Dipyridamole augments the antiinflammatory response during human endotoxemia

Bart P Ramakers, Niels P Riksen, Thijmen H Stal, Suzanne Heemskerk, Petra van den Broek, Wilbert H M Peters, Johannes G van der Hoeven, Paul Smits, Peter Pickkers, Bart P Ramakers, Niels P Riksen, Thijmen H Stal, Suzanne Heemskerk, Petra van den Broek, Wilbert H M Peters, Johannes G van der Hoeven, Paul Smits, Peter Pickkers

Abstract

Introduction: In animal models of systemic inflammation, the endogenous nucleoside adenosine controls inflammation and prevents organ injury. Dipyridamole blocks the cellular uptake of endogenous adenosine and increases the extracellular adenosine concentration. We studied the effects of oral dipyridamole treatment on innate immunity and organ injury during human experimental endotoxemia.

Methods: In a randomized double-blind placebo-controlled study, 20 healthy male subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide; LPS) intravenously after 7-day pretreatment with dipyridamole, 200 mg slow release twice daily, or placebo.

Results: Nucleoside transporter activity on circulating erythrocytes was reduced by dipyridamole with 89% ± 2% (P < 0.0001), and the circulating endogenous adenosine concentration was increased. Treatment with dipyridamole augmented the LPS-induced increase in the antiinflammatory cytokine interleukin (IL)-10 with 274%, and resulted in a more rapid decrease in proinflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6 levels directly after their peak level (P < 0.05 and < 0.01, respectively). A strong correlation was found between the plasma dipyridamole concentration and the adenosine concentration (r = 0.82; P < 0.01), and between the adenosine concentration and the IL-10 concentration (r = 0.88; P < 0.0001), and the subsequent decrease in TNF-α (r = -0.54; P = 0.02). Dipyridamole treatment did not affect the LPS-induced endothelial dysfunction or renal injury during experimental endotoxemia.

Conclusions: Seven-day oral treatment with dipyridamole increases the circulating adenosine concentration and augments the antiinflammatory response during experimental human endotoxemia, which is associated with a faster decline in proinflammatory cytokines.

Trial registration: ClinicalTrials (NCT): NCT01091571.

Figures

Figure 1
Figure 1
Schematic representation of the adenosine metabolism. Dipyridamole acts as an adenosine reuptake inhibitor through inhibition of the nucleoside transporter. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; SAH, S-adenosylhomocysteine.
Figure 2
Figure 2
Schematic presentation of the endotoxemia experiments.
Figure 3
Figure 3
Correlations between (a) the dipyridamole concentration at the moment of LPS administration and the (peak) adenosine concentration, 2 hours after LPS administration; (b) the peak adenosine concentration and peak IL-10 levels; (c) peak IL-10 concentrations and the decline in TNF-α levels (t = 2 to t = 90 minutes after LPS administration); and (d) peak IL-10 concentrations and the decline in IL-6 levels.
Figure 4
Figure 4
Box-and-whiskers (whiskers, range) of the cytokine response after LPS administration in placebo-treated subjects (open symbols) and dipyridamole-treated subjects (solid symbols), n = 10 subjects per group. The probability values refer to the statistical difference between the placebo- and dipyridamole-treated groups in response to LPS administration, as analyzed with a two-way ANOVA. *P < 0.05 between groups, as analyzed with a Bonferroni posttest.
Figure 5
Figure 5
Dose-response curve of intrabrachial infusion of (a) acetylcholine, (b) nitroprusside, and (c) norepinephrine on forearm blood flow (FBF) before (open symbols, dotted line) and 4 hours after administration of 2 ng/kg Escherichia coli LPS (solid symbols). Data are presented as percentages of baseline FBF of the intervention arm (mean ± SEM; n = 10 per group). Left panel shows placebo-treated subjects; right panel, subjects treated with dipyridamole. The probability values refer to the statistical difference between the dose-response curves, as analyzed with two-way ANOVA.
Figure 6
Figure 6
Box-and-whiskers (whiskers, range) of the endotoxemia-induced changes in FRAP. FRAP increases during endotoxemia, in both dipyridamole- and placebo-treated subjects (P = 0.08 and 0.02, respectively). No differences between groups were found, as analyzed with two-way ANOVA (P = 036).

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