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Comparative electrophysiologic effects of adenosine triphosphate and adenosine in the canine heart: influence of atropine, propranolol, vagotomy, dipyridamole and aminophylline.

The electrophysiologic effects of adenosine triphosphate (ATP) and adenosine and the modification of these effects by atropine, propranolol, vagotomy, dipyridamole and aminophylline were studied in a canine model. Both ATP and adenosine exerted transient, dose-dependent negative chronotropic and dromotropic effects on the sinoatrial and atrioventricular nodes, respectively. At all doses tested, the effects of ATP were more pronounced. Treatment with either atropine or propranolol plus bilateral cervical vagotomy attenuated the effects of ATP but not of adenosine. In the presence of propranolol plus vagotomy, both the negative chronotropic and dromotropic effects of ATP and adenosine were enhanced and attenuated in a similar manner by dipyridamole and aminophylline. Thus, when ATP and adenosine are injected rapidly into the right atrium of the intact canine heart, vagal involvement in the mechanism of action of ATP but not of adenosine is mainly responsible for the difference in the magnitude of the electrophysiologic effects of these 2 compounds, and only a small part of the electrophysiologic effects of ATP are the result of its degradation to adenosine.

Adenosine↗

Usefulness of dipyridamole-thallium-201 perfusion scanning for distinguishing ischemic from nonischemic cardiomyopathy.

To determine noninvasively the etiology of left ventricular (LV) dysfunction, 22 patients with a diagnosis of cardiomyopathy determined via cardiac catheterization and 5 normal control subjects underwent radionuclide ventriculography and intravenous dipyridamole-thallium-201 perfusion scanning. Both ischemically and nonischemically induced LV dysfunction had comparable global LV ejection fractions (24 +/- 6 vs 23 +/- 8%, respectively) and extent of segmental wall motion abnormalities. Right ventricular ejection fraction was significantly better in the group with an ischemic etiology of LV dysfunction (41 +/- 26 vs 13 +/- 10%, p less than 0.005) but significant group overlap was present. However, computer-assisted analysis of dipyridamole-thallium-201 myocardial perfusion scanning demonstrated more homogeneous myocardial perfusion in idiopathic cardiomyopathy (mean perfusion defect 25 +/- 11 vs 6 +/- 6%, p less than 0.001) and successfully predicted the correct etiology of LV dysfunction in 20 of 22 (91%) patients.

Cardiomyopathies↗

Prognostic value of intravenous dipyridamole thallium scintigraphy after an acute myocardial ischemic event.

Seventy-seven patients recovering from an acute coronary event were studied by intravenous dipyridamole thallium scintigraphy to evaluate the prognostic value and safety of the test in this patient subset. Forty-four patients (58%) had unstable angina and 33 (42%) had an acute myocardial infarction. One death occurred within 24 hours of testing. Sixty-eight patients were followed for an average of 12 months; 25, 31 and 23% had a fixed, reversible or combined thallium defect on their predischarge thallium scan. During follow-up, 10 patients died or had a nonfatal myocardial infarction; in each case, a reversible or combined myocardial thallium defect was present. Univariate analysis of 17 clinical, scintigraphic and angiographic variables showed that a reversible thallium defect and the angiographically determined extent of coronary artery disease were predictors of future cardiac events. The extent of coronary disease and global left ventricular ejection fraction were predictors of subsequent reinfarction or death. Logistic regression analyses revealed that a reversible thallium defect (p less than 0.001) and the extent of coronary disease (p less than 0.009) were the only significant predictors of a cardiac event. When death or reinfarction were the outcome variables, the extent of coronary disease (p less than 0.02) and left ventricular ejection fraction (p less than 0.06) were the only variables selected. Thus, intravenous dipyridamole thallium scintigraphy after an acute coronary ischemic syndrome is a useful and relatively safe noninvasive test to predict subsequent cardiac events.

Aged↗

Noninvasive cardiac risk stratification of diabetic and nondiabetic uremic renal allograft candidates using dipyridamole-thallium-201 imaging and radionuclide ventriculography.

