Relative potencies of dipyridamole and related agents as inhibitors of cyclic nucleotide phosphodiesterases: Possible explanation of mechanism of inhibition of platelet function

McElroy, F.A.; Philp, Richard B.

doi:10.1016/0024-3205(75)90170-8

Cited by 70 publications

(15 citation statements)

References 24 publications

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“…Multiple forms of PDE activity are found in human blood platelets [7,9,10] and the presence of these PDE activities was confirmed in preliminary studies here. Cyclic AMP PDE was therefore assayed using two substrate concentrations, 0.2 /~M and 250 #M, to reflect the high and low affinity activities respectively.…”

Section: Resultssupporting

confidence: 72%

“…Cyclic nucleotide PDE activities from human blood platelets were measured by the method of THOMPSON et al, [6] directly from the freeze-thawed platelet-rich plasma (PRP) as described previously [7]. PRP (platelet count of 4 x 105/mm 3) was prepared from trisodium citrate anticoagulated blood [8] and was freezethawed once before assay.…”

Section: Phosphodiesterase Assaymentioning

confidence: 99%

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Cyclic nucleotide phosphodiesterase inhibition by a benzoic acid derivative

Killackey

Philp

1985

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Acetylsalicylic acid (ASA) and three structurally related benzoic acid derivatives, 2-acetylbenzoic acid (ABA), 3-methylphthalide (3-MP), and 3-hydroperoxy-3-methylphthalide (3-HMP), were tested for inhibitory effects on three human blood platelet cyclic nucleotide phosphodiesterase (PDE) activities. 3-MP caused a dose-dependent inhibition of the high and low affinity cyclic AMP PDE activities and the cyclic GMP PDE activity. 3-HMP had some inhibitory effects but only on the low affinity cyclic AMP PDE activity. ASA and ABA had no effects. This study shows that progressive structural changes in the ASA molecule can shift the pharmacological profile from a cyclooxygenase inhibitor (ASA) to an inactive compound (ABA) to a PDE inhibitor (3-MP) and back again to a cyclooxygenase inhibitor (3-HMP). It is proposed that the potent anti-inflammatory effects of 3-MP, which differ from those of ASA, are mediated through the inhibition of the cyclic nucleotide PDE system.

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Section: Resultssupporting

confidence: 72%

Section: Phosphodiesterase Assaymentioning

confidence: 99%

Cyclic nucleotide phosphodiesterase inhibition by a benzoic acid derivative

Killackey

Philp

1985

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“…Dipyridamole appears to potentiate myocardial preconditioning (14). In humans, dipyridamole is not a suitable tool to potentiate the cardioprotective effect of endogenous adenosine (15,16) and this might be due to its nonspecific actions like stimulation of prostacycline release and inhibition of phosphodiesterase (17,18).…”

Section: Introductionmentioning

confidence: 99%

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

Rongen¹,

Smits²,

Donck³

et al. 1995

J. Clin. Invest.

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In 12 healthy male volunteers (27-53 yr), a placebo-controlled randomized double blind cross-over trial was performed to study the effect of the intravenous injection of 0.25, 0.5, 1, 2, 4, and 6 mg draflazine (a selective nucleoside transport inhibitor) on hemodynamic and neurohumoral parameters and ex vivo nucleoside transport inhibition. We hypothesized that an intravenous draflazine dosage without effect on hemodynamic and neurohumoral parameters would still be able to augment the forearm vasodilator response to intraarterially infused adenosine. Heart rate (electrocardiography), systolic blood pressure (Dinamap 1846 SX; Critikon, Portanje Electronica BV, Utrecht, The Netherlands) plasma norepinephrine and epinephrine increased dose-dependently and could almost totally be abolished by caffeine pretreatment indicating the involvement of adenosine receptors. Draflazine did not affect forearm blood flow (venous occlusion plethysmography). Intravenous injection of 0.5 mg draflazine did not affect any of the measured hemodynamic parameters but still induced a significant ex vivo nucleoside-transport inhibition of 31.5±4.1% (P < 0.05 vs placebo). In a subgroup of 10 subjects the brachial artery was cannulated to infuse adenosine (0.15, 0.5, 1.5, 5, 15, and 50 ,ug/100 ml forearm per min) before and after intravenous injection of 0.5 mg draflazine. Forearm blood flow amounted 1.9+0.3 ml/100 ml forearm per min for placebo and 1.8±0.2, 2.0±0.3, 3.8±0.9, 6.3±1.2, 11.3±2.2, and 19.3±3.9 ml/100 ml forearm per min for the six incremental adenosine dosages, respectively. After the intravenous draflazine infusion, these values were 1.6±0.2 ml/100 ml forearm per min for placebo and 2.1±0.3, 3.3±0.6, 5.8±1.1, 6.9±1.4, 14.4±2.9, and 23.5±4.0 ml/100 ml forearm per min, respectively (Friedman ANOVA: P < 0.05 before vs after draflazine infusion). In conclusion, a 30-50% inhibition of adenosine transport significantly augments the fore- arm vasodilator response to adenosine without significant systemic effects. These results suggest that draflazine is a feasible tool to potentiate adenosine-mediated cardioprotection in man. (J. Clin. Invest. 1995. 95:658-668.)

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“…In addition to these in vivo observations, inhibition of ADP-induced platelet aggregation and release reaction in vitro by dipyridamole has been observed (5,6). The drug was previously shown to inhibit platelet phosphodiesterase (7)(8)(9) and the uptake of glucose (6), and adenosine (10)(11)(12) by platelets. Dipyridamole also potentiated the inhibitory effect of adenosine on ADP-induced platelet aggregation (7,8,13), and it was proposed that this is due to accumulation of adenosine which activates the platelet adenylate cyclase (14).…”

Section: Introductionmentioning

confidence: 99%