of CAD.

Adult↗

PubMed1994

Dipyridamole first-pass radionuclide ventriculography: prediction of future cardiac events.

Dipyridamole thallium myocardial perfusion imaging is a useful alternative to stress testing in the diagnostic and prognostic assessment of patients with coronary artery disease. The diagnostic use of dipyridamole radionuclide ventriculography is much more controversial, but no long-term prognostic studies have been reported. Imaging results of 159 consecutive patients who were referred for dipyridamole first-pass radionuclide ventriculography were correlated with subsequent cardiac events over a mean follow-up period of 11 months. An abnormal response to dipyridamole infusion (any reduction in wall motion or absolute decrease in global left ventricular ejection fraction of > or = 5 ejection fraction units) was associated with an increased incidence of nonfatal myocardial infarction (4.5% vs 0%, p < 0.05) and cardiac-related death (9% vs 1%, p < 0.001). The sensitivity, specificity, and negative predictive value of dipyridamole first-pass radionuclide ventriculography in predicting future cardiac events were 86%, 71%, and 98%, respectively, with a relative risk of 15 (confidence interval 12.06 to 18.1). In conclusion, dipyridamole first-pass radionuclide ventriculography demonstrated significant prognostic value in a large unselected patient population. This technique may provide a widely applicable and useful alternative to dipyridamole thallium perfusion imaging in the assessment of cardiac risk in patients with coronary artery disease.

Aged↗

PubMed1993

Morphine-evoked release of adenosine from the spinal cord occurs via a nucleoside carrier with differential sensitivity to dipyridamole and nitrobenzylthioinosine.

We have investigated the potential role of a bi-directional nucleoside carrier in the release of endogenous adenosine from spinal cord synaptosomes by examining the effects of dipyridamole and nitrobenzylthioinosine (NBI) on evoked release of adenosine. When 40 pmol adenosine were added to synaptosomes, only 70 +/- 2% was recovered, suggesting 30% uptake of adenosine. Dipyridamole (0.1-10 microM) reduced this uptake and also increased basal adenosine release, probably due to inhibition of the re-uptake of adenosine derived from released nucleotide. In contrast, NBI (0.1-10 microM) had no effect on either uptake of added adenosine or on basal release of adenosine. Addition of K+ (24 mM) and morphine (10 microM) produced a 50-60% increase in the release of adenosine, and this was reduced 35-98% by both dipyridamole and NBI (0.01-10 microM). Dipyridamole (0.01-1 microM) had no effect on the release of nucleotides (detected as adenosine) induced by noradrenaline, 5-hydroxytryptamine (5-HT) and capsaicin (50 microM each), although 10 microM dipyridamole significantly reduced release evoked by noradrenaline and 5-HT. This latter effect of dipyridamole was determined not to be due to inhibition of ATP release when measured directly. Within the spinal cord, there is a removal system for adenosine which is dipyridamole-sensitive but NBI-insensitive. Release of adenosine, but not nucleotides, appears to occur via this carrier system. The inhibition of release by NBI, but its lack of effect on uptake, suggests the involvement of heterogeneous carrier molecules in adenosine uptake and release from the spinal cord.

Adenosine↗

PubMed1996

Dipyridamole enhances interleukin-1beta-stimulated nitric oxide production by cultured rat vascular smooth muscle cells.

We examined whether dipyridamole affected interleukin-1beta-stimulated nitric oxide (NO) production by cultured rat vascular smooth muscle cells. Interleukin-1beta stimulated the production of nitrite and nitrate, stable metabolites of NO, in a dose- and time-dependent manner in vascular smooth muscle cells. Dipyridamole (1-100 mu M) enhanced interleukin-1beta-induced nitrite production in a dose- and time-dependent manner. The mRNA expression of inducible NO synthase was up-regulated by dipyridamole (0.3-10 mu M) treatment in a dose-dependent manner. Both 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) and dibutyryl adenosine 3',5'-cyclic monophosphate (db-cAMP) enhanced the nitrite production in the presence of interleukin-1beta. Dipyridamole up-regulated the effect of both 8-bromo-cGMP and db-cAMP on the interleukin-1beta-induced nitrite production. Dipyridamole increased the intracellular cAMP content in the presence of interleukin-1beta (10 ng/ml), but did not affect the intracellular cGMP content. 8R*,9S*,11S*-(-)-9-hydroxy-9-n-hexyloxy-8-methyl-2,3,9,10- tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo-(a,g)-cy cloocta ++-(c,d,e)-trinden-1-one (KT 5720), a selective inhibitor of cAMP-dependent protein kinase, abolished the enhancement of interleukin-1beta-induced nitrite production by dipyridamole, whereas 8R*,9S*,11S*-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-ep oxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cyclo-octa-(c,d,e)-tr inden-1-one (KT 5823), an inhibitor of cGMP-dependent protein kinase, did not attenuate the enhancement. Furthermore, Rolipram and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-20-1724), cAMP-specific phosphodiesterase type IV inhibitors, augmented the interleukin-1beta-induced nitrite production. We concluded that dipyridamole enhanced the interleukin-1beta-induced NO production via an increase in intracellular cAMP content in cultured rat vascular smooth muscle cells.