The ability of noninvasive risk stratification using dipyridamole-thallium-201 (Tl-201) imaging and radionuclide ventriculography to predict perioperative and long-term cardiac events (myocardial infarction or cardiac death) was evaluated in 36 uremic diabetic and 29 nondiabetic candidates for renal allograft surgery. Of the 35 patients who underwent renal allograft surgery 8 +/- 7 months after the study, none had transient Tl-201 defects (although 13 had depressed left ventricular ejection fraction) and none developed perioperative cardiac events. During a mean follow-up of 23 +/- 11 months, 6 (9%) patients developed cardiac events. Logistic regression analysis was used to compare the predictive value of clinical data (including age, sex, diabetes, chest pain history, allograft recipient) and radionuclide data. Presence of transient Tl-201 defect and left ventricular ejection fraction were the only significant predictors of future cardiac events (p less than 0.01). No other patient variables, including diabetes or receiving a renal allograft, had either univariate or multivariate predictive value. All 3 patients with transient Tl-201 defects had cardiac events compared with only 3 of 62 (5%) patients without transient Tl-201 defect (p less than 0.0001). Mean left ventricular ejection fraction was lower in patients with cardiac events (44 +/- 13%) compared with patients without cardiac events (57 +/- 9%, p less than 0.005). Overall, 5 of 6 patients with cardiac events had either transient Tl-201 defects or depressed left ventricular ejection fraction. Dipyridamole-Tl-201 imaging and radionuclide ventriculography may be helpful in identifying uremic candidates for renal allograft surgery who are at low risk for perioperative and long-term cardiac events.

Adult↗

Decreased coronary vasodilatory capacity in hypertrophic cardiomyopathy determined by split-dose thallium-dipyridamole myocardial scintigraphy.

Split-dose thallium-dipyridamole myocardial scintigraphy was performed in patients with nonobstructive hypertrophic cardiomyopathy (HC) who had angiographically normal coronary arteries. The dipyridamole-induced increases in thallium-201 uptake, calculated to evaluate coronary vasodilatory capacity, were significantly lower in 30 patients with HC than in 13 control subjects (177 +/- 58 vs 281 +/- 46%) and the reductions were observed in both the septal and lateral segments. The reductions of the septal segment in HC patients were significantly greater than those in 10 hypertensive patients with comparable degrees of septal hypertrophy. Of patients with HC, 16 had increases in thallium uptake well below the normal range. Compared with those having normal increases, these patients had significantly lower exercise duration (11 vs 15 minutes), with 33% having ST depression develop at a workload less than or equal to 80 watts. These data indicate that approximately one-half of patients with HC have impaired coronary vasodilatory capacity that could be an important pathophysiologic abnormality of HC resulting in the development of myocardial ischemia and the impairment of cardiac performance during exercise.

Adolescent↗

Reverse redistribution of thallium-201 detected by SPECT imaging after dipyridamole in angina pectoris.

Reverse redistribution refers to a thallium-201 perfusion defect that develops or becomes more evident on delayed imaging compared with the initial image immediately after stress. To determine the diagnostic importance of reverse redistribution after intravenous dipyridamole, thallium-201 single photon emission computed tomography and quantitative coronary arteriography were performed in 90 men with angina pectoris. Of the 250 myocardial segments analyzed, reverse redistribution was present in 17 (7%). Minimal coronary cross-sectional area in proximal vessel segments was less than or equal to 2.0 mm2 more often in regions with transient perfusion abnormalities than in regions with reverse redistribution (66 vs 29%, p less than 0.05). Compared with regions exhibiting transient perfusion abnormalities, regions with reverse redistribution had larger proximal arterial diameters (1.9 +/- 1.1 vs 1.3 +/- 1.1 mm, p less than 0.001) and cross-sectional areas (3.9 +/- 3.1 vs 2.2 +/- 2.6 mm2, p less than 0.001). Coronary artery dimensions and relative stenosis severity did not differ between those regions with normal perfusion and those with reverse redistribution. Reverse redistribution detected by thallium-201 single photon emission computed tomographic imaging after dipyridamole is uncommon, appears to occur as frequently in normal subjects as in patients undergoing coronary arteriography and does not indicate the presence of severe coronary artery disease.

