Caffeine prevents protection in two human models of ischemic preconditioning.
OBJECTIVE
We studied whether caffeine impairs protection by ischemic preconditioning (IP) in humans.


BACKGROUND
Ischemic preconditioning is critically dependent on adenosine receptor stimulation. We hypothesize that the adenosine receptor antagonist caffeine blocks the protective effect of IP.


METHODS
In vivo ischemia-reperfusion injury was assessed in the thenar muscle by 99mTc-annexin A5 scintigraphy. Forty-two healthy volunteers performed forearm ischemic exercise. In 24 subjects, this was preceded by a stimulus for IP. In a randomized double-blinded design, the subjects received caffeine (4 mg/kg) or saline intravenously before the experiment. At reperfusion, 99mTc-annexin A5 was administered intravenously. Targeting of annexin was quantified by region-of-interest analysis, and expressed as percentage difference between experimental and contralateral hand. In vitro, we assessed recovery of contractile function of human atrial trabeculae, harvested during heart surgery, as functional end point of ischemia-reperfusion injury. Field-stimulated contraction was quantified at baseline and after simulated ischemia-reperfusion, in a paired approach with and without 5 min of IP, in the presence (n=13) or absence (n = 17) of caffeine (10 mg/l).


RESULTS
Ischemic preconditioning reduced annexin targeting in the absence of caffeine (from 13 +/- 3% to 7 +/- 1% at 1 h, and from 19 +/- 2% to 9 +/- 3% at 4 h after reperfusion, p = 0.006), but not after caffeine administration (targeting 11 +/- 2% and 16 +/- 3% at 1 and 4 h). In vitro, IP improved post-ischemic functional recovery in the control group, but not in the caffeine group (8 +/- 3% vs. -8 +/- 5%, p=0.003).


CONCLUSIONS
Caffeine abolishes IP in 2 human models at a dose equivalent to the drinking of 2 to 4 cups of coffee. (The Effect of Caffeine on Ischemic Preconditioning; http://clinicaltrials.gov/ct/show/NCT00184912?order=1; NCT00184912).
Riksen
Niels P
NP
Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. N.Riksen@aig.umcn.nl
Zhou
Zhigang
Z
Oyen
Wim J G
WJ
Jaspers
Rogier
R
Ramakers
Bart P
BP
Brouwer
Rene M H J
RM
Boerman
Otto C
OC
Steinmetz
Neil
N
Smits
Paul
P
Rongen
Gerard A
GA
D000328:Adult; D017304:Annexin A5; D002110:Caffeine / Q000009:adverse effects* / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000494:pharmacology*; D004311:Double-Blind Method; D006801:Humans; D019194:Ischemic Preconditioning; D008297:Male; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000502:physiology; D015609:Organotechnetium Compounds; D058915:Purinergic P1 Receptor Antagonists; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D018047:Receptors, Purinergic P1 / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*
D017304:Annexin A5; D000697:Central Nervous System Stimulants; D015609:Organotechnetium Compounds; D058915:Purinergic P1 Receptor Antagonists; D019275:Radiopharmaceuticals; D018047:Receptors, Purinergic P1; C417036:technetium Tc 99m annexin V; D002110:Caffeine