On the role of adenosine in classical and interorgan preconditioning of the heart

Although adenosine is cardioprotective in the rat, there is general agreement that adenosine is not involved in ischemic preconditioning (IPC) in this species. Because evidence is accumulating that the signal transduction pathway leading to cardioprotection by IPC is stimulus-dependent, we hypothesized that the failure to show a role for adenosine might be due to the use of brief IPC stimuli. We therefore investigated whether myocardial adenosine receptor activation (and which of its subtypes) would play a role in IPC in the rat heart when longer IPC stimuli are employed. The concept of ischemic preconditioning (intraorgan protection) has been expanded to interorgan preconditioning (IOPC; myocardial protection by brief ischemia in other organs). The mechanism underlying IOPC remains elusive, however, although a role for adenosine and activation of a neurogenic pathway has been postulated. We therefore also tested the hypothesis that adenosine released by the remote ischemic organ stimulates local afferent nerves, which leads to activation of myocardial adenosine receptors. In pentobarbital-anesthetized rats, a preconditioning stimulus consisting of 3 sequences of 3-min coronary artery occlusion (CAO) each followed by 5 min of reperfusion limited infarct size produced by a 60-min CAO which was not affected by a high dose of the adenosine receptor antagonist 8-(p-sulfophenyl)theophylfine (8-SPT). In contrast, the protection afforded by a single 15-min CAO was abolished by the same dose of 8-SPT demonstrating not only the involvement of adenosine in IPC in rats, but also that this depends critically on the IPC stimulus. Selective blockade of A(1)-(low dose of 8-SPT) or A(3)-receptors (MRS-1191), blunted the protection by classical IPC with a 15-min CAO, while a combination of 10SPT and MRS 1191 abolished classical IPC, which implies that activation of both A(1)- and A(3)-receptors contributed to the protection by the 15-min CAO. IOPC with a 15-min mesenteric artery occlusion (MAO15), reduced infarct size produced by a 60-min CAO, which was abolished by pretreatment with the ganglion blocker hexamethonium, but not when hexamethonium was administered at 5 ruin of mesenteric artery reperfusion. In contrast, 8-SPT abolished IOPC independent of the timing of administration (either before or 5min following MAO15), indicating that adenosine receptors downstream of the neurogenic pathway (i.e. in the heart) are involved. Involvement of small intestinal adenosine receptors is suggested by the finding that intramesenteric artery (but not intraportal vein) infusion of adenosine (10 mug/min) was as cardioprotective as MAO15. This protection was also prevented by hexamethonium. In conclusion, in IOPC by a 15-min MAO adenosine locally released during small intestinal ischemia stimulates afferent nerves in the mesenteric bed during early reperfusion, thereby initiating a neurogenic pathway that ultimately leads to activation of myocardial adenosine receptors and hence cardioprotection.