Adult↗

Usefulness of single-photon emission computed tomography of thallium-201 uptake after dipyridamole infusion for detection of coronary artery disease.

The diagnostic performance of single-photon emission computed tomography (SPECT) and planar imaging of thallium-201 uptake for the detection of coronary artery disease (CAD) was compared in 79 patients who underwent both dipyridamole thallium-201 scintigraphy and coronary angiography. Clinical subgroups were assigned by severity of CAD, presence of a prior myocardial infarction and the number of narrowed coronary arteries. The overall detection of CAD was 89% for SPECT and 67% for planar (p less than 0.001). For the anterior vascular territory, sensitivities for SPECT and planar imaging were 69 and 44% (p less than 0.01), respectively; for the posterior vascular territory, sensitivities were 80 and 54% (p less than 0.01). Receiver-operating characteristic analysis, using a 5-point evaluation scale, was performed for the anterior and posterior vascular territories. Receiver-operating characteristic curves generated for SPECT and planar studies demonstrated improved diagnostic performance by SPECT in the anterior vascular territory, but showed similar performance in the posterior territory because of lower SPECT specificity despite higher sensitivity at clinically relevant decision thresholds. In each clinical subgroup of patients, the detection of CAD by SPECT was significantly superior to that by planar imaging, regardless of the severity of stenosis or the number of significantly narrowed coronary arteries, or whether a myocardial infarction was present. Thus, SPECT thallium-201 scintigraphy is an important and necessary clinical tool for detecting CAD after dipyridamole infusion.

Adult↗

Dipyridamole thallium-201 imaging versus dobutamine echocardiography for the evaluation of coronary artery disease in patients unable to exercise.

The present study used 51 patients in a prospective, crossover, blinded comparison of dipyridamole thallium-201 imaging and dobutamine echocardiography for (1) detection of coronary artery disease (CAD), (2) detection of inducible ischemia, and (3) determination of myocardial viability. The detection of CAD was based on quantitative defects on initial planar thallium-201 images and resting or inducible wall motion abnormalities on echocardiography. Detection of ischemia was based on redistribution on delayed thallium-201 images and inducible wall motion abnormality on echocardiography. The myocardium in a region with resting wall motion abnormality was considered viable if it showed either redistribution or > 50% activity on delayed thallium-201 images, and if regional function either improved or worsened on echocardiography. The tests were comparable for the detection of CAD (53 and 59%, respectively, p = 0.23). Thallium-201 was superior to echocardiography for the detection of ischemia (35 vs 14%, respectively, p = 0.01). Although the incidence of viable myocardium was equivalent by the 2 tests (100 and 96%, respectively, p = 0.99) for each abnormally moving segment in the 24 patients with resting wall motion abnormality on echocardiography, it was greater on thallium-201 imaging (98 vs 68%, p < 0.01). It is concluded that because of its better ability to detect inducible myocardial ischemia and determine viability in myocardial segments showing reduced function, dipyridamole thallium-201 imaging appears to be superior to dobutamine echocardiography for the evaluation of CAD in patients unable to exercise.

Adult↗

Detection of viable tissue in healed infarcted myocardium by dipyridamole thallium-201 reinjection and regional wall motion studies.

Reinjection imaging with thallium-201 (Tl-201) may provide a convenient method of assessing myocardial viability. Twenty patients with a previous Q-wave healed myocardial infarction were examined to evaluate the detection of viable tissue in infarcted segments. All patients underwent to evaluate the detection of viable tissue in infarcted segments. All patients underwent dipyridamole Tl-201 tomographic imaging with reinjection of 1 mCi of Tl-201 after redistribution. Radionuclide ventriculography was performed before and after administration of 5 mg of dinitrate isosorbide sublingually for regional wall motion analysis. Patients presented with 38 fixed defects, 12 of which demonstrated improved Tl-201 uptake on reinjection; 10 of 12 reinjection-reversible segments were hypokinetic or normal after administration of nitrates, whereas 22 of 26 nonreversible segments remained akinetic or dyskinetic (p < 0.001). Of 20 patients, 9 had reinjection-reversible segments; coronary angiography revealed a patent infarct-related artery or collaterals, or both, in 7 of these patients. The infarct-related artery was patent or collaterals were present, or both, in 4 of 11 patients who did not improve with reinjection. It is concluded that reinjection of Tl-201 during dipyridamole Tl-201 scintigraphy may frequently detect viable tissue in infarcted segments in patients with a Q-wave infarction. Segments with reinjection reversibility usually do not remain dyskinetic or akinetic after administration of nitrates and have some residual flow on coronary angiography.

