A denosine is an endogenous nucleoside that has potent electrophysiologic effects.1-4 As an antiarrhythmic agent, adenosine has several unique properties: 1) it is an intermediate metabolite (Figure 1), 2) it has a very short half-life (less than 1.5 seconds), 3) its effects are mediated by specific membrane receptors coupled to guanine nucleotide binding proteins (G proteins), and 4) it has sitespecific actions in the myocardium with important differential effects in supraventricular and ventricular tissue.' Adenosine also has an important role in regulating the myocardial oxygen supply-demand balance. Adenosine achieves this by increasing oxygen supply through coronary vasodilation and by reducing oxygen demand by decreasing myocardial contractility, antagonizing the effects of catecholamines, and depressing automaticity and conduction within the sinus and atrioventricular (AV) nodes.' Recently, the United States Food and Drug Administration approved the use of adenosine for therapy of paroxysmal supraventricular tachycardia (PSVT), the first clinical application of adenosine. The purpose of this review is to present a rational approach for the therapeutic applications of adenosine for cardiac arrhythmias based on an understanding of its cellular and integrative mechanisms of action.

Cardiac electrophysiology of adenosine. Basic and clinical concepts.

Adenosine is an autacoid that plays a critical role in regulating cardiac function, including heart rate, contractility, and coronary flow. In this chapter, current knowledge of the functions and mechanisms of action of coronary flow regulation and electrophysiology will be discussed. Currently, there are four known adenosine receptor (AR) subtypes, namely A(1), A(2A), A(2B), and A(3). All four subtypes are known to regulate coronary flow. In general, A(2A)AR is the predominant receptor subtype responsible for coronary blood flow regulation, which dilates coronary arteries in both an endothelial-dependent and -independent manner. The roles of other ARs and their mechanisms of action will also be discussed. The increasing popularity of gene-modified models with targeted deletion or overexpression of a single AR subtype has helped to elucidate the roles of each receptor subtype. Combining pharmacologic tools with targeted gene deletion of individual AR subtypes has proven invaluable for discriminating the vascular effects unique to the activation of each AR subtype. Adenosine exerts its cardiac electrophysiologic effects mainly through the activation of A(1)AR. This receptor mediates direct as well as indirect effects of adenosine (i.e., anti-beta-adrenergic effects). In supraventricular tissues (atrial myocytes, sinuatrial node and atriovetricular node), adenosine exerts both direct and indirect effects, while it exerts only indirect effects in the ventricle. Adenosine exerts a negative chronotropic effect by suppressing the automaticity of cardiac pacemakers, and a negative dromotropic effect through inhibition of AV-nodal conduction. These effects of adenosine constitute the rationale for its use as a diagnostic and therapeutic agent. In recent years, efforts have been made to develop A(1)R-selective agonists as drug candidates that do not induce vasodilation, which is considered an undesirable effect in the clinical setting.

/pdf/adenosine-receptors-and-the-heart-role-in-regulation-of-2pcurdcfcs.pdf

Adenosine Receptors and the Heart: Role in Regulation of Coronary Blood Flow and Cardiac Electrophysiology

The A1 adenosine receptor is the best characterized of the widely distributed purinergic receptor family. The purified brain A1 receptor is a monomeric 35- to 36-kDa glycoprotein. A1 receptors can be clearly distinguished from A2 adenosine receptors on the basis of structure activity relationships with selective ligands. Recent structure activity data suggest that subtypes of A1 (A1a, A1b, and A3) and A2 (A2a and A2b) receptors may exist. A1 receptor-mediated responses are coupled via multiple pertussis toxin-sensitive GTP binding proteins (G proteins) to many different effectors in various tissues: adenylate cyclase, phospholipase C, Na+- Ca2+ exchange, Ca2+ channels, Cl- channels, and K+ channels. The formation of calcium-mobilizing inositol phosphates can either be enhanced or inhibited. In general, adenosine has been found to act in concert with other hormones or neurotransmitters in either an inhibitory or a stimulatory way. The myriad modulatory actions of adenosine suggest that: 1) adenosine may si...

Structure and function of A1 adenosine receptors.

