Abstract 2316: Ranolazine, a Late Sodium Current Inhibitor, as an Adjunct to Cardioplegia Further Reduces Contracture during Ischemia and Reperfusion
Although cardioplegia (CP) protects myocardium during ischemic cardiac arrest, cardioplegic preservation can be suboptimal for increasingly complex cardiac surgical patients. Ranolazine (Ran), a novel antianginal agent, was recently shown to mitigate ischemia-induced Ca2+ overload via its inhibitory effects on the late Na+ current, but the benefit of Ran during cardioplegic arrest is not known. The purpose of the study was to investigate the therapeutic potential of Ran as an adjunct to CP. Hearts isolated from female Sprague-Dawley rats were Langendorff-perfused and exposed to normothermic global ischemia for 40 min followed by 30-min reperfusion (I/R). Three groups were studied: control buffer (n = 10); crystalloid CP (Fremes, n = 12); CP supplemented with Ran (n = 12). CP was bolus-injected with or without Ran at the time of ischemia. End-diastolic pressure (EDP), developed pressure, dP/dtmin, and dP/dtmax were measured throughout the study. CP significantly delayed onset of ischemic contracture (defined as a time to 20 mmHg of EDP), compared to control (25 ± 2 min in CP alone vs. 12 ± 1 min in control, p < 0.05). Ran added to CP further delayed the time to contracture (34 ± 2 min in Ran, p < 0.05 compared to CP alone). Consistent with these findings, the area under the diastolic pressure curve during the entire period of ischemia was significantly smaller in CP + Ran versus CP alone (p < 0.05). I/R caused dramatic elevations in EDP during reperfusion. CP lessened the extent of the reperfusion contracture (32 ± 3 mmHg in CP alone vs. 76 ± 3 mmHg in control, p < 0.05). Addition of Ran to CP further lessened the contracture (17 ± 2 mmHg in Ran, p < 0.05 compared to CP alone). I/R severely depressed systolic cardiac contractile function. The impairment in contractile function was significantly reduced by CP, as well as CP + Ran, but there was no statistical difference between the two groups. While CP alone reduced the onset of cardiac contracture in this model of I/R, addition of Ran to CP further enhanced the cardioprotection. These results suggest the potential therapeutic efficacy of Ran as an adjunct to CP and further support the protective role of late Na+ current inhibition.