Coronary Angiography↗

Prospective trial of warfarin and dipyridamole in patients with membranoproliferative glomerulonephritis.

A prospective trial of warfarin and dipyridamole was performed in patients with membranoproliferative glomerulonephritis. Eighteen completed either a control or treatment year, and 13 completed both a control and treatment year. To obviate the bias of excluding control patients who had renal failure after one year, both an unpaired and a paired analysis were performed. The unpaired analysis compared 10 patients followed for an initial control year with eight patients receiving treatment first. Renal function remained stable over the year in the treated group, but worsened in the control group. Slopes of regression lines for reciprocal serum creatinine values were significantly different between groups (p less than 0.025). Urine protein excretion also decreased in the treated group. Four of 10 control patients had a two-fold increase in serum creatinine levels, but no treatment patient did. In the paired crossover analysis, significant differences in renal function were detected between control and treatment years in six patients whose renal function significantly changed over one of the years. In every instance, there was better preservation of renal function in the treatment year. Urinary protein also decreased significantly over the treatment year compared with the control year. Bleeding was the most frequent complication. These data suggest that warfarin and dipyridamole have a beneficial effect on renal function in membranoproliferative glomerulonephritis.

Adult↗

Prognostic implications of a negative dipyridamole-thallium scan: results in 360 patients.

PATIENTS AND METHODS: A total of 360 patients with either normal perfusion (314) or fixed defects (46) on dipyridamole-thallium scans were followed over an average period of 16 months. Of the 360 patients, 194 subsequently underwent major noncardiac surgery. RESULTS: There were a total of eight cardiac events including two postoperative complications (one fatal and one nonfatal myocardial infarction) and six cardiac events during long-term follow-up (one sudden death and five nonfatal infarctions). During the follow-up period, three patients underwent coronary artery bypass surgery. The low cardiac event rate could not be explained by a low pretest likelihood of coronary artery disease: 77% of the 360 patients had either typical angina pectoris, a previous myocardial infarction, or peripheral vascular disease, which is associated with a high prevalence of coronary artery disease. CONCLUSIONS: In patients with a high pretest likelihood of coronary artery disease, the absence of thallium redistribution on a dipyridamole-thallium scan denotes a very low (1%) cardiac risk for major noncardiac surgery as well as low long-term cardiac mortality (0.3%) and morbidity (1.4%) rates. The coronary death rate is comparable to that of patients with minimal (less than 50%) coronary stenoses.

Clinical Protocols↗

Endotoxic shock in the primate: effects of aspirin and dipyridamole administration.

A primate model was utilized to study the cardiovascular and coagulation effects of endotoxic shock. The therapeutic effectiveness of drugs such as aspirin and dipyridamole, which diminish platelet aggregation and adherence, were evaluated. From the data, it appears that the kidney is a target organ in endotoxic shock, at least when a bolus injection of endotoxin is administered. The precipitate falls in the renal artery flow (p less than 0.01) and platelet count (p less than 0.01), which occur 3 minutes after the intravenous injection of endotoxin, can be prevented in part by pretreatment with aspirin (40 mg/kg of body weight). The changes in the coagulation profile were of less magnitude, and the fibrin degradation products appeared late in the group pretreated with aspirin as compared to the other groups. The combination of dipyridamole and aspirin was not as effective as aspirin alone in achieving the apparently protective effect. The study suggests that the administration of aspirin to patients with gram-negative infections may be beneficial.

Animals↗

Nucleoside transporter of pig erythrocytes. Kinetic properties, isolation and reaction with nitrobenzylthioinosine and dipyridamole.

