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Ann Thorac Surg 1995;60:843-846
© 1995 The Society of Thoracic Surgeons

III: New Directions in Surgical Myocardial Protection

Protective Effects of Adenosine in the Reversibly Injured Heart

Robert D. Lasley, PhD, Robert M. Mentzer, Jr, MD

Department of Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin

Abstract

Background. There is substantial evidence that the nucleoside adenosine reduces postischemic ventricular dysfunction (ie, myocardial stunning). Studies performed in our laboratory have attempted to address the mechanism of adenosine-mediated protection of the reversibly injured heart.

Methods. Experiments were performed in isolated perfused rat and rabbit hearts and in in situ canine and porcine preparations. The role of adenosine A1 receptors was assessed by using adenosine A1 receptor agonists and antagonists, and by measuring interstitial fluid purine levels with the cardiac microdialysis technique.

Results. In isolated perfused hearts, treatment immediately before ischemia with adenosine and adenosine A1 receptor analogues significantly improved postischemic ventricular function, effects that were blocked by a selective adenosine A1 receptor antagonist. In in situ canine and porcine preparations, pretreatment with adenosine and an adenosine deaminase inhibitor increased preischemic interstitial fluid adenosine levels and attenuated regional myocardial stunning. Adenosine treatment was also associated with improved myocardial phosphorylation potential in isolated guinea pig hearts and in the in situ porcine preparation.

Conclusions. These results suggest that adenosine-induced attenuation of myocardial stunning is mediated via adenosine A1 receptor activation and enhancement of postischemic myocardial phosphorylation potential.

Myocardial ischemia is characterized by decreased ventricular function and reduced myocardial energetics. If coronary blood flow is restored within 15 to 20 minutes ischemia-induced injury is reversible, but myocardial contractility may remain depressed for hours to days, a phenomenon termed myocardial stunning [1]. Although difficult to document and quantify, it is thought that myocardial stunning occurs in patients who have undergone revascularization by coronary artery bypass grafting, coronary thrombolytic therapy or angioplasty, and heart transplantation [2, 3]. This may delay the benefits of myocardial reperfusion, and thus considerable research has focused on elucidating the mechanisms of stunning and deriving therapeutic interventions to minimize cardiac ischemic injury.

One such agent/intervention that has generated substantial interest in the treatment of the ischemic heart is the nucleoside adenosine. Adenosine has been reported to delay the onset of ischemic contracture [4], reduce the rates of adenosine triphosphate (ATP) catabolism and intracellular H+ and Ca2+ accumulation during ischemia [4–6], improve postischemic myocardial phosphorylation potential [7], attenuate myocardial stunning [6–9], and reduce infarct size [10]. These beneficial effects have been demonstrated with both exogenous adenosine and the preservation of endogenous adenosine with adenosine transport and metabolism inhibitors.

Although the exact mechanism remains to be determined, substantial progress has been made in elucidating the mechanism of adenosine's cardioprotective effect. Adenosine's role as an adenine nucleotide precursor, and its ability to increase coronary blood flow and reduce heart rate (via its negative chronotropic and dromotropic effects) may be beneficial to the ischemic heart, but these effects do not appear to play a major role in the cardioprotective effect of adenosine in the completely ischemic (ie, zero flow) heart. The recent focus on adenosine's cardioprotective effects has concentrated primarily on the role of adenosine receptors. Adenosine exerts its effects in the nonischemic heart via the activation of specific adenosine receptor subtypes [11]. Adenosine A1 receptors located on cardiac myocytes mediate the agent's negative chronotropic/dromotropic and antiadrenergic effects, and adenosine A2 receptors, located predominantly on endothelial cells, mediate the coronary blood flow effects. The protective effects of adenosine in the reversibly injured heart appear to be mediated, at least in part, via the activation of adenosine A1 receptors. The beneficial effects of adenosine on ischemic contracture and postischemic function in isolated perfused rat hearts are mimicked by adenosine A1 receptor analogues and blocked by adenosine A1 receptor antagonists [4, 6]. As shown in Figure 1Go, adenosine and adenosine A1 receptor analogue R-phenylisopropyladenosine pretreatments in rat and rabbit isolated perfused hearts attenuate postischemic contractile dysfunction, effects that are blocked by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. Pretreatment with adenosine A2 receptor agonists has no beneficial effect on the onset of contracture or postischemic function in isolated hearts [4, 6] or on postischemic regional function in in vivo canine myocardium [12]. Further support for an adenosine A1 receptor mechanism is the observation that the cardioprotective effect of adenosine in isolated perfused rat hearts is blocked by pretreatment with pertussis toxin [13]. Pertussis toxin catalyzes the adenosine diphosphate (ADP) ribosylation of the alpha subunit of an inhibitory guanine nucleotide binding protein, thus rendering it inactive. Myocardial adenosine A1 receptors are coupled to inhibitory guanine nucleotide binding proteins, and pertussis toxin pretreatment blocks A1 receptor-mediated effects in atrial and ventricular myocytes [11].



