Abstract
Pentostatin (2-deoxycoformycin) is a potent inhibitor of adenosine deaminase and has been demonstrated to augment endogenous adenosine levels during regional and global myocardial ischemia. Based on the rationale that increasing endogenous adenosine during ischemia may be cardioprotective, the objective of this study was to determine if adenosine deaminase inhibition with pentostatin could improve postischemic contractile dysfunction (stunning) in open-chest anesthetized dogs. All animals underwent 15 min of coronary occlusion followed by 3 h of reperfusion preceded by an intravenous bolus of either 0.2 mg/kg of pentostatin (n=8) or saline (n=7). Sonomicrometers were plced in the ischemic area and were used to measure systolic wall thickening before, during, and after occlusion of the left anterior descending artery. Myocardial blood flow was measured with tracer labeled microspheres at baseline, 10 min of occlusion and at 1 h of reperfusion. Both groups were equally dyskinetic during occlusion (−21±5% of baseline thickening in the controls and −28±8% in the pentostatin group). The pentostatin group, however, demonstrated better contractile function at all time points during reperfusion, which was significantly different from the control group at 3 h of reperfusion. The improvement in regional function in the pentostatin group was not due to significant disparities in hemodynamic variables, size of the region at risk, or in collateral blood flow. These results indicate that pentostatin can ameliorate the severity of myocardial stunning, an effect we propose is due to increasing endogenous levels of adenosine during the ischemic interval. Although significant improvement was detected with pentostatin, the improvement was modest compared to controls, suggesting that the utility of inhibiting adenosine deaminase to modify regional mechanical stunning is limited.
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Abd-Elfattah AS, Ding M, Dyke CM, Wechsler AS (1993) Protection of the stunned myocardium: Selective nucleoside transport blocker administered after 20 minutes of ischemia augments recovery of ventricular function. Circulation 88: II-336–II-343
Bolli R (1990) Mechanism of myocardial “stunning”. Circulation 82: 723–738
Bolli R (1992) Myocardial “stunning” in man. Circulation 86: 1671–1691
Bolling SF, Bies LE, Bove EL, Gallagher KP (1990) Augmenting intracellular adenosine improves myocardial recovery. J Thorac Cardiovasc Surg 99: 469–474
Brauwald E, Kloner RA (1982) The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 66: 1146–1149
Breisblatt WM, Stein KL, Wolfe CJ, Follansbee WP, Capozzi J, Armitage JM, Hardesty RL (1987) Acute myocardial dysfunction and recovery: A common occurrence after coronary bypass surgery. J Am Coll Cardiol 10: 710–712
Bunch FT, Thornton J, Cohen MV, Downey JM (1992) Adenosine is an endogenous protectant against stunning during repetitive ischemic episodes in the heart. Am Heart J 124: 1440–1445
Dhasmana JP, Dignerness SB, Geckle JM, Ng TC, Glickson JD, Blackstone EH (1983) Effect of adenosine deaminase inhibitors on the heart's functional and biochemical recovery from ischemia: a study utilizing the isolated rat heart adapted to 31P nuclear magnetic resonance. J Cardiovasc Pharm 5: 1040–1047
Dorheim T, Hoffman A, Van Wylen DGL, Mentzer RM (1991) Enhanced interstitial fluid adenosine attenuates myocardial stunning. Surgery 110: 136–145
Ely SW, Berne RM (1992) Protective effects of adenosine in myocardial ischemia. Circulation 85: 893–904
Ferrari R, Odoardo V (1991) Stunning: Damaging or protective to the myocardium? Cardiovasc Drugs Therapy 5: 939–946
