Robert D. Lasley

Protective effects of adenosine in the reversibly injured heart.

BACKGROUNDnThere 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.nnnMETHODSnExperiments 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.nnnRESULTSnIn 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.nnnCONCLUSIONSnThese results suggest that adenosine-induced attenuation of myocardial stunning is mediated via adenosine A1 receptor activation and enhancement of postischemic myocardial phosphorylation potential.

Salutary effects of exogenous adenosine administration on in vivo myocardial stunning

Augmentation of endogenous adenosine levels is associated with decreased myocardial ischemic-reperfusion injury. The purpose of this study was to determine whether exogenous adenosine administered before ischemia could attenuate postischemic myocardial dysfunction. Regional myocardial stunning was induced by 15 minutes of coronary artery occlusion and 90 minutes of reperfusion in an open-chest canine preparation. Regional ventricular function was assessed by measurement of systolic wall thickening. Control untreated hearts were compared with two groups of hearts treated immediately before ischemia with intracoronary adenosine (5 micrograms/kg per minute and 50 micrograms/kg per minute). A fourth group of hearts was treated for the first 30 minutes of reperfusion with adenosine (50 micrograms/kg per minute). Preischemic adenosine administration increased coronary flow sixfold to sevenfold without altering regional function, mean arterial pressure, or left ventricular end-diastolic pressure. Both adenosine pre-treatments attenuated stunning compared with results in control animals (14.7% +/- 5.1% and 21.6% +/- 7.3% of preischemic systolic wall thickness versus -14.0% +/- 10%). Adenosine treatment during reperfusion transiently increased function in parallel with increased coronary blood flow, but after termination of the infusion regional function was not different from that in control stunned hearts (-5.0% +/- 13.1% of preischemic systemic wall thickness). These results indicate that adenosine pretreatment is associated with attenuation of stunning, an effect that can be produced at doses that do not alter systemic hemodynamics.

Different effects of an adenosine A1 analogue and ischemic preconditioning in isolated rabbit hearts

BACKGROUNDnIschemic preconditioning reduces infarct size, but its effects on postischemic function are variable. Adenosine, which is thought to play a role in ischemic preconditioning, reduces both infarct size and postischemic dysfunction. The purpose of this study was to compare the cardioprotective effects of ischemic preconditioning and an adenosine A1 receptor agonist on recovery of function and infarct size in isolated rabbit hearts.nnnMETHODSnKrebs buffer-perfused hearts (at least 7 per group) were subjected to 60 minutes of global ischemia (37 degrees C) and 60 minutes of reperfusion. Ventricular function was assessed by measuring left ventricular developed pressure, and infarct size (percentage of the left ventricle) was determined by tetrazolium staining.nnnRESULTSnControl hearts exhibited 34% +/- 6% infarct size and 56% +/- 4% recovery of preischemic left ventricular developed pressure. Ischemic preconditioning reduced infarct size to 13% +/- 1% but had no effect on recovery of function (65% +/- 5%). Hearts treated with the adenosine A1 agonist R-phenylisopropyladenosine for 5 minutes immediately before ischemia exhibited both reduced infarct size (10% +/- 2%) and enhanced postischemic recovery of left ventricular developed pressure (86% +/- 3%). Termination of the R-phenylisopropyladenosine treatment before ischemia eliminated its beneficial effects. The adenosine A1 receptor antagonist DPCPX blocked both of the effects of R-phenylisopropyladenosine but did not block ischemic preconditioning.nnnCONCLUSIONSnThese results demonstrate fundamental differences between the cardioprotective effects of adenosine A1 receptor activation and ischemic preconditioning.

The role of adenosine in extended myocardial preservation with the University of Wisconsin solution.

The purpose of this study was to determine the role that adenosine plays in enhanced myocardial preservation during cold storage with the University of Wisconsin solution. Hearts from adult rabbits were flushed with University of Wisconsin solution with or without adenosine and stored at 4 degrees C for 24 hours. Interstitial fluid purine levels during the period of cold storage were estimated with cardiac microdialysis probes. In a second series of experiments hearts were flushed with University of Wisconsin solution with or without adenosine or St. Thomas Hospital cardioplegic solution and stored for 18 hours (4 degrees C). Functional recovery was assessed by reperfusing the hearts on a Langendorff apparatus (100 cm H2O) for 45 minutes with Krebs-Henseleit buffer. During cold storage dialysate adenosine concentrations in hearts flushed with University of Wisconsin solution were 20- to 40-fold greater than adenosine levels in hearts flushed without adenosine. After 45 minutes of reperfusion hearts preserved with University of Wisconsin solution exhibited a rate-pressure product of 11,098 +/- 576 mm Hg/min, significantly greater than that for hearts flushed with University of Wisconsin solution minus adenosine (8106 +/- 780 mm Hg/min) and St. Thomas Hospital solution (7317 +/- 768 mm Hg/min). These results suggest that adenosine plays a major role in enhanced myocardial preservation with the University of Wisconsin solution, possibly by maintaining elevated interstitial fluid adenosine levels during the period of cold storage.

