Cardioplegic strategies for calcium control - Low Ca2+, high Mg2+, citrate, or Na+/H+ exchange inhibitor HOE-642

Background-Ca2+ over-load plays an important role in the pathogenesis of ca rdioplegic ischemia-reperfusion injury. The standard technique to control C a2+ overload has been to reduce Ca2+ in the cardioplegic solution (CP). Rec ent reports suggest that Na+/H+ exchange inhibitors can also prevent Ca2+ o verload. We compared 4 crystalloid CPs that might minimize Ca2+ overload in comparison with standard Mg2+-containing CP: (1) low Ca2+ CP (0.25 mmol/L) , (2) citrate CP/normal Mg2+ (1 mmol/L Mg2+), (3) citrate CP/high Mg2+ (9 m mol/L Mg2+), and (4) the addition of the Na+/H+ exchange inhibitor HOE-642 (Cariporide). We also tested the effect of citrate titration in vitro on th e level of Free Ca2+ and Mg2+ in CPs. Methods and Results-Isolated working rat heart preparations were perfused w ith oxygenated Krebs-Henseleit buffer and subjected to 60 minutes of 37 deg reesC arrest and reperfusion with CPs with different Ca2+ concentrations. C ardiac performance, including aortic flow (AF), was measured before and aft er ischemia. Myocardial high-energy phosphates were measured after reperfus ion. The in vitro addition of citrate to CP (2%, 21 mmol/L) produced parall el reductions in Mg2+ anti Ca2+. Because only Ca2+ was required to be low, the further addition of Mg2+ increased free Mg2+, but the highest level ach ieved was 9 mmol/L. Citrate Cf significantly impaired postischemic function (AF 58.3+/-2.5% without citrate versus 41.6+/-3% for citrate with normal M g2+, P<0.05, versus 22.4+/-6.2% for citrate with high Mg2+, P<0.05). Low-Ca 2+ CP (0.25 mmol/L Ca2+) significantly improved the recovery of postischemi c function in comparison with standard CP (1.0 mmol/L Ca2+) (AF 47.6+/-1.7% versus 58.3+/-2.5%, P<0.05). The addition of HOE-642 (1 <mu>mol/L) to CP s ignificantly improved postischemia function (47.6+/-1.7% without HOE-642 ve rsus 62.4+/-1.7% with HOE-642, P<0.05). Postischemia cardiac high-energy ph osphate levels were unaffected by Ca2+ manipulation. Conclusions-(1) A lowered Ca2+ concentration in CP is beneficial in Mg2+-co ntaining cardioplegia. (2) The use of citrate to chelate Ca2+ is detrimenta l in the crystalloid-perfused isolated working rat heart, especially with h igh Mg2+. (3) The mechanism of citrate action is complex, and its use limit s precise simultaneous control of Ca2+ and Mg2+. (4) HOE-642 in CP is as ef ficacious in preservation of the ischemic myocardium as is the direct reduc tion in Ca2+.