PREISCHEMIC AS WELL AS POSTISCHEMIC APPLICATION OF A CALCIUM-ANTAGONIST AFFORDS CARDIOPROTECTION IN THE ISOLATED GUINEA-PIG HEART

Objective: The aim was to answer the following questions: (1) Does tre atment with calcium antagonists have to be begun before ischaemia or i s postischaemic application also protective? (2) When applied before i schaemia, do calcium antagonists have to depress preischaemic cardiac function in order to elicit protection? (3) Is cardioprotection a matt er of improved reflow or do the agents influence the degree of oxidati ve injury during reperfusion? Methods: Isolated working guinea pig hea rts underwent ischaemia (15 min) and reperfusion (15 min). The calcium antagonist gallopamil was given either before (0.1 nM and 1 nM) or af ter ischaemia (0.1 nM) during early reperfusion (first 5 min). Recover y was defined as postischaemic compared to preischaemic external heart work, expressed in percent. Oxidative stress was assessed by the rele ase of glutathione (GSH). Lactate release served as a measure of the i schaemic challenge. The ability of gallopamil to scavenge oxygen radic als directly was investigated in an in vitro chemiluminescence assay. Results: Pump function of control hearts recovered to only 28% after r eperfusion. Pretreatment with 0.1 and 1 nM gallopamil improved recover y to the same extent (48.7% and 43.4%, respectively); however, postisc haemic application of 0.1 nM gallopamil afforded equal protection (45. 4% recovery). Only the higher concentration of 1 nM gallopamil depress ed preischaemic external heart work (by 11%). During earliest reperfus ion (1-5 min), release of GSH only tended to be lower in treated heart s. During the subsequent minutes of reperfusion (5-15 min), release of GSH was significantly less in hearts postischaemically treated with 0 .1 nM gallopamil (40 pmol . min(-1) v 940 pmol min(-1) for controls). In contrast, ischaemia-induced lactate release did not differ between the groups. Gallopamil did not scavenge reactive oxygen species in vit ro. Conclusions: Short term postischaemic application of the calcium a ntagonist gallopamil is almost as effective at restoring pump function as preischaemic application which, in turn, does not have to depress preischaemic cardiac function in order to elicit protection. A reducti on of oxidative stress during reperfusion seems to contribute to the b eneficial effects of postischaemic application of gallopamil, but a di rect oxygen radical scavenging activity of gallopamil is not involved.