Pentostatin-augmented interstitial adenosine prevents postcardioplegia injury in damaged hearts

Abstract

This study tests the hypothesis that the adenosine deaminase inhibitor pentostatin (2-deoxycoformycin), when given before ischemia or during infusions of blood cardioplegia, augments interstitial adenosine levels and prevents postcardioplegia dysfunction in hearts with antecedent ischemia. Twenty-one anesthetized dogs were placed on cardiopulmonary bypass, and the hearts were made globally ischemic for 30 minutes. Dogs received blood cardioplegia with no pentostatin (BCP group, n = 6), pretreatment pentostatin (0.2 mg/kg) infused 5 minutes before global ischemia (PS-PTx group, n = 7), or pentostatin included only in the blood cardioplegia without pretreatment (PS-BCP group, n = 8). Microdialysate myocardial adenosine levels (an index of interstitial fluid levels) increased only modestly in the BCP group (from 0.55 ± 0.13 μM to 2.64 ± 0.50 μM) and the PS-BCP group (from 0.55 ± 0.18 μM to 1.08 ± 0.48 μM) during normothermic ischemia, but interstitial adenosine levels were not augmented further during cardioplegic arrest in either group. In contrast, the adenosine level in the PS-PTx group was significantly ( p < 0.05) augmented during global ischemia (from 0.50 ± 0.13 μM to 63.16 ± 28.08 μM) and cardioplegia infusion (to 15.26 μM ± 5.61 μM). Relative to baseline, postischemic left ventricular performance (end-systolic pressure-volume relation) was depressed in both the BCP (from 5.5 ± 1.2 mm Hg/mL to 3.8 ± 0.4 mm Hg/mL) and PS-BCP groups (from 7.1 ± 0.9 mm Hg/mL to 3.8 ± 0.7 mm Hg/mL). In contrast, PS-PTx restored postischemic performance (from 6.2 ± 0.5 mm Hg/mL to 7.5 ± 0.9 mm Hg/mL). Similar preservation of postischemic function in the PS-PTx group was observed with preload recruitable stroke work. There were no group differences in postischemic diastolic stiffness. Myocardial myeloperoxidase activity (an index of neulrophil accumulation) was significantly less in the PS-PTx group (0.39 ± 0.07 U/g of tissue) than in the BCP (0.65 ± 0.09 U/g of tissue) and PS-BCP groups (0.67 ± 0.12 U/g of tissue). We conclude that pentostatin used as a pretreatment before cardioplegia augments endogenous adenosine levels, reduces postischemic dysfunction, and inhibits neutrophil accumulation in ischemically injured canine hearts.