Anesthetic cardioprotection: the role of adenosine

Abstract

Brief periods of cardiac ischemia and reperfusion exert a protective effect against subsequent longer ischemic periods, a phenomenon coined ischemic preconditioning. Similarly, repeated brief episodes of coronary occlusion and reperfusion at the onset of reperfusion, called post-conditioning, dramatically reduce infarct sizes. Interestingly, both effects can be achieved by the administration of any volatile anesthetic. In fact, cardio-protection by volatile anesthetics is an older phenomenon than ischemic pre- or post-conditioning. Although the mechanism through which anesthetics can mimic ischemic pre- or post-conditioning is still unknown, adenosine generation and signaling are the most redundant triggers in ischemic pre- or post-conditioning. In fact, adenosine signaling has been implicated in isoflurane-mediated cardioprotection. Adenosine acts via four receptors designated as A1, A2a, A2b, and A3. Cardioprotection has been associated with all subtypes, although the role of each remains controversial. Much of the controversy stems from the abundance of receptor agonists and antagonists that are, in fact, capable of interacting with multiple receptor subtypes. Recently, more specific receptor agonists and new genetic animal models have become available paving way towards new discoveries. As such, the adenosine A2b receptor was shown to be the only one of the adenosine receptors whose cardiac expression is induced by ischemia in both mice and humans and whose function is implicated in ischemic pre- or post-conditioning. In the current review, we will focus on adenosine signaling in the context of anesthetic cardioprotection and will highlight new discoveries, which could lead to new therapeutic concepts to treat myocardial ischemia using anesthetic preconditioning.

Figure 1. Adenosine generation and signaling in cardioprotection

Extracellular generation via CD39 (Apyrase) and CD73 (5'-Ectonucleotidase) lead to increased adenosine levels during conditions of limited oxygen availability such as hypoxia or ischemia. Signaling via all four adenosine receptors (A1, A2a, A2b, A3) has been associated with cardioprotection. The A2b (highlighted by dotted lines) is the only receptor that has been shown to be induced in mice and men during ischemia and being involved in pre- and postconditioning of the heart. The A1 is the only adenosine receptor investigated in anesthetic preconditioning so far. APC=anesthetic preconditioning, IP= ischemic preconditioning, PC= ischemic postconditioning.

Figure 2. Light-elicited cardiac Period 2 stabilization

A hallmark of the mammalian circadian pacemaker is its ability to be synchronized by light, thus allowing organisms to adapt to temporal variations of natural light conditions. Photic stimuli are transmitted from the retina to target neurons in the brain, where they are transduced to the molecular clockwork. Light activation of melanopsin receptors in the retinal ganglion cells lead to the transcriptional induction of Period 2 (Per2) and concomitant synchronization. Peripheral tissues display oscillations in Per2 expression similar to those of the brain, probably through secreted signaling molecules. Following exposure to 12 h of darkness, wildtype mice were exposed to indicated times of daylight (13,000 lux) and compared to controls that were maintained at room light (200 lux). Analysis of cardiac Per2 protein levels revealed a significant protein increase - in a time dependent manner - following daylight exposure when compared to room light.

Figure 3. Diurnal variations of adenosine mediated cardioprotection

CD73, the key enzyme of adenosine generation, the adenosine receptor A2b (Adora2b), and the Adora2b dependent circadian rhythm protein Period 2 (Per2) and infarct sizes follow a circadian pattern over a 24 h time period. Infarct sizes are lowest when Adora2b or Per2 protein levels are highest in the heart. Based on these findings anesthetic preconditioning could be most effective during time points where the heart is especially vulnerable to ischemia. APC=anesthetic preconditioning.