Dipyridamole augments the antiinflammatory response during human endotoxemia.

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.

• Authors: 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
• Journal: Critical care (London, England) (Crit Care) Vol. 15 Issue 6 Pg. R289 ( 2011) ISSN: 1466-609X [Electronic] England
• PMID: 22129171 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Endotoxins
• Equilibrative Nucleoside Transport Proteins
• Nitroprusside
• Dipyridamole
• endotoxin, Escherichia coli
• Creatinine
• Glutathione Transferase
• Acetylcholine
• Norepinephrine

Topics

• Acetylcholine (pharmacology)
• Creatinine (urine)
• Dipyridamole (therapeutic use)
• Double-Blind Method
• Endotoxemia (drug therapy, immunology)
• Endotoxins (pharmacology)
• Equilibrative Nucleoside Transport Proteins (antagonists & inhibitors)
• Forearm (blood supply)
• Glutathione Transferase (urine)
• Humans
• Immunity, Innate (drug effects)
• Inflammation (microbiology)
• Male
• Nitroprusside (pharmacology)
• Norepinephrine (pharmacology)
• Oxidative Stress (drug effects)
• Young Adult