Adenosine deaminase inhibitor in cardioplegia enhanced function preservation of the hypothermically stored rat heart.

Adenosine (ADO) has been shown to be protective to the ischemic-reperfused myocardium. This study tested the hypothesis that inhibition of myocardial adenosine deaminase during cold storage will elevate tissue ADO content, improve the cardiac function, and preserve ATP. The isolated rat hearts (6-9 hearts/group) were flushed with a cardioplegic solution containing 0-75 microM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and immersion-stored at 0 degree C for 9 hr. Function was assessed after 30 min working reperfusion. Function of the unstored hearts (n = 11, mean +/- SE) including heart rate (293 +/- 13 bpm), aortic flow (AF; 52.5 +/- 1.1 ml/min), coronary flow (CF; 23.5 +/- 1.3 ml/min), cardiac output (CO; 76.0 +/- 2.1 ml/min), systolic pressure (SP; 136 +/- 2 mmHg), diastolic pressure (DP; 63 +/- 1 mm Hg), work (90.5 +/- 3.4 g-m/min), and coronary vascular resistance (CVR; 2.77 +/- 0.14 mmHg-min/ml) served as controls. Heart rate in all stored hearts returned to normal after reperfusion. Recovery of other function in no-EHNA group was: AF, 52 +/- 7; CF, 55 +/- 5; CO, 53 +/- 6; SP, 79 +/- 4; DP, 93 +/- 3; work, 47 +/- 7; and CVR, 171 +/- 15% of control. EHNA improved functional recovery in a dose-dependent fashion. At the optimal concentration of 25 microM, the recovery was: AF, 83 +/- 6; CF, 68 +/- 4; CO, 78 +/- 5; SP, 90 +/- 3; DP, 105 +/- 5; work, 77 +/- 8; and CVR 151 +/- 9% of control. ADO A1 receptor antagonists, 8-phenyltheophylline (1 microM) and 1,3-dipropyl-8-cyclopentylxanthine (0.1 microM) blocked the effects of 25 microM EHNA; the recovery of CO was reduced to 65 +/- 3 and 50 +/- 2% of the control, respectively. Tissue ADO content in 25 microM EHNA hearts at the end of storage was 95 +/- 19 nmol/g dry wt, which was significantly elevated from 15 +/- 3 nmol/g dry wt in no-EHNA hearts. EHNA also caused a 45-fold increase in the release of ADO over no-EHNA group during the first 10 min of reperfusion. But EHNA treatment did not cause any change in either end-storage or end-reperfusion myocardial ATP levels. Thus EHNA in cardioplegic solution inhibited cardiac ADO catabolism during long-term hypothermic storage and improved function preservation partially via an ADO A1 receptor-mediated mechanism without invoking ATP conservation.