Does caffeine reduce dipyridamole-induced protection against ischemia-reperfusion injury?

Dipyridamole has several pharmacological properties including phosphodiesterase
inhibition, inhibition of the equilibrative nucleoside transporter (ENT1) and
scavanging of free radicals. Of these properties, inhibition of the
equilibrative nucleoside transporter has been characterized in detail in humans
in vivo. Based on this action of dipyridamole, we hypothesized that this drug
prevents ischemia-reperfusion injury by augmenting the protective actions of
endogenous adenosine. This hypothesis was recently confirmed in our forearm
model of ischemia-reperfusion injury with annexin A5 scintigraphy as read-out
variable. In this model, dipyridamole appeared to be protective against
ischemia-reperfusion injury. Although this study has demonstrated significant
ex-vivo inhibition of ENT1 on erythrocytes by dipyridamole, other properties of
dipyridamole could still be responsible for this observed benefit.
Caffeine is a rather potent competitive antagonist of adenosine receptors
in-vitro and in-vivo. In humans, we have shown that caffeine inhibits
adenosine-induced vasodilatation. Furthermore, caffeine inhibits the
hemodynamic actions of ENT inhibitors in humans in-vivo. Recently, we also have
demonstrated that caffeine prevents the protective action of ischemic
preconditioning in our forearm ischemia-reperfusion model as well as in an
ex-vivo human atrial model. In this study, caffeine did not affect annexin A5
targetting after ischemic exercise in the absence of ischemic preconditioning.

The purpose of this project is to explore the interaction between caffeine and
dipyridamole on ischemia-reperfusion injury in the forearm.

20 Healthy male volunteers will receive a one-week treatment with dipyridamole
(slow release; 200 mg twice daily). On day 7, volunteers will visit the
research centre after a 24 hour abstinence from caffeine containing beverages.
Here caffeine (4 mg/kg) or placebo will be infused intravenously in 10 minutes
in a randomized double-blind fashion. 30 Minutes thereafter ischemic isometric
muscle contraction of the non dominant forearm will be performed. Upon
reperfusion radiolabeled Annexin A5 is injected intravenously. Annexin A5
retention will be recorded by nuclear imaging of both hands 60 and 240 minutes
after injection of Annexin A5. The non-exercising hand serves as an internal
control for non-specific Annexin A5 binding.

10 Volunteers receive coffeine 4mg/kg intravenously just before ischemic
exercise. The other 10 volunteers will receive placebo (0,9% NaCl).

This study will be executed at the Clinical Research Centre Nijmegen under
close medical supervision. All medical personnel at the research centre has
been trained in basic life support, including the use of an assisted electric
defibrillator (AED), which is available at the research centre.
Treatment with placebo, caffeine or dipyridamole is not expected to harm the
volunteers. During the first days of treatment, a headache may occur. Ischemic
hand gripping will temporarily result in pain in the forearm. This is
completely reversible upon reperfusion.
Administration of radiolabeled annexin A5 results in an effective dose of less
than 5 mSv, well within the range of accepted exposure to radioactivity for
human research. Participation in this research does not interfere with possible
diagnostic or therapeutic procedures with X-rays of radioactivity in the
future. For research purposes, volunteers will only be allowed to participate
in studies involving radioactivity once per 2 years.
Occurrence of an allergic reaction is theoretically possible upon
administration of Annexin A5, however there have been no allergic reaction
reported in all volunteers exposed to Annexin A5.
The volunteers will not benefit directly from participating in this study.