Research

Dipyridamole augments the antiinflammatory response during human endotoxemia

Bart P Ramakers^1,2, Niels P Riksen^1,3, Thijmen H Stal², Suzanne Heemskerk^1,2, Petra van den Broek¹, Wilbert HM Peters⁴, Johannes G van der Hoeven², Paul Smits¹ and Peter Pickkers^2,5*

• * Corresponding author: Peter Pickkers p.pickkers@ic.umcn.nl

Author Affiliations

¹ Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands

² Department of Intensive Care Medicine, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands

³ Department of Internal Medicine, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands

⁴ Department of Gastroenterology, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands

⁵ Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands

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Critical Care 2011, 15:R289 doi:10.1186/cc10576

Published: 30 November 2011

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.