Cochrane Review: Dipyridamole for Preventing Major Vascular Events in Patients With Vascular Disease

Schryver, E.L.L.M. De; Algra, Ale; Gijn, J. van

doi:10.1161/01.str.0000082381.23938.0e

Cited by 56 publications

(34 citation statements)

References 25 publications

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“…1 A metaanalysis of comparable trials concluded that the dipyridamole/aspirin combination was effective in secondary prevention of vascular events but expressed concern that this was the result of the inordinate contribution of a single clinical trial, ESPS 2. 6 A subsequent metaanalysis confirmed the effectiveness of dipyridamole/ aspirin in preventing recurrence of ischemic stroke and other vascular events, even when results from ESPS 2 were not included in the analysis. 7 A post hoc analysis of the data from ESPS 2 showed that the efficacy of the dipyridamole/aspirin combination was greater in patients with the highest risk of stroke and those who had other cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 92%

Role of Adenosine and Nitric Oxide on the Mechanisms of Action of Dipyridamole

Gamboa

Abraham

Diedrich

et al. 2005

Stroke

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Background and Purpose-The combination of dipyridamole and aspirin has been shown to be more effective than aspirin alone in the secondary prevention of stroke. Dipyridamole may act by inhibiting adenosine uptake, thus potentiating its actions. Dipyridamole also inhibits cGMP-specific phosphodiesterases (PDE) and, through this mechanism, could potentiate cGMP-mediated actions of nitric oxide. Methods-To define the mechanism of action of dipyridamole, we studied the local vascular effects of adenosine, acetylcholine (NO-mediated dilation), and nitroprusside (cGMP-mediated dilation) in a double-blind study after treatment with dipyridamole/aspirin (200 mg dipyridamole/25 mg aspirin twice a day) or aspirin control for 7 days in 6 normal volunteers. Vasodilators were administered into the brachial artery in the nondominant arm in random order and forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results-Adenosine at a dosage of 125 g/min increased FBF from 4.6Ϯ0.9 to 29.4Ϯ5.3 (539% increase) with dipyridamole/aspirin and from 3.9Ϯ0.8 to 12Ϯ2.5 mL/100 mL forearm/min (208% increase) with aspirin alone (Pϭ0.007). In contrast, dipyridamole/aspirin did not alter the response to acetylcholine or to nitroprusside. The magnitude of adenosine-induced vasodilation correlated with plasma dipyridamole concentrations (r 2 ϭ0.6); no correlation was observed with acetylcholine-or nitroprusside-induced vasodilation. Similar potentiation of adenosine, but not acetylcholine or nitroprusside, was observed in 7 additional subjects when adenosine, acetylcholine, and nitroprusside were given in random order before and 2 hours after a single dose of dipyridamole/aspirin. Conclusion-The

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Section: Discussionmentioning

confidence: 92%

Role of Adenosine and Nitric Oxide on the Mechanisms of Action of Dipyridamole

Gamboa

Abraham

Diedrich

et al. 2005

Stroke

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“…Dipyridamole is a cardiovascular drug that is currently being used in the clinic because of 1) its coronary dilatory properties and 2) its ability to inhibit platelet aggregation (Humphreys et al, 2002;MacWalter and Shirley, 2002;Pettigrew and Williams, 2002;De Schryver et al, 2003). This is based, at least in part, on some interesting pharmacological effects elicited by dipyridamole (DPY) on cardiac myocytes and other mammalian cells, in that it is recognized to be 1) an inhibitor of phosphodiesterases V and VI, thereby increasing intracellular levels of cyclic AMP, and even more potently cyclic GMP (Komas et al, 1991;Beavo, 1995), and 2) an inhibitor of nucleoside transport (Hammond et al, 1985).…”

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confidence: 99%

Dipyridamole Alters Cardiac Substrate Preference by Inducing Translocation of FAT/CD36, but Not That of GLUT4

Luiken

Coort²,

Willems³

et al. 2004

Mol Pharmacol

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In cardiac myocytes, uptake rates of glucose and long-chain fatty acids (FA) are regulated by translocation of GLUT4 and FA translocase (FAT)/CD36, respectively, from intracellular stores to the sarcolemma. Insulin and contractions are two major physiological stimuli able to induce translocation of both transporters and therefore enhance the uptake of both substrates. Interestingly, the cardiovascular drug dipyridamole was able to enhance FA uptake but had no effect on glucose uptake. The selective stimulatory effect of dipyridamole on FA uptake was unrelated to its effects on phosphodiesterase inhibition and on nucleoside transport inhibition. However, dipyridamole-stimulated FA uptake was abolished in the presence of sulfo-N-succinimidylpalmitate, which indicated that FAT/CD36 is involved in the uptake process. Furthermore, the effect was additive to that of insulin but not to that of the AMPelevating agent oligomycin, indicating that dipyridamole stimulates FAT/CD36-mediated FA uptake by activating the AMP-activated protein kinase (AMPK) signaling pathway. Dipyridamole, however, neither influenced the intracellular AMP content nor induced activation of AMPK. Finally, dipyridamole was able to induce FAT/CD36 translocation from intracellular storage sites to the sarcolemma but had no effect on the subcellular distribution of GLUT4. It is concluded that beyond AMP-activated protein kinase the contraction-induced and AMPK-mediated signal branches off into separate mobilization of GLUT4 and of FAT/CD36, and that dipyridamole activates a yet unidentified target in the FAT/CD36 mobilizing branch.

