The anti-ischaemic activity of the calmodulin antagonists trifluperazine, felodipine, W-7 and calmidazolium has been investigated in electrically paced guinea-pig hearts, perfused according to Langendorff, which were subjected to 60 min of global ischaemia followed by 30 min of reperfusion. At concentrations that induced a comparable reduction in cardiac contractile force, trifluperazine, felodipine and to a lesser extent W-7, were associated with improvement of post-ischaemic functional (LVP and coronary flow) and biochemical parameters (CrP and ATP). Furthermore, felodipine and trifluperazine delayed the onset and suppressed the maximum tension of the ischaemic contracture was observed. In contrast, calmidazolium had no anti-ischaemic effects. This lack of anti-ischaemic activity of the most potent calmodulin antagonist calmidazolium, as well as the significant calcium entry blocking activity of both trifluperazine and felodipine suggest that additional factors besides calmodulin antagonism may contribute to the anti-ischaemic activity of these compounds.