We recently observed that
dipyridamole pretreatment significantly enhanced the
infarct size (IS)-limiting effect of preconditioning (PC), which was attenuated by
adenosine receptor antagonist. This potentiation of PC was interpreted to result from inhibition of
nucleoside transport by
dipyridamole, but contribution of other
pharmacologic actions of
dipyridamole could not be excluded. To confirm that inhibition of
nucleoside transport leads to PC enhancement, we assessed alteration of mild PC by two different
nucleoside transport inhibitors,
dilazep and
R75231, which, unlike
dipyridamole, lack action on
phosphodiesterase (PDE) and
prostacyclin.
Myocardial infarction was induced in rabbits by 30-min
coronary occlusion and 72-h reperfusion. IS and area at risk (AAR) were determined by histology and fluorescent particles, respectively. Rabbits either were untreated or received
dilazep (0.34 mg/kg intravenously, i.v.) or
R75231 (0.05 mg/kg i.v.) before
coronary occlusion. In other groups of rabbits, PC was conducted with 2-min
ischemia and 5-min reperfusion with or without injection of the
nucleoside transport inhibitor (0.34 or 0.10 mg/kg
dilazep or 0.05 mg/kg of
R75231) before PC. IS expressed as percentage of AAR (%IS/AAR) was 43.9 +/- 2.3% (SE) in untreated controls;
dilazep (0.34 mg/kg) and
R75231 alone did not modify IS (%IS/AAR = 50.6 +/- 4.7 and 42.7 +/- 11.9%, respectively). PC tended to reduce IS (%IS/AAR = 33.3 +/- 3.5%), but the combination of
dilazep or
R75231 with PC significantly limited %IS/AAR (%IS/AAR = 22.5 +/- 5.0% after low-dose
dilazep plus PC, 27.6 +/- 4.9% after high-dose
dilazep plus PC, and 19.9 +/- 3.6%, after
R75231 plus PC).(ABSTRACT TRUNCATED AT 250 WORDS)