Adenosine and the Stunned Heart

Abstract Adenosine is one agent under investigation as a therapeutic intervention of myocardial stunning. Adenosine caused numerous effects on the cardiovascular system through its interaction with A1 and A2 receptors. We investigated adenosine A1 receptor mediated mechanisms of cardiac protection in the stunned rat myocardium. Previous studies showed that both adenosine and R‐phenylisopropyladenosine (PIA), an A1 receptor agonist, prolonged the time to onset of ischemic contracture in ischemic isolated rat hearts. Phenylaminoadenosine, an A2 receptor agonist, did not have any effect, while receptor antagonists blocked adenosine and PIA action. Direct attenuation of the effects of myocardial stunning was observed by altering levels of interstitial fluid adenosine. Our laboratory has shown that administration of erthro‐9(2‐hydroxy‐3‐nonyl) adenine (EHNA; an adenosine deaminase inhibitor) to dogs subjected to left anterior descending coronary artery (LAD) occlusion followed by reperfusion results in dramatic increases in ischemic levels of interstitial fluid adenosine and postischemic myocardial function. Using a similar model in dogs, we have shown that exogenous intracoronary adenosine (50 μg/kg per min) augmented postischemic recovery of function, as assessed by significant enhancement (p < 0.01) of systolic wall thickness (7.0 ± 3.0 pretreatment vs −5.7 ± 1.7 controls). These data support the role for an adenosine A1 receptor mediated mechanism for protection against myocardial stunning.

Preconditioning and its Potential Role in Myocardial Protection During Cardiac Surgery

Myocardial preconditioning is the phenomenon whereby a brief stress to the heart (e.g., ischemia, hypoxia, etc.) prior to a prolonged period of ischemia renders the heart more resistant to ischemic injury. The cardioprotective effects of preconditioning include reduced infarct size and reduced ventricular arrhythmias. Preconditioning also is associated with beneficial metabolic effects during the prolonged ischemia, effects that also are observed during intermittent cardioplegia. However, there are conflicting reports about the effects of preconditioning on postischemic ventricular function. Although adenosine is thought to be the endogenous mediator of ischemic preconditioning, there are some important differences between adenosine and ischemic preconditioning mediated cardioprotection.

Myocardial protection: The adenosine story

It has been recognized for many years that the purine nucleoside adenosine exerts numerous effects in mammalian myocardium. During the last decade, an in particular over the last 5 years, substantial evidence has accumulated that adenosine also exerts beneficial effects in the ischemic/reperfused myocardium. The cardioprotective effects of adenosine are manifest by attenuation of reversible postischemic ventricular dysfunction (i.e., stunning) and reduction of myocardial infarct size. These effects can be produced by augmenting endogenous adenosine levels with adenosine deaminase inhibitors and nucleoside transport inhibitors and by infusing adenosine (intracoronary or intravenous). Similar to adenosines effects in nonischemic hearts, the cardioprotective effects of adenosine are mediated by activation of extracellular adenosine receptors. The results of studies with adenosine receptor agonists and antagonists indicate that adenosines beneficial effect in reversibly and irreversibly injured myocardium is mediated primarily via adenosine A1 receptor activation. The protective effects of adenosine appear to occur during ischemia since adenosine infusion during reperfusion neither attenuates stunning nor reduces infarct size. Adenosine is cardioprotective in rats, rabbits, dogs, and pigs, and initial clinical reports indicate that adenosine may enhance myocardial protection during open heart surgery in humans. This review will summarize the current state of knowledge on the cardioprotective effects of adenosine in experimental and clinical studies. Drug Dev. Res. 39:314–318, 1996

Metabolically Based Treatment of Stunned Myocardium

Reversible myocardial ischemia is associated with a rapid decrease in contractility and prolonged postischemic ventricular dysfunction, due in part to altered intracellular calcium handling and/or contractile protein dysfunction. The maintenance of intracellular calcium homeostasis and force development by the contractile apparatus are dependent upon the free energy derived from ATP hydrolysis. This energy of hydrolysis is determined by the myocardial phosphorylation potential, an estimate of which can be made from the ratio (CrP)/(Cr) x (P1). Results from in vitro and in vivo studies suggest that pyruvate enhances contractility in both normal and stunned myocardium by enhancing myocardial phosphorylation potential. In regionally stunned porcine myocardium, pyruvate infusion increased recovery of regional ventricular function from 33% ± 4% of preischemic systolic wall thickening to 81% ± 4% and increased the (CrP)/(Cr) x (P1) ratio fivefold from 0.21 ± 0.04 to 1.05 ± 0.08. Thus, metabolic substrates that enhance myocardial energetics and ventricular function may be effective agents for attenuating postischemic ventricular function.

Receptor-Mediated and Metabolic Effects of Adenosine in Ischemic and Postischemic Myocardium

Myocardial ischemia is associated with rapid decreases in cardiac contractility and the high-energy phosphates creatine phosphate (CrP) and adenosine triphosphate (ATP). Ischemic durations of 20 minutes or less induce no cell necrosis, but upon reperfusion the myocardium at risk exhibits prolonged contractile dysfunction, which may persist for hours to days. This postischemic depressed contractility, despite restoration of normal coronary blood flow, is defined as stunned myocardium. Longer durations of ischemia are associated with cell death, that is, myocardial infarction. Although the exact mechanisms underlying ischemic/ reperfusion injury are not known, there is substantial evidence that the purine nucleoside adenosine protects the heart against both myocardial stunning and infarction, in part via activation of sarcolemmal adenosine A1 receptors located on the cardiac myocytes [1,2]. This review will focus on the receptor-mediated and metabolic effects of adenosine in the ischemic heart and the attenuation of postischemic ventricular dysfunction by adenosine.

Adenosine and Adenosine Receptor Protection of the Ischemic Heart

The purine nucleoside adenosine modulates the myocardial response to an imbalance in oxygen supply and demand by inducing coronary vasodilatation, negative dromotropy and chronotropy, and anti-adrenergic effects (1). Substantial evidence also exists that endogenous and exogenous adenosine modulate the heart’s response to the most severe form of oxygen supply/demand imbalance, i.e. myocardial ischemia. This review will summarize the results of work performed in our laboratory on the effects of adenosine in the ischemic and postischemic heart.