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“…11) Therefore, it is likely that various responses as well as inhibition of OAB are evoked if the concentration of extracellular adenosine is increased by the inhibition of ENT1. In fact, an ENT1 inhibitor, dipyridamole, exhibits coronary dilating effects and antiplatelet aggregation activity, 28) while draflazine exhibits myocardial protection effects during ischemia in humans. 29) Whether or not KW-7158 also exerts these pharmacological effects awaits further investigation.…”

Section: Discussionmentioning

confidence: 99%

The Anti-overactive Bladder Activity of KW-7158 Is Mediated by Blocking Equilibrative Nucleoside Transporter-1

Nishiya

Yamagata

Fukuda

et al. 2014

Biological & Pharmaceutical Bulletin

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KW-7158 is a novel therapeutic candidate for treating overactive bladder (OAB) with a unique mode of action: suppression of sensory afferent nerves. However, the molecular target of this compound remains unknown. We herein report the identification of the KW-7158 target to be equilibrative nucleoside transporter-1 (ENT1). A membrane protein expression library of ca. 7000 genes was expressed in a dorsal root ganglion cell line, which we had previously generated, and subjected to screening for binding with a fluorescent derivative that retains high binding activity to the target. The screening revealed that only cells transfected with an ENT1 expression vector exhibited significant binding. We next performed [ 3 H]KW-7158 binding experiments and an adenosine influx assay and found that KW-7158 binds to and inhibits ENT1. To further demonstrate the pharmacological relevance, we evaluated other known ENT1 inhibitors (nitrobenzylthioinosine, dipyridamole, draflazine) in an in vitro bladder strip contraction assay and the rat spinal cord injury OAB model. We found that all of the inhibitors exhibited anti-OAB activities, of which the potencies were comparable to that of adenosine influx inhibition in vitro. These studies demonstrated that the pharmacological target of KW-7158 is ENT1, at least in the rat OAB model. Our results will aid understanding of the precise mechanism of action of this drug and may also shed new light on the use of the adenosine pathway for the treatment of OAB.Key words nociceptive neuron; overactive bladder; adenosine transporter; drug target identification KW-7158 is a drug candidate for overactive bladder (OAB).1-3) Pharmacological studies using rats with xyleneirritated bladders, 4) cultured dorsal root ganglion (DRG) neurons, 5) and isolated bladder strips 6) suggest that KW-7158 has a unique mechanism of action, namely, it inhibits the contraction of the bladder smooth muscle by suppressing the activity of sensory nerves. This unique mode of action distinguishes KW-7158 as a drug candidate that may be free from the side effects caused by other anti-OAB drugs. However, the molecular target of KW-7158 remains elusive.We have previously shown that the target exists in the rat DRG using [ 3 H] KW-7158 radioligand binding assays. 6) To facilitate target identification, we have generated various DRG neuron-like cell lines, including TRD-10 cells, which express a large amount of the target, and TRD-49 cells, which express a negligible amount of the target. 6)In this study, using the DRG cell lines and a KW-7158 fluorescent derivative, we first screened the membrane protein expression library to identify clones expressing KW-7158 binding molecules. This resulted in the identification of a single clone that codes equilibrative nucleoside transporter-1 (ENT1). Further in vitro and in vivo pharmacological studies demonstrated that KW-7158 is a novel ENT1 inhibitor and that the inhibition of ENT1 counteracts overactive bladder in the rat spinal cord injury OAB model. MATERIALS AND METHODSReagents KW-...

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Cochrane Review: Dipyridamole for Preventing Major Vascular Events in Patients With Vascular Disease

Cited by 56 publications

References 25 publications

Role of Adenosine and Nitric Oxide on the Mechanisms of Action of Dipyridamole

Role of Adenosine and Nitric Oxide on the Mechanisms of Action of Dipyridamole

Dipyridamole Alters Cardiac Substrate Preference by Inducing Translocation of FAT/CD36, but Not That of GLUT4

The Anti-overactive Bladder Activity of KW-7158 Is Mediated by Blocking Equilibrative Nucleoside Transporter-1

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