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  		Fig 1. . Effects of pretreatment with adenosine (ADO) (100 µmol/L) and the adenosine A1 agonist R-phenylisopropyladenosine (PIA) (1 µmol/L) in the presence or absence of the adenosine A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (5 and 2.5 µmol/L) on postischemic function in isolated perfused rat and rabbit hearts, respectively. Rat hearts were reperfused for 45 minutes after 30 minutes of global normothermic ischemia. Rabbit hearts were reperfused for 60 minutes after 60 minutes global normothermic ischemia. (LVDP = left ventricular developed pressure; *p < 0.05 versus control [Cont] hearts.)

 
Because the myocyte A1 receptor is exposed to the interstitial fluid (ISF) compartment, ISF adenosine levels determine the effective concentration of adenosine at the A1 receptor. If adenosine protects the ischemic heart via an adenosine A1 receptor mechanism, manipulations that enhance ISF adenosine levels should improve recovery of postischemic function. We have been able to test this hypothesis with the aid of cardiac microdialysis. This technique, which has been described in detail [14, 15], involves the implantation of a small piece of hollow dialysis fiber into the ventricular wall. The fiber is perfused with a saline solution, and the dialysate obtained provides an estimate of ISF metabolites. Figure 2Go illustrates the effects of pretreating isolated perfused rat hearts with increasing concentrations of adenosine (1, 10, and 100 µmol/L). All three concentrations of adenosine produced maximal coronary vasodilatation, but only treatments with 10 and 100 µmol/L adenosine, which elevated preischemic ISF adenosine concentrations, were associated with improved postischemic function [16]. We have reported similar findings in in vivo canine [8, 9] and porcine [7] models of regional ischemia ie, the elevation of preischemic ISF adenosine levels with either exogenous adenosine or the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine HCl is associated with attenuation of myocardial stunning.



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  		Fig 2. . Effects of adenosine (ADO) on preischemic dialysate adenosine levels and recovery of postischemic function (left ventricular developed pressure [LVDP]) in isolated perfused rat hearts. Hearts were treated for 10 minutes immediately before 30 minutes of global normothermic ischemia. Open bars = dialysate adenosine concentration; closed bars = percent recovery of preischemic LVDP; *p < 0.05 versus control [Cont] hearts.)

 
The timing of the adenosine/analogue treatment appears to be critical for adenosine's antistunning effect. Adenosine and adenosine A1 receptor analogues must be administered before ischemia to improve postischemic contractile dysfunction. Ambrosio and associates [17] reported that the infusion of 100 µmol/L adenosine during reperfusion in isolated perfused rabbit hearts did not attenuate stunning, but similar doses of adenosine administered before ischemia have been shown to exert a cardioprotective effect [6, 18]. The necessity of adenosine pretreatment for attenuation of myocardial stunning has also been reported in in vivo preparations. Sekili and colleagues [19] and Randhawa and co-workers [9] reported that intracoronary adenosine infusion before coronary artery occlusion in the dog improved postischemic regional systolic wall thickening; however, adenosine infusion during the first hour of reperfusion did not produce a sustained attenuation of stunning. Randhawa and co-workers [9] observed a transient increase in systolic wall thickening when adenosine was infused during reperfusion, an effect that was not observed in normal myocardium. This effect dissipated with the same time course as adenosine-induced hyperemia, suggesting that the increased wall thickening was due to the Gregg effect. Similar to results obtained with adenosine, adenosine A1 receptor analogues have been reported to attenuate stunning in vivo only when administered before ischemia [12, 20]. These results indicate that adenosine A1 receptor activation exerts its beneficial effects in the reversibly injured heart primarily during ischemia.

It must be pointed out that there are differences in the timing of adenosine's beneficial effects in reversibly and irreversibly injured myocardium. In the reversibly injured (stunned) heart adenosine appears to exert its protective effects during ischemia, not reperfusion. In addition, adenosine A1 receptors must be occupied/activated at the onset of ischemia to preserve postischemic ventricular function. Adenosine and adenosine A1 analogue treatments immediately before ischemia attenuate stunning in isolated rat hearts [6], but if these treatments are terminated before the onset of ischemia, postischemic function is not improved [21, 22]. Similar findings have been reported in isolated rabbit hearts [23] and in in vivo canine myocardium [19, 20]. The beneficial metabolic effects of adenosine and A1 analogue pretreatments also subside if these treatments are terminated before ischemia [22].

