EXOGENOUS ADENOSINE, SUPPLIED TRANSIENTLY DURING REPERFUSION, AMELIORATES DEPRESSED ENDOGENOUS ADENOSINE PRODUCTION IN THE POSTISCHEMIC RAT-HEART

Adenosine (ADO) is an important endogenous protective metabolite of th e heart which also exerts beneficial effects when exogenously supplied before or after ischemia. Previous studies established that after ini tial massive release of ADO, its endogenous production could be signif icantly reduced following myocardial ischemia. However, the mechanism and consequences of this phenomenon are not clear. We investigated whe ther this suppressed endogenous ADO production could be reversed by a transient supply of exogenous ADO during reperfusion. Furthermore, we studied the recovery of mechanical function, coronary flow and myocard ial nucleotide levels after this intervention. Three concentrations of ADO were applied: 1 mu M, which exerts maximal vasodilatation; 30 mu M, optimal for adenylate resynthesis; and 1 mM which exerts a cardiopl egic effect. Rat hearts perfused in the Langendorff mode were divided into five groups (n=6-9 per group): all hearts had transient (30-s) is chemia at 20 min (TI-1) and 70 min (TI-3) of perfusion. Group 1 (contr ol) had an additional transient (30-s) ischemia at 45 min (TI-2). Grou p 2 (ischemic control) had 10-min ischemia at 30 min; groups 3, 4 and 5 also had 10-min ischemia at 30 min but were reperfused for the initi al 15 min with 1 mu M, 30 mu M or 1 mM ADO. Developed tension, coronar y now and coronary effluent purines and pyrimidines were measured thro ughout the 75-min experimental period. Nucleotide content was evaluate d in freeze-clamped hearts at the end of the experiment. Endogenous AD O release to the coronary effluent increased immediately after TI-1 in all groups. This increase was similar after TI-1 and after TI-3 in co ntrol, while it was reduced to 30% in ischemic control group. In the 3 0 mu M ADO group the increase in endogenous ADO release after TI-3 was restored and was similar to that after TI-1. A similar trend was obse rved with 1 mM ADO, while in 1 mu M group recovery of endogenous ADO r elease after TI-3 was not observed. The highest recovery of developed tension (+S.E.) occurred with 1 mu M and 30 mu M ADO (72+/-3% and 72+/ -5% of pre-ischemic value, respectively) compared to 53+/-5% and 63+/- 5% in ischemic control and 1 mM ADO groups, respectively (P<0.05). Cor onary now was restored 30 s after 10 min ischemia in hearts treated wi th 1 mu M and 30 mu M ADO, whereas more than 2 min were necessary in i schemic control or 1 mM ADO groups. Furthermore, hyperemic response af ter TI-3 was significantly enhanced in the 1 mu M or 30 mu M ADO group s. ATP content at the end of reperfusion was highest in the 30 mu M AD O group (18.9+/-0.5 mu mol/g dry wt.) as compared to ischemic control, 1 mu M or 1 mM ADO groups (15.2+/-0.6, 16.4+/-0.4, and 17.2+/-0.4 mu mol/g dry wt. respectively). Concentrations of other nucleotide tripho sphates (GTP, UTP and CTP) were similar in all hearts subjected to 10- min ischemia. In summary, depressed endogenous ADO production in the p ost-ischemic heart could be ameliorated by transient supply of exogeno us ADO during reperfusion at 30 mu M concentration. This effect was fo und to be related to the elevation of the adenine nucleotide pool. How ever, restoration of endogenous ADO production was not necessary for i mprovement in the recovery of mechanical function by exogenous ADO. (C ) 1997 Academic Press Limited