Adenosine and ischemic preconditioning

Abstract

Adenosine is released in large amounts during myocardial ischemia and is capable of exerting potent cardioprotective effects in the heart. Although these observations on adenosine have been known for a long time, how adenosine acts to achieve its anti-ischemic effect remains incompletely understood. However, recent advances on the chemistry and pharmacology of adenosine receptor ligands have provided important and novel information on the function of adenosine receptor subtypes in the cardiovascular system. The development of model systems for the cardiac actions of adenosine has yielded important insights into its mechanism of action and have begun to elucidate the sequence of signalling events from receptor activation to the actual exertion of its cardioprotective effect. The present review will focus on the adenosine receptors that mediate the potent anti-ischemic effect of adenosine, new ligands at the receptors, potential molecular signalling mechanisms downstream of the receptor, mediators for cardioprotection, and possible clinical applications in cardiovascular disorders.

Fig. 1

Agonists at the various adenosine receptor subtypes. Non-selective as well as selective agonists are shown. K_i values, in nM, for A₁, A_2A and A₃ receptors (rat, unless indicated) are shown in that order below the structure and name for each compound.

Fig. 2

Antagonists at the various adenosine receptor subtypes. The structure and K_i values for adenosine receptor antagonists are shown. K_i values, in nM, for A₁, A_2A and A₃ receptors (rat, unless indicated) are indicated in that order below the structure and name for each compound.

Fig. 3

Preconditioning Protocol. The protocol has been used in most of the experimental studies on ischemic preconditioning. The preconditioning studies carried out in patients undergoing PTCA also employed a similar protocol.

Fig. 4

A working model for the sequence of signaling events leading to the cardioprotective effect of ischemic preconditioning. In this model, the preconditioning process is divided into two phases, the initiation phase during which the process is triggered, and the maintenance phase during which the actual cardioprotection is exerted. The roles of adenosine receptor, phospholipases, diacylglycerol, protein kinase C and K_ATP channel are proposed.