Adenosine receptor subtypes in the heart: therapeutic opportunities and challenges.

FOUR SUBTYPES OF ADENOSINE RECEPTORS (A1, A2A, A2B, and A3 receptors) are known to exist (26). Traditionally, the A1-adenosine receptor has been thought to be the only subtype expressed in ventricular cardiomyocytes. By inhibiting adenylyl cyclase, the A1 receptor attenuates the positive inotropic effect of b-adrenergic receptor stimulation (or other interventions that stimulate adenylyl cyclase). Another function of the A1 receptor is to protect against the injury caused by myocardial ischemia and reperfusion. This latter function of the A1 receptor may be related to its antiadrenergic properties as well as to activation of the ATP-dependent potassium channel. There is increasing evidence, however, that other adenosine receptor subtypes also exist in ventricular myocytes and that they may have important physiological functions. In the February 1999 issue of this journal (AJP: Heart Circ. Physiol.), Norton and co-workers (24) proposed that A2A receptors are expressed in rat ventricular cardiomyocytes and that they serve to counteract the antiadrenergic effects of A1-adenosine receptors. This conclusion is based on the observation that in isolated rat hearts and isolated adult rat ventricular cardiomyocytes, the antiadrenergic effects of adenosine are potentiated in the presence of selective A2A-receptor antagonists; that is, blockade of A2A receptors enhances the ability of adenosine to antagonize the positive inotropic effects of b-adrenergic stimulation. The report by Norton and colleagues (24) is the first indication that A2A receptors exert proadrenergic effects in the intact rat heart. Although the physiological and pathophysiological roles of cardiomyocyte A2A receptors remain to be determined, the modulating influence of A2A receptors on adrenergic function is a potentially important observation that may have implications for a variety of clinical settings such as coronary artery disease and heart failure. The effects of A2A-receptor agonists and antagonists in these settings are likely to be complex and will require further investigation. On the one hand, it can be envisioned that antagonists of A2A receptors may provide a therapeutic benefit in situations in which an enhanced antiadrenergic response is desirable, such as during acute myocardial ischemia. On the other hand, there is evidence that stimulation of A2A receptors after reperfusion is beneficial by inhibiting neutrophil function (11) and, possibly, augmenting coronary flow. With the increasing interest in the clinical use of adenosine or A1 agonists to protect the ischemic myocardium (14, 15, 18–20, 22), it will be important to determine whether selective manipulation (activation/antagonism) of A2A receptors can be used to potentiate the anti-ischemic effectiveness of A1-receptor activation. Another area that warrants investigation pertains to the pathophysiological roles of A1 and A2A receptors in modulating the response to adrenergic stimuli in patients with congestive heart failure, a condition in which plasma adenosine levels are increased (8). The significance of the proand antiadrenergic actions of A1 and A2A receptors, respectively, in this setting needs to be elucidated. From a therapeutic standpoint, adenosine agonists or antagonists that selectively target A1 or A2A receptors may be useful either to protect the failing heart from chronic, excessive adrenergic stimulation or to potentiate the inotropic response to such stimulation when clinically indicated. The clinical implications of the proadrenergic action of adenosine A2A receptors, however, are not limited to myocardial ischemia and heart failure. For example, it is conceivable that selective antagonists of A2A receptors may enhance the effectiveness of adenosine in terminating supraventricular arrhythmias. In addition to the A2A-adenosine receptor, there is also evidence that A3-adenosine receptors may be expressed in ventricular cardiomyocytes. The A3-adenosine receptor is the most recently identified subtype; like the A1-adenosine receptor, it is negatively coupled to adenylyl cyclase. Using embryonic chick cardiomyocytes, Strickler and co-workers (30) observed that A3-adenosine-receptor agonists inhibit isoproterenolinduced increases in cAMP and that activation of A3-adenosine receptors provides tolerance against hypoxic injury. Thus it has been hypothesized that both A1 and A3 receptors are expressed in cardiomyocytes and that they serve similar functions. It appears that the protection afforded by A3 receptors occurs via a protein kinase C-dependent pathway (2, 16). Whether A3 receptors are expressed in adult cardiomyocytes, however, is still unclear. The present observations by Norton et al. (24) that AB-MECA [N6-(4-aminobenzyl)-58-N-methylcarboxamido-adenosine], a moderately selective A3receptor agonist, did not exert an antiadrenergic effect in isolated rat hearts seem to support the concept that A3 receptors may not be present in the ventricular