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CLINICAL RESEARCH: ISCHEMIC PRECONDITIONING

Caffeine Prevents Protection in Two Human Models of Ischemic Preconditioning

Niels P. Riksen, MD^_*,,_*, Zhigang Zhou, MD^_*, Wim J.G. Oyen, MD, PhD, Rogier Jaspers, MD, Bart P. Ramakers, MSc^_*, Rene M.H.J. Brouwer, MD, PhD, Otto C. Boerman, PhD, Neil Steinmetz, MD, PhD^||, Paul Smits, MD, PhD^_*, and Gerard A. Rongen, MD, PhD^_*,

^_* Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
Department of Cardiothoracic Surgery, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
^|| North American Scientific, Theseus Imaging Division, Boston, Massachusetts.

Manuscript received February 15, 2006; revised manuscript received April 4, 2006, accepted April 10, 2006.

^_* Reprint requests and correspondence: Dr. Niels P. Riksen, Department of Pharmacology-Toxicology 149, Radboud University Nijmegen Medical Center, Geert Grooteplein 21, 6525 EZ Nijmegen, the Netherlands. (Email: N.Riksen{at}aig.umcn.nl).

OBJECTIVES: 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 [ClinicalTrials.gov] ).

Abbreviations and Acronyms   IP = ischemic preconditioning   Isch Ex = ischemic exercise

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