Protection by verapamil in the calcium paradox: dependence on micromolar calcium

Myocardial protection by verapamil in the calcium paradox has been the subject of considerable controversy. In order to reassess the protective properties of verapamil in the normothermic isolated rat heart three injury levels (minimal, subtotal, total calcium paradox) caused by increasing flow rates (1, 2, 9 ml . min-1) or volumes (5, 10, 45 ml) of calcium free perfusion (5 min) before calcium repletion (15 min) were determined in the presence and absence of verapamil (2 mumol . litre-1) using enzymatic, metabolic, and physiological indices. Verapamil supplementation had minimal effect on tissue injury in the 45 ml and 10 ml volume group of hearts but afforded considerable protection in the 5 ml volume group. The addition of EDTA (0.1 mmol . litre-1) to the calcium free perfusate in the 5 ml volume group produced a subtotal calcium paradox on which verapamil had no effect. Conversely, when 20 mumol . litre-1 calcium was added to the otherwise calcium free perfusate in the 45 ml volume group a minimal calcium paradox was created on which verapamil had a substantial protective effect. It is concluded that tissue protection by verapamil in the calcium paradox requires the presence in the myocardium of both verapamil and trace amounts of calcium before the onset of calcium repletion. Tissue protection by verapamil is therefore limited to minimal injury types.