Caffeine Prevents Protection in Two Human Models of Ischemic Preconditioning

Caffeine Prevents Protection in 2 Human Models of Ischemic Preconditioning Niels P. Riksen, Zhigang Zhou, Wim J. G. Oyen, Rogier Jaspers, Bart P. Ramakers, Rene M. H. J. Brouwer, Otto C. Boerman, Neil Steinmetz, Paul Smits, Gerard A. Rongen Ischemic preconditioning is mediated by adenosine receptor stimulation. We demonstrated that the adenosine receptor antagonist caffeine impairs ischemic preconditioning in 2 human models of ischemia-reperfusion injury. Targeting of 99mTc-Annexin A5 after ischemic exercise was used as end point of ischemia-reperfusion injury in the thenar muscle in vivo. In vitro, recovery of contractile function of human atrial trabeculae was used as end point. In both models, caffeine impaired the beneficial effects of preconditioning in a concentration that is attained in daily life after drinking 2 to 4 cups of coffee. We studied whether caffeine impairs protection by ischemic preconditioning (IP) in humans. Ischemic preconditioning is critically dependent on adenosine receptor stimulation. We hypothesize that the adenosine receptor antagonist caffeine blocks the protective effect of IP. 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). 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). Caffeine abolishes