Animals↗

PubMed1979

Effects of dipyridamole in experimental atherosclerosis. Action on PGI2, platelet aggregation and atherosclerotic plaque formation.

Experimental atherosclerosis in rabbits induced by feeding a standard atherogenic diet for 4 months resulted in an increased sensitivity of platelets to the proaggregatory action of collagen and ADP. Treatment with dipyridamole (3 x 10 mg/day i.m.) for 4 weeks normalized platelet loss in atherosclerotic rabbits and abolished the increased sensitivity to proaggregatory collagen, but not to ADP. Dipyridamole treatment lowered basal as well as PGI2-induced cAMP levels below values seen in platelets from normal rabbits, but the stimulation by PGI2 relative to basal cAMP levels was not affected or even increased by dipyridamole treatment. Dipyridamole did not affect the increased sensitivity of platelets from atherosclerotic rabbits to the antiaggregatory action of PGI2, indicating that dipyridamole decreased absolute cAMP levels, probably due to reduction of the adenine nucleotide pool in platelets without affecting the adenylate cyclase function. Dipyridamole enhanced atherosclerotic plaque formation in arterial walls. Basal as well as PGI2-stimulated cAMP content was lower in homogenates from atherosclerotic than from normal aortic tissue. Dipyridamole-treated animals showed a further decrease in basal as well as PGI2-stimulated cAMP content of the aortic tissue, suggesting that this decrease in cAMP content may be linked to the enhanced proliferative activity seen in artherosclerotic plaque formation.

Adenosine↗

PubMed1982

Inhibitory mechanism of dipyridamole on platelet aggregation ex vivo.

The effects of dipyridamole on platelet aggregation ex vivo and in vitro and on platelet cyclic AMP phosphodiesterase (PDE) were studied, and the mechanism of the ex vivo effects was assessed. Both the ADP- and collagen-induced aggregations ex vivo were inhibited dose-responsively by oral administration of dipyridamole. Maximum dipyridamole levels in the plasma were reached at 30 min after the administration. The inhibitory effects of dipyridamole on platelet aggregation ex vivo reached a maximum at between 1 and 2 hrs. On the other hand, the ADP-induced aggregation in vitro and cyclic AMP PDE activity were not inhibited until after 10 min of incubation at a low concentration of dipyridamole. This mode of inhibition of platelet aggregation in vitro and of cyclic AMP PDE activity agreed with the mode of inhibition in the case of platelet aggregation ex vivo. It is suggested therefore that the ex vivo effects, observed with only a low dipyridamole concentration in the plasma, may be due primarily to inhibition by dipyridamole of the cyclic AMP PDE in platelets.

Adenosine Diphosphate↗

PubMed1990

Effect of aspirin and dipyridamole treatment on prostacyclin production by human veins.

Patients admitted for surgical removal of varicose veins were treated in a blinded manner for 48 hours prior to surgery with either placebo, low-dose aspirin (25 mg twice daily), dipyridamole (150 mg twice daily) or both. Segments of vein excised at surgery were incubated with or without sodium arachidonate and subsequent prostacyclin (PGI2) production was measured without knowledge of treatment given. During the first 5 minute period of incubation in the presence of arachidonate, veins from dipyridamole-treated patients demonstrated increased (by 75%) arachidonate-stimulated PGI2 production compared to placebo-treated patients. By contrast, PGI2 production was reduced by 64% by aspirin treatment and 67% by aspirin plus dipyridamole compared to placebo-treated patients (p = less than 0.05). In unstimulated vein segments incubated in the absence of arachidonate, spontaneous PGI2 production during the first 5 minute incubation period was increased 32% following dipyridamole treatment but was unchanged following aspirin treatment. By contrast, unstimulated (spontaneous) PGI2 production in patients treated with aspirin plus dipyridamole was reduced by 57% (p = less than 0.05), compared to both placebo- and aspirin-treated patients, and by 71% (p = less than 0.05) compared to dipyridamole-treated patients. With repeated change of incubation medium, the ability of vein walls to produce PGI2 declined. This exhaustion was not prevented by drug treatment. However, drug effects between patient treatment groups were consistent over successive incubation periods. These results suggest that certain therapeutic benefits that might be achieved by enhancement of PGI2 production from vascular endothelium following dipyridamole treatment may be reduced by simultaneous aspirin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