Cardioplegic strategies for calcium control: low Ca(2+), high Mg(2+), citrate, or Na(+)/H(+) exchange inhibitor HOE-642.

BACKGROUND: Ca(2+) overload plays an important role in the pathogenesis of cardioplegic ischemia-reperfusion injury. The standard technique to control Ca(2+) overload has been to reduce Ca(2+) in the cardioplegic solution (CP). Recent reports suggest that Na(+)/H(+) exchange inhibitors can also prevent Ca(2+) overload. We compared 4 crystalloid CPs that might minimize Ca(2+) overload in comparison with standard Mg(2+)-containing CP: (1) low Ca(2+) CP (0.25 mmol/L), (2) citrate CP/normal Mg(2+) (1 mmol/L Mg(2+)), (3) citrate CP/high Mg(2+) (9 mmol/L Mg(2+)), and (4) the addition of the Na(+)/H(+) exchange inhibitor HOE-642 (Cariporide). We also tested the effect of citrate titration in vitro on the level of free Ca(2+) and Mg(2+) in CPs. METHODS AND
RESULTS: Isolated working rat heart preparations were perfused with oxygenated Krebs-Henseleit buffer and subjected to 60 minutes of 37 degrees C arrest and reperfusion with CPs with different Ca(2+) concentrations. Cardiac performance, including aortic flow (AF), was measured before and after ischemia. Myocardial high-energy phosphates were measured after reperfusion. The in vitro addition of citrate to CP (2%, 21 mmol/L) produced parallel reductions in Mg(2+) and Ca(2+). Because only Ca(2+) was required to be low, the further addition of Mg(2+) increased free Mg(2+), but the highest level achieved was 9 mmol/L. Citrate CP significantly impaired postischemic function (AF 58.3+/-2. 5% without citrate versus 41.6+/-3% for citrate with normal Mg(2+), P:<0.05, versus 22.4+/-6.2% for citrate with high Mg(2+), P:<0.05). Low-Ca(2+) CP (0.25 mmol/L Ca(2+)) significantly improved the recovery of postischemic function in comparison with standard CP (1.0 mmol/L Ca(2+)) (AF 47.6+/-1.7% versus 58.3+/-2.5%, P:<0.05). The addition of HOE-642 (1 micromol/L) to CP significantly improved postischemia function (47.6+/-1.7% without HOE-642 versus 62.4+/-1. 7% with HOE-642, P:<0.05). Postischemia cardiac high-energy phosphate levels were unaffected by Ca(2+) manipulation.
CONCLUSIONS: (1) A lowered Ca(2+) concentration in CP is beneficial in Mg(2+)-containing cardioplegia. (2) The use of citrate to chelate Ca(2+) is detrimental in the crystalloid-perfused isolated working rat heart, especially with high Mg(2+). (3) The mechanism of citrate action is complex, and its use limits precise simultaneous control of Ca(2+) and Mg(2+). (4) HOE-642 in CP is as efficacious in preservation of the ischemic myocardium as is the direct reduction in Ca(2+).