Preischaemic as well as postischaemic application of a calcium antagonist affords cardioprotection in the isolated guinea pig heart

Abstract

The aim was to answer the following questions: (1) Does treatment with calcium antagonists have to be begun before ischaemia or is postischaemic application also protective? (2) When applied before ischaemia, do calcium antagonists have to depress preischaemic cardiac function in order to elicit protection? (3) Is cardioprotection a matter of improved reflow or do the agents influence the degree of oxidative injury during reperfusion? Isolated working guinea pig hearts underwent ischaemia (15 min) and reperfusion (15 min). The calcium antagonist gallopamil was given either before (0.1 nM and 1 nM) or after ischaemia (0.1 nM) during early reperfusion (first 5 min). Recovery was defined as postischaemic compared to preischaemic external heart work, expressed in percent. Oxidative stress was assessed by the release of glutathione (GSH). Lactate release served as a measure of the ischaemic challenge. The ability of gallopamil to scavenge oxygen radicals directly was investigated in an in vitro chemiluminescence assay. Pump function of control hearts recovered to only 28% after reperfusion. Pretreatment with 0.1 and 1 nM gallopamil improved recovery to the same extent (48.7% and 43.4%, respectively); however, postischaemic application of 0.1 nM gallopamil afforded equal protection (45.4% recovery). Only the higher concentration of 1 nM gallopamil depressed preischaemic external heart work (by 11%). During earliest reperfusion (1-5 min), release of GSH only tended to be lower in treated hearts. 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 vitro. Short term postischaemic application of the calcium antagonist 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 reduction of oxidative stress during reperfusion seems to contribute to the beneficial effects of postischaemic application of gallopamil, but a direct oxygen radical scavenging activity of gallopamil is not involved.