Rapid kinetic techniques were used to measure the transport of uridine in pig erythrocytes in zero-trans entry and exit and equilibrium exchange protocols. The kinetic parameters were computed by fitting appropriate integrated rate equations to the time-courses of transmembrane equilibration of radiolabeled uridine. Transport of uridine conformed to the simple carrier model with directional symmetry, but differential mobility of substrate-loaded and empty carrier. At 5 degrees C, the carrier moved about 30-times faster when loaded than when empty. Uridine transport was inhibited in a concentration-dependent manner by nitrobenzylthioinosine and dipyridamole and the inhibition correlated with the binding of the inhibitors to high-affinity binding sites on the cells (Kd about 1 and 10 nM, respectively). Thus, in its kinetic properties, differential mobility when empty and loaded, and sensitivity to inhibition by nitrobenzylthioinosine and dipyridamole, the transporter of pig erythrocytes is very similar to that of human erythrocytes. Also, the total number of high-affinity binding sites for nitrobenzylthioinosine and dipyridamole/cell were similar for the two cell types and the [3H]nitrobenzylthioinosine-labeled carrier of pig erythrocytes, just as that of human red cells, was mainly recovered in the band 4.5 protein fraction of Triton X-100-solubilized membranes. However, sodium dodecylsulfate-polyacrylamide gel electrophoresis of photoaffinity-labeled band 4.5 membrane proteins indicated a slightly higher molecular weight for the transporter from pig than human erythrocytes. We have also confirmed the lack of functional sugar transport in erythrocytes from adult pigs by measuring the uptake of various radiolabeled sugars. But in spite of the lack of functional sugar transport we recovered as much band 4.5 protein from pig as from human erythrocyte membranes.

Affinity Labels↗

Comparison of the equilibrium exchange of nucleosides and 3-O-methylglucose in human erythrocytes and of the effects of cytochalasin B, phloretin and dipyridamole on their transport.

Because of similarities in the physical and molecular properties of the nucleoside and sugar transporters of human erythrocytes and the photoaffinity labeling of the sugar transporter by 8-azidoadenosine (Jarvis et al. (1986) J. Biol. Chem. 261, 11077-11085), we have directly compared the equilibrium exchange of uridine and 3-O-methylglucose in these cells as measured by rapid kinetic techniques under identical experimental conditions. Both the Michaelis-Menten constant and maximum velocity were about 100-fold higher for 3-O-methylglucose exchange than for uridine exchange so that the first order rate constants for both transporters were about the same. When calculated on the basis of the number of nucleoside and sugar carriers per red cell estimated by equilibrium binding of nitrobenzylthioinosine and cytochalasin B, respectively, the turnover numbers for the sugar and nucleoside carriers with 3-O-methylglucose and uridine, respectively, as substrates were quite similar. Various sugars up to concentrations of 108 mM had no effect on the exchange of 500 microM uridine or adenosine, and uridine up to a concentration of 50 mM had no effect on the exchange of 10 mM 3-O-methylglucose. Adenosine, on the other hand, inhibited 3-O-methylglucose exchange in a concentration dependent manner, though not very effectively (IC50 approximately equal to 3 mM). Both uridine and 3-O-methylglucose exchange were inhibited in a concentration dependent manner by cytochalasin B, phloretin and dipyridamole, but cytochalasin B and phloretin were 100-times more effective in inhibiting 3-O-methylglucose than uridine exchange, whereas the opposite was the case for the inhibition by dipyridamole.

3-O-Methylglucose↗

Na(+)-dependent, active nucleoside transport in mouse spleen lymphocytes, leukemia cells, fibroblasts and macrophages, but not in equivalent human or pig cells; dipyridamole enhances nucleoside salvage by cells with both active and facilitated transport.