The effect of hypoxia on endothelium-dependent and endothelium-independent vasodilation was studied in phenylephrine-precontracted, isolated rings of rabbit first-branch pulmonary artery. Concentration-dependent relaxation responses to the endothelium-dependent dilators methacholine, ATP, and the calcium ionophore (A23187) as well as to the endothelium-independent dilators sodium nitroprusside and isoproterenol were obtained before, during, and after exposure to hypoxia (PO2 = 42 +/- 1 mm Hg) in the presence of indomethacin (2.8 x 10(-5) M). This moderate degree of hypoxia inhibited (p less than 0.05) endothelium-dependent but not endothelium-independent relaxation responses without producing irreversible vascular damage. In parallel experiments, cyclic GMP accumulation in pulmonary vascular rings in response to maximal doses of the above vasodilators was measured in the presence and absence of hypoxia. Cyclic GMP accumulation in response to endothelium-dependent dilators (methacholine, ATP, and A23187) was inhibited (p less than 0.05) by hypoxia while cyclic GMP accumulation in response to the endothelium-independent dilator sodium nitroprusside was not. When phenylephrine precontracted vessels were exposed to hypoxia in the absence of vasodilators, a small, transient increase in tension occurred, which was greater in endothelium-intact than in endothelium-denuded vessels (0.70 +/- 0.12 vs. 0.09 +/- 0.03 g, respectively; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-dependent relaxation and cyclic GMP accumulation in rabbit pulmonary artery are selectively impaired by moderate hypoxia.

Hypoxia is a potent coronary-vasodilating signal; its mechanisms are still controversial. We have assessed the possible role of nitric oxide (NO) in hypoxic coronary vasodilatation (HCVD) in isolated guinea pig hearts perfused at constant pressure. HCVD was elicited by a 1-minute 100% N2 exposure; coronary flow doubled within 1 minute of hypoxia (early phase) and returned to baseline within 40 seconds after reoxygenation (late phase). The early phase of HCVD was associated with a rapid approximately eightfold increase in cGMP overflow, an indication of NO release. The specific NO synthase inhibitor N omega-methyl-L-arginine (NMA, 0.1-1 mM) antagonized HCVD and the associated increase in cGMP spillover (maximum inhibition, approximately 65%); excess arginine (1.2 mM) prevented both effects. The late phase of HCVD was associated with an increase in adenosine overflow and was attenuated by the adenosine receptor antagonist BW A1433 (1 microM; maximum inhibition, approximately 45%). Indomethacin (10 microM) inhibited HCVD in spontaneously beating hearts by approximately 35% but had no effect in hearts paced at faster rates. NMA and BW A1433 were more effective in combination than alone (maximum inhibition, approximately 72%). However, irrespective of the concentrations used, there was no synergism among the anti-HCVD effects of NMA, BW A1433, and indomethacin, nor was HCVD completely inhibited by the antagonists, whether alone or in combination. Our findings indicate that NO is an important mediator of the early phase of HCVD, whereas additional mechanisms and/or factors, including adenosine and vasodilatatory prostaglandins, contribute to the late phase.

Nitric oxide is a mediator of hypoxic coronary vasodilatation. Relation to adenosine and cyclooxygenase-derived metabolites.

Adenosine has been shown to have a negative dromotropic effect and has been implicated in mediating atrioventricular conduction disturbances induced by hypoxia. This study was designed to determine the ability of various alkylxanthines including two novel derivatives, i.e., BW A533U and BW A1433U, to 1) attenuate adenosine- and hypoxia-induced atrial to His bundle (AH) interval prolongation, 2) compete for binding of 125I-aminobenzyladenosine to ventricular membranes and 3) inhibit myocardial phosphodiesterase. In normoxic isolated perfused hearts (n = 20) instrumented for measurement of atrioventricular conduction time and left ventricular pressure, BW A1433U (0.1 microM) or BW A533U (5 microM) attenuated AH interval prolongation induced by adenosine (5 microM) by 90%, but neither xanthine derivative attenuated the AH interval prolongation induced by acetylcholine (0.11 microM), digoxin (0.91 microM) or D600 (1.3 microM). In four additional hearts, BW A1433U at concentrations of up to 10 microM had no effect on left ventricular pressure or AH interval. BW A1433 or BW A533U (50 microM) inhibited myocardial cyclic AMP phosphodiesterase by only 11.5 +/- 1.6 and 26.6 +/- 2.6%, respectively. Schild analysis of adenosine concentration-response curves obtained in the absence and presence of BW A533U and BW A1433U (n = 14) yielded pA2 values of (mean +/- S.E.M.) 6.32 +/- 0.10 and 7.70 +/- 0.08, respectively. pKd values for BW A533U and BW A1433U binding to adenosine receptors on ventricular membranes were 6.36 and 6.94, respectively. In a separate series of 19 hearts, BW A533U and BW A1433U were shown to attenuate hypoxia-induced AH interval prolongation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of the effects of adenosine and hypoxia on atrioventricular conduction time by two novel alkylxanthines: correlation with binding to adenosine A1 receptors.

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Antagonism of the effects of adenosine and hypoxia on atrioventricular conduction time by two novel alkylxanthines: correlation with binding to adenosine A1 receptors.