In contrast to the above requirements for adenosine's antistunning effect, adenosine appears to exert beneficial effects during both ischemia and reperfusion in irreversibly injured myocardium. Pretreatment with adenosine and adenosine A1 analogues reduces infarct size [10, 24, 25], and the administration of adenosine receptor blockers after ischemia has been reported to increase infarct size [26]. This latter finding suggests that adenosine modulates reperfusion injury after prolonged occlusions. In addition, a transient infusion of adenosine that is terminated before ischemia does not attenuate stunning, but does reduce infarct size [10, 24].

Although adenosine receptor–mediated modulation of signal transduction has been the primary focus of adenosine's cardioprotective effect, adenosine also exerts beneficial metabolic effects in the ischemic heart. The reduced rates of catabolism (decreased rates of ATP breakdown and H+ accumulation) associated with adenosine pretreatment are mimicked by adenosine A1 receptor analogues, suggesting that A1 receptor activation decreases myocardial oxygen demand in the ischemic heart. Adenosine treatment has also been reported to improve postischemic myocardial phosphorylation potential [7, 27]. Phosphorylation potential is an index of the energy derived from the hydrolysis of ATP, which provides the energy for energy-dependent cellular processes such as the sarcoplasmic reticulum Ca2+-Mg2+ ATPase, the sarcolemmal Ca2+ ATPase, and the myofibrillar contractile apparatus (actomyosin ATPase). This energy of hydrolysis can be expressed by the equation: [ATP]/([ADP] x [Pi]) = [CrP]/([Cr] x [Pi]) x H+/Kck, where [Pi] = inorganic phosphate concentration, [Cr] = creatine concentration, [CrP] = creatine phosphate concentration, H+ is the cytosolic hydrogen ion concentration, and Kck the pH- and Mg2+-dependent creatine kinase equilibrium constant. Adenosine treatment (100 µmol/L) in the nonischemic isolated perfused guinea pig heart did not alter phosphorylation potential, but phosphorylation potential was increased in the postischemic heart [27]. We also have reported that intracoronary adenosine pretreatment in an in vivo porcine regional ischemia preparation was associated with attenuation of myocardial stunning and increased postischemic phosphorylation potential [7]. Similar to the isolated heart studies, during the adenosine pretreatment phosphorylation potential did not increase. It is interesting to note that adenosine infusion in normal myocardium has no effect on either function or phosphorylation potential, but in the stunned heart adenosine increases both function and phosphorylation potential. It is thus possible that adenosine-induced attenuation of myocardial stunning is due in part to increased phosphorylation potential and thus improved sarcoplasmic reticulum calcium handling. The sarcoplasmic reticulum Ca2+-Mg2+ ATPase, which is highly energy dependent, has been reported to be depressed in stunned myocardium [28], and postischemic function has been shown to correlate well with postischemic phosphorylation potential [29]. It remains to be determined whether adenosine receptor activation plays any role in adenosine-mediated increased myocardial phosphorylation potential.

Adenosine is also cardioprotective in clinically relevant models of cardiopulmonary bypass. The addition of adenosine and adenosine metabolism inhibitors to crystalloid and blood cardioplegic solutions, both during normothermic and hypothermic ischemia, have been shown to enhance postischemic ventricular function in intact animal models [30–32]. Adenosine also appears to be a key component of the University of Wisconsin heart preservation solution. Isolated rabbit hearts preserved for 18 hours with standard University of Wisconsin solution, containing 5 mmol/L adenosine, exhibited better recovery of function than hearts flushed with University of Wisconsin solution in which adenosine was omitted [33].

In summary, there is substantial experimental evidence that adenosine exerts numerous beneficial effects in the ischemic/reperfused heart. Although the exact mechanism of action remains to be determined, these effects appear to be related to adenosine A1 receptor activation and improved postischemic myocardial phosphorylation potential. Experimental evidence indicates that adenosine A1 receptor activation exerts its effects primarily during ischemia, whereas adenosine's modulation of phosphorylation potential occurs during reperfusion. Because human ventricular myocardium has been shown to contain adenosine A1 receptors, there is a strong likelihood that adenosine will be beneficial in the setting of cardiac operations and heart preservation. In fact, preliminary evidence obtained at the University of Wisconsin in a subset of patients undergoing coronary artery bypass grafting suggests that adenosine-supplemented cardioplegia is well tolerated and may reduce postoperative ventricular dysfunction.

Acknowledgments

The work described was supported by grants to Dr Mentzer from the National Institutes of Health, and to Dr Lasley from the American Heart Association, Wisconsin Affiliate.

Footnotes

Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sep 25–28, 1994.

Address reprint requests to Dr Lasley, Department of Surgery, University of Wisconsin School of Medicine, Rm H4/383 Clinical Science Center, 600 Highland Ave, Madison, WI 53792.

References

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