Forman MA, Velasco CE (1991) Role of adenosine in the treatment of myocardial stunning. Cardiovasc Drugs Therap 5: 901–908
Gallagher KP, Osakada G, Matsuzaki M, Miller M, Kemper WS, Ross J Jr (1985) Nonuniformity of inner and outer systolic wall thickening. Am J Physiol 249 (Heart Circ Physiol 18): H241–H248
Gallagher KP, Buda AJ, Pace D, Gerren RA, Schlafer M (1986) Failure of superoxide dismutase and catalase to alter size of infarction in conscious dogs after three hours of occlusion followed by reperfusion. Circulation 73: 1065–1076
Hudspeth DA, Williams MW, Zhao Z-Q, Sato H, Nakanishi K, McGee S, Hammon JW, Vinten-Johansen J, Van Wylen DGL (In press) Pretreatment with pentostatin augments interstial fluid adenosine and prevents postischemic dysfunction in canine hearts protected with blood cardioplegia. Annals of Thoracic Surgery
Klohs WD, Kraker AJ (1992) Pentostatin: Future directions. Pharmacol Rev 44: 459–477
Lawson CS, Downey JM (1993) Preconditioning: State of the art myocardial protection. Cardiovasc Res 27: 542–550
Li GC, Vasquez JA, Gallagher KP, Lucchesi BR (1990) Myocardial protection with preconditioning. Circulation 82: 609–619
Ning X-H, Zweng TN, Gallagher KP (1990) Ejection- and isovolumic contraction-phase wall thickening in nonischemic myocardium during coronary occlusion. Am J Physiol 258 (Heart Circ Physiol 27): H490–H499
Norton ED, Jackson EK, Virmani R, Forman MB (1991) Effect of intravenous adenosine on myocardial reperfusion injury in a model with low myocardial collateral blood flow. Am Heart J 122: 1283–1291
Olaffsson B, Forman MB, Puett DW (1987) Reduction of reperfusion injury in the canine preparation by intercoronary adenosine: importance of the endothelium and the no-reflow phenomenon. Circulation 76: 1135–1145
Roberts AJ, Spies M, Meyers SN, Moran JM, Sanders JH, Lichtenthal PR, Michaelis LL (1980) Early and long-term improvement in left ventricular performance following coronary bypass surgery. Surgery 88: 467–475
Sasayama S, Franklin D, Ross JJ, Kemper WS, McKown D (1976) Dynamic changes in left ventricular wall thickness and their use in analyzing cardiac function in the conscious dog. Am J Cardiol 38: 870–879
Stirling MC, Choy M, McClanahan TB, Schott RJ, Gallagher KP (1991) Effects of ischemia on epicardial segment shortening. J Surg Res 50: 30–39
Van Belle H (1993) Nucleoside transport inhibition: A therapeutic approach to cardioprotection via adenosine? Cardiovasc Res 27: 68–76
Van Wylen DGL (1993) Inhibition of adenosine deaminase with pentostatin augments interstitial fluid adenosine during regional myocardial ischemia (abstract). Circulation 88: I-432
Vivaldi MT, Kloner RA, Schoen FJ (1985) Triphenyltetrazolium staining of irreversible ischemic injury following coronary artery occlusion in rats. Am J Pathol 121: 522–530
Woo PWK, Dion HW, Lange SM, Dahl LF, Durham LJ (1974) Anovel adenosine and Ara-A deaminase inhibitor, (R)-3-(2-deoxy-beta-D-erythropentofuranosyl)-3, 6, 7, 8 tetrahydroimidazo (4, 5-d) (1, 3) diazepin-8-ol. J Heterocycl Chem 11: 641–643
Zughaib ZM, Abd-Elfattah AS, Jeroudi MO, Sun J-Z, Sekili S, Tang X-L, Bolli R (1993) Augmentation of endogenous adenosine attenuates myocardial ‘stunning’ independently of coronary flow or hemodynamic effects. Circulation 88: 2359–2369
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McClanahan, T.B., Ignasiak, D.P., Martin, B.J. et al. Effect of adenosine deaminase inhibition with pentostatin on myocardial stunning in dogs. Basic Res Cardiol 90, 176–183 (1995). https://doi.org/10.1007/BF00789447
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DOI: https://doi.org/10.1007/BF00789447