Formycin B influx studies have shown that P388 and L1210 mouse leukemia cells, mouse L929 cells, mouse RAW 309 Cr.1 cells, LK35.2 mouse B-cell hybridoma cells and cultured mouse peritoneal macrophages express both Na(+)-dependent, active and nonconcentrative, facilitated nucleoside transport systems. In the mouse cell lines, active transport represented only a minor nucleoside transport component and was detected only by measuring formycin B uptake in the presence of dipyridamole or nitrobenzylthioinosine, strong inhibitors of facilitated, but not of active, nucleoside transport. Inhibition of facilitated transport resulted in the concentrative accumulation of formycin B in cells expressing active nucleoside transport. Concentrative formycin B accumulation was abolished by treatment of the cells with gramicidin or absence of Na+ in the extracellular medium and strongly inhibited by ATP depletion or ouabain treatment. Mouse macrophages accumulated formycin B to 70-times the extracellular concentration in the absence of dipyridamole during 90 min of incubation at 37 degrees C. Thus active transport represents a major nucleoside transport system of these cells, similarly as previously reported for mouse spleen lymphocytes. In contrast to the various types of mouse cells, active formycin B transport was not detected in human HeLa cells, human H9, Jurkat and CEM T lymphoidal cells and pig spleen lymphocytes. These cells expressed only facilitated nucleoside transport with kinetic properties similar to those of the facilitated transporters of other mammalian cells.

Animals↗

Interaction of dipyridamole with lipids in mixed Langmuir monolayers.

Dipyridamole (DIP), a well known coronary vasodilator and coactivator of anti-tumor activity of a number of drugs, forms stable Langmuir monolayers with the zwitterionic lipid dipalmitoylphosphatidylcholine (DPPC) and the negatively charged dipalmitoylphosphatidylglycerol (DPPG) at an air/aqueous solution interface. The drug binds to the lipid molecules and change their packing density in the monolayer in the process of compression, the effect depending on the drug location in the monolayer, protonation of the drug and also on the charge state of the lipid. The incorporation of dipyridamole (DIP) into neutral DPPC monolayers causes them to be more expanded at low DIP concentrations but more condensed at high concentrations, resembling the effect of cholesterol. Maximum expansion occurs for a DIP concentration of 2 mol%. For slightly charged DPPG monolayers spread on ultra pure water, the monolayers become increasingly more expanded with increasing DIP concentrations. For the negatively charged DPPG monolayers spread on buffer solutions, the incorporation of DIP has similar effects to that observed for DPPC monolayers. This is probably due to the interaction between the charged DPPG molecules and the protonated DIP molecules. Also, introduction of protonated DIP brings an increase in surface potential of DPPG monolayers because the negative contribution from the double layer is decreased. The results indicated that DIP molecules are located deeper in the hydrophobic region of DPPC monolayers, whereas in DPPG ones they appear to be located very close to the polar head region. Due to the electrostatic interaction of protonated DIP with the charges on the polar heads of lipids it is inclined with respect to the plane of the monolayer.

1,2-Dipalmitoylphosphatidylcholine↗

Effects of two nucleoside transport inhibitors, dipyridamole and soluflazine, on purine release from the rat cerebral cortex.

The effects of two nucleoside transport inhibitors, dipyridamole and soluflazine, on adenosine, inosine and oxypurine release from the normoxic and hypoxic/ischemic rat cerebral cortex have been studied. Dipyridamole (500 micrograms/kg) enhanced adenosine release during hypoxic/ischemic challenges in comparison with saline-injected controls. It decreased the hypoxia/ischemia-elicited releases of inosine, hypoxanthine and xanthine. Both basal and hypoxia/ischemia-elicited releases of uric acid were elevated. Soluflazine, administered topically or systemically, failed to enhance adenosine release and did not consistently alter the hypoxia/ischemia-evoked releases of inosine, hypoxanthine and xanthine. Basal release of uric acid was elevated. The failure of either drug to elevate the basal or hypoxia/ischemia-evoked releases of adenosine above predrug levels illustrates one of the problems which may be inherent in the use of bidirectional nucleoside transport inhibitors for the manipulation of adenosine levels in the cerebral interstitial fluid.

Adenosine↗

Comparison of the inhibitory effects on the guinea-pig taenia coli of adenine nucleotides and adenosine in the presence and absence of dipyridamole.

Dipyridamole potentiated the inhibitory responses to ATP and ADP and in particular responses to AMP and adenosine. The results are discussed in relation to the known actions of dipyridamole and suggest that adenine nucleotides are metabolized to adenosine during contact with the preparation; and that previous observations of the relative potencies of adenine nucleotides and nucleosides do not represent the actual receptor agonist potencies because of rapid uptake of adenosine into the tissues